View allAll Photos Tagged modulation
Kate Beck
Modulation , 2010
Graphite of paper on aluminum
12 x 12 inches
PG# KB.0019
Pelavin Gallery is proud to announce a solo exhibition of recent work by American artist, Kate Beck. This show will include large scale poured oil paintings and graphite drawings on aluminum panel. This will be Beck’s first solo exhibition at the gallery, and in New York City.
In this new body of work, Beck continues her engagement with repetitive tonal rendering as a means of interaction between light and shadow, human thought and consciousness, and the dynamic architectonics of space. This time she takes the essence of form further by using aluminum substrates, allowing modulating marks of graphite and poured oil to accumulate and shift amidst the confines of the geometric shapes. Tension oscillates between formalistic geometry and existential space; an allusion to thought and consciousness, and the passage of time.
For more information, please visit pelavingallery.com
Camera: Polaroid SX-70 Land Camera PolaSonic Model2. Film: Impossible Project PX 70 Cool Color Shade.
Silicon nanowires
Lab-on-a-chip (LOC) systems for molecular diagnostics at very low concentrations are becoming increasingly important for applications requiring high-throughput biomolecular analyses, such as protein arrays for basic molecular biology research, disease marker identification, and pharmaceutical drug screening. Techniques and methods used for protein arrays are improving, however, progress has been hindered by size and detection constraints. First, conventional protein arrays require relatively large sample volumes. One strategy for overcoming this problem is to significantly decrease the size and consequently the sample volume of the protein interaction assay, an ideal application of LOC. Secondly, the detection of protein and chemical pathogens (targets) is currently most commonly done using fluorescence detection of the probe-target binding. Although very sensitive, fluorescence detection suffers from the need to label the molecular target, which can lead to alterations in target-receptor interactions caused by conformational changes or steric hindrance induced by the label. The efficiency of labeling varies from protein to protein, making comparisons a challenge. In addition, attaching fluorophores may influence the way in which proteins bind to other molecules causing background signals. For these reasons, there is considerable effort to investigate alternatives for fluorescent detection. Label-free sensors detect the hybridization of an affinity complex using a variety of methods including optical, mechanical, and electrochemical techniques. We are exploring the sensing limitations of silicon nanowires (Si-NWs) to electrochemically detect probe-target binding based on surface charge modulation, hence label-free detection. Si-NW sensors can be considered as nanoscale versions of the ion-sensitive field effect transistor (ISFET) sensors, invented by prof. dr. ir. Piet Bergveld in 1969, the previous chair holder of the BIOS group. The Si-NWs have been reported as capable of providing a highly sensitive label-free biomolecular sensor that can be manufactured into dense arrays and additionally provide a real-time electrical output that easily integrated with conventional data recording equipment. However, the majority of these reports fail to carefully study the sensing limitations, critical device characteristics and interface behavior.
Listen: A Music and Video Experiment
Featured video art and experimental music throughout the Murphy Art Center -- including Alchemy in Suite 3, Suite 4 next door and multiple spaces upstairs near Big Car. www.bigcar.org
Friday, March 6, 2009.
Big Car's First Friday show for March featured a bevy of local, regional, national and international video and sound artists. All of the music accompanied video art projections. The night included a show of Herron video artists in Suite 214 next door to Big Car (see artist statements below), a program of experimental videos from other local artists in Suite 3 and 4 on street level (J. Andrew Salyer, Jennie Mynhier, Laura Salyer, Jim Walker, Flounder Lee) and a Microcinema screening (FATELESS, Color + Modulation, SLIDE, Hub Culture Retrospectives: Antarctica, Independent Exposure: Asthmatic Kitty Records Edition 2008, The Collected Films of Ryan Jeffery, Op Art, Modular Moves, Jellies: The Art of Nature) also in Suite 214. For more about Microcinema visit www.microcinema.com.
The night's musical offerings in Suite 215 (Big Car's regular space) and in other nearby spaces included performances by Butler University's Ensemble 48 (playing a soundtrack to the silent film "Man with the Movie Camera"), Marck Ferrari, Ben Ishmael Revival, Shiny Black Shirt, Sea Krowns, Ensemble 48, Actuel, Playboy Psychonauts, Stallio, Sky Thing and Tonos Triad.
Also in the street level space that night, Big Car also hosted the installation "Unified Fields" that featured the interactive music and art of duo Mana2 (Jordan Munson, Michael Drews).
The event was sponsored by Microcinema and was a partnership with the Toby at the IMA.
Title: Concha Renaissance San Juan Resort
Other title: Concha
Creator: Toro, Osvaldo 1914-1995; Ferrer, Miguel, 1915-2004; Salvadori, Mario George, 1907-1997; Marvel & Marchand Architects
Creator role: Architect
Date: 1958 (original) 2008 (renovation)
Current location: San Juan, Puerto Rico
Description of work: Renaissance Hotels tasked architect Jose R. Marchand and interior designer Jorge Rossello with renovating and saving this beachside landmark. "[B]y the mid-1990s the venerable La Concha hotel had been shuttered, abandoned and left to rot...Originally designed by Osvaldo Toro and Miguel Ferrer, with an eccentric but utterly loveable seashell-shaped restaurant by Mario Salvatori [sic], La Concha was a beautifully massed, expertly sited, vividly inventive building perfectly in sync with its time. Closely attuning the hotel to its sun-swept setting, the architects created deep-shading overhangs, open corridors, windows and doors that gave onto lush interior courtyards and provided cross ventilation, and beautifully lacy quiebra-sol (their take on a brise-soleil) for further modulation of the light and heat" (Frank, Michael. "La Concha Revival". Architectural Digest. Aug 2009, p. 103-104. Print).
Description of view: View of the south facade of the hotel from the pool and lounge area with the brise-soleils also in view.
Work type: Architecture and Landscape
Style of work: Modern: International Style
Culture: Puerto Rican
Materials/Techniques: Concrete
Water
Trees
Source: Pisciotta, Henry (copyright Henry Pisciotta)
Date photographed: May 13, 2008
Resource type: Image
File format: JPEG
Image size: 3072H X 2304W pixels
Permitted uses: This image is posted publicly for non-profit educational uses, excluding printed publication. Other uses are not permitted. For additional details see: alias.libraries.psu.edu/vius/copyright/publicrightsarch.htm
Collection: Worldwide Building and Landscape Pictures
Filename: WB2010-0274 Concha.JPG
Record ID: WB2010-0274
Sub collection: resorts
Copyright holder: Copyright Henry Pisciotta
History Of Electronic Dance Music Documentary. Directed by Iara Lee
www.vjsmag.com/wp-content/uploads/2013/04/MV5BMTQ5ODA5NjE...
www.vjsmag.com/modulations-documentary/
#Films#Documentary, #Music
I had two bodies that I used in racing. The one on the right was mostly used and when it was new, the plastic fairing was in better shape. Note the "1701" Star Trek reference on the numbering... hehehe...
HMJ300B-TDD
SoleNode IP Mesh Microwave Video Transmitter
HMJ300B-TDD transmitter combined with other SoleNode Receiver to create a fluid self forming, ad hoc, mobile and dynamic surveillance mesh network.
Just using a single frequency to routes video, voices and data, GPS around the wireless network, mostly simplifying frequency management, and the entire mesh just need 2Mhz of bandwidth (4,6,8,16Mhz as optional)
Using HMJ's patented COFDM modulation and therefore offer excellent RF penetration and performance in multipath and harsh environment.
The highly flexible mesh topology ensure video, voice and data, GPS can be exchanged between moving nodes in a point-to-point or multi-point fashion, also each node can be acted as repeater for expanded range.
HMJ300B-TDD transmitter can be connected to third party composite cameras using the AVI option or Third party IP cameras can also be directly connected to the SoleNode mesh network.
Optional AES128 or AES256 encryption make safe and secure link.
Using provided Commander PC software application in-build mapping display to configure and monitor the deployed mesh network and surveillance system, and video can be real-time viewed on PC device or recorded using compatible recorders.
www.dropbox.com/s/sqft3gycu6nyg85/IP%20Mesh%20Vdieo%20Tx%...
More information, please visit our website at en.hmjtx.com, detailed datasheet available on request.
Here's some spec's on this sweet system. It's a "Matrix" system, meaning that it has the ability to change all of it's routings on every preset.
Instead of being tied to one signal flow you can have any signal flow you want, when you want. Which is pretty handy for score music composer & guitar instrumental musician who has to constantly change the signal flow.
The switcher has a software interface that allows you to create an icon for each device and it's corresponding input(s) & Output(s), then using the mouse, connect the rig you want to have at that moment with no extra devices connected to the signal path for the cleanest path possible from pick ups to speakers.
A matrix switcher has 16x Inputs & 16x Outputs, so we decided to put 5 switchers in this system, connected them to each other & bunch of other cool gear. Each switcher has a "Group" responsibility:
1. "Master" - Magnetic & Piezo Inputs + 4x Amplifiers + 1 Axe FX ("Front End" of 4 Wire Config) + Multiple Connections to the other Switchers
2. "Harmonics" - Octave, Fuzz & Overdrive devices.
3. "Dynamics" - Compressors, EQ's Filters, Synthesizers.
4. "Modulations" - Chorus, Phaser, Flanger, UniVibe, & Tremolo.
5. "Time" - Delays & Reverbs + Axe FX ("Back End") for Reverb, Delay & Looper.
Any order & combination of series & parallel is possible, the possibilities for signal routings are only limited by the player's imagination...
On April 6 I performed at the Woodview Coffeehouse open mic. My past two times there I'd included excerpts from my novel Covenant . But since we were in the middle of Passover in addition to Good Friday, I read from my 20-years-ago journal entry, "The Old Men of Revere Beach." After beginning with extemporaneous a cappella singing, I put my Yiddish brogue to good use here.
I was also fascinated by an instrument that one of the featured performers (in the duo Pete Price and Mike Roberts) used. He called it a "paddlewheel harmonica," which I think is the perfect name for it, although my Google search for that term turned up empty. For the first part of the set I couldn't help but notice this weird thing on the floor. From where I sat, it didn't even look like a musical instrument. Then it literally came into play for a song with a "modulation" (change in key) and captivated me. You can see one here.
When I told Mary about the harmonica, she expressed her interest in a slide kazoo. Simple enough, I thought. Not. I've found references to alto slide kazoos, tenor slide kazoos, contrabass slide kazoos, electric slide kazoos, and discussion on what kind of a mouthpiece to use on a slide kazoo. Though I believe the "left-handed E-flat slide kazoo" mentioned in one post plays in the same orchestra as PDQ Bach's Left-Handed Sewer Flute, lovingly detailed on the cover of this debut album, which I grew up with along with other mishegas.
Networked Fabrication for Urban Provocations.
Shifting Paradigms from Mass Production to Mass Customization
Computational architecture and design course
Conventional construction methods all depart from the basic premises of mass production: standardization, modulation and a production line. What these systems developed during the last two centuries fail to take into account are the evolutionary leaps and bounds the manufacturing industry has taken over the last decades. With the introduction of CNC technologies and rapid prototyping machines have altered the paradigms of fabrication forever. It is due to these new tools that it is now possible to create (n) amount of completely unique and different pieces with the same amount of energy and material that is required to create (n) identical pieces. The possibilities for implementation of new forms, textures, materials and languages are infinite due to the versatility that these new tools offer a growing network of architects, designers, fabricators that are integrating them into their professional practices to generate unique and precise objects that respond to countless data and real-life conditions.
Instructors:
Monika Wittig [ LaN, IaaC ]
Shane Salisbury [ LaN, IaaC ]
Filippo Moroni [ SOLIDO, Politecnico di Milano ]
MS Josh Updyke [ Advanced Manufacturing Institute, KSU, Protei ]
Aaron Gutiérrez Cortes [ Amorphica ]
Networked Fabrication for Urban Provocations.
Shifting Paradigms from Mass Production to Mass Customization
Computational architecture and design course
Conventional construction methods all depart from the basic premises of mass production: standardization, modulation and a production line. What these systems developed during the last two centuries fail to take into account are the evolutionary leaps and bounds the manufacturing industry has taken over the last decades. With the introduction of CNC technologies and rapid prototyping machines have altered the paradigms of fabrication forever. It is due to these new tools that it is now possible to create (n) amount of completely unique and different pieces with the same amount of energy and material that is required to create (n) identical pieces. The possibilities for implementation of new forms, textures, materials and languages are infinite due to the versatility that these new tools offer a growing network of architects, designers, fabricators that are integrating them into their professional practices to generate unique and precise objects that respond to countless data and real-life conditions.
Instructors:
Monika Wittig [ LaN, IaaC ]
Shane Salisbury [ LaN, IaaC ]
Filippo Moroni [ SOLIDO, Politecnico di Milano ]
MS Josh Updyke [ Advanced Manufacturing Institute, KSU, Protei ]
Aaron Gutiérrez Cortes [ Amorphica ]
This is the Karnage VST Plugin, an analogue/subtractive synth that was a result of a collaboration between Kriminal and Krakli Software. An absolute beast of a synth. Very useful for making noise, industrial, and electronic music
Features:
-Two oscillators with width (fatness setting) and wave-shape control, a sub oscillator/white noise oscillator mixable with a level control.
-24db/12db Filter modulated by a dedicated envelope, velocity, and up to 2 LFOs.
-A dedicated ring modulation section that can use keyboard tracking, velocity, envelope, and up to 2 LFOs for modulation of Ring Freq.
-Amp section where amplitude can be modulated by velocity and a dedicated envelope - with it's own built-in compressor. Plus Velocity control of Amp and Filter ADSR Decay.
-A performance section that has Poly-Mono switch, Glide, Glissando and retrigger switches with Time control on the glide. Glide can be routed to OSC1, OSC2 or Both.
-A dedicated distortion unit which uses pre and post filtering (it is this which can give Karnage its unique sound). The modulation (LFO1 or LFO2) is of the pre-post cutoff but the types of filters are set by the shape control so all sorts of effects are possible from a phasing type of modulation to a vocally formant shifting effect, (talk-box effect).
-Two LFOs, whose rate is controlled manually or by host tempo. Destinations are Filter, Ring Modulation and Distortion for both LFOs and you can apply each LFO to more than one destination at once. The LFOs also have MIDI Trigger On/Off (Gate).
-Full set of 128 presets by a variety of respected patch-makers.
via
Eine kürzlich veröffentlichte Studie der McGill University weist auf Sojamilch als die beste pflanzliche Milchoption hin, aber die Realität ist nicht ganz so einfach.
Die Studie untersuchte die vier am häufigsten konsumierten pflanzlichen Milchprodukte auf der ganzen Welt: Soja, Mandeln, Reis und Kokosnuss. Sie verglichen sie nicht nur miteinander, sondern auch mit Kuhmilch, die aus ernährungsphysiologischer Sicht der „klare Gewinner“ war: Die Autoren schreiben, dass sie die „perfekte Zusammensetzung der Nährstoffe“ für Kühe hat und der Zusammensetzung des Menschen ähnelt Muttermilch.
Unter den Optionen auf pflanzlicher Basis setzte sich jedoch Sojamilch durch, und aus rein nährstoffbasierter Sicht ist es schwer zu argumentieren: Sojamilch, so die Wissenschaftler, „fand man heraus, dass es mit Kuhmilch am besten vergleichbar ist Gesamtnährstoffbilanz “, berichtet TIME. “Es ist auch der höchste Proteinanteil aller untersuchten alternativen Milchoptionen, mit etwa 7 bis 12 Gramm (und etwa 95 Kalorien) pro Portion.”
Im Vergleich dazu hat Reismilch vor allem relativ niedrige Nährstoffgehalte und einen höheren Zuckergehalt, was die Autoren der Studie zu der Überzeugung veranlasst, dass Säuglinge, die Reismilch konsumieren, sogar an Unterernährung leiden könnten. Kokosnussmilch war unterdessen sehr arm an Eiweiß, obwohl der Bericht seine Auswirkungen auf gutes Cholesterin gutheißt; und Mandelmilch, die reich an einfach ungesättigten Fettsäuren und relativ kalorienarm ist, war bei Eiweiß und Kohlenhydraten niedriger als bei Kuh- oder Sojamilch.
Gesundheit beginnt und endet nicht mit Nährstoffen
Nur weil Sojamilch ein ähnliches Nährwertprofil wie Kuhmilch aufweist, bedeutet dies jedoch nicht, dass es für Sie besser ist als andere pflanzliche Milch – oder sogar für Sie.
“Sojamilch kann eine sichere Alternative zu Kuhmilch sein”, sagt Dr. Mark Hyman, Direktor des Cleveland Clinic Center for Functional Medicine. “Es gibt jedoch eine Reihe wichtiger Vorbehalte.”
Er zitiert beispielsweise, dass 95 Prozent aller Sojabohnen gentechnisch verändert sind, das heißt, dass sie wahrscheinlich zumindest Spuren von Glyphosat enthalten, ein Herbizid, das von Monsanto als Roundup vertrieben wird. Ein Großteil des in den USA angebauten Sojas ist gentechnisch so konstruiert, dass er den Auswirkungen von Glyphosat standhält, was bedeutet, dass es mit der Chemikalie stark besprüht werden kann und wird, was zahlreiche Studien, einschließlich einer Überprüfung der Weltgesundheitsorganisation aus dem Jahr 2015, ergeben haben kann krebserregend sein.
Die Wahl von Bio-Sojamilch kann diese Probleme abmildern (obwohl betrügerische Einfuhren von herkömmlichem Soja im letzten Jahr bedeuten, dass es immer noch schwierig ist, absolut sicher zu sein, dass Ihre Sojamilch keine Pestizide enthält), aber Dr. Hyman weist darauf hin, dass sogar Bio-Sojamilch unerwünschte Inhaltsstoffe enthalten kann. Einige Sojamilch enthält Gerstenmalz – eine Glutenquelle – sowie Zucker und Carrageenan, einen Emulgator, der mit erhöhter Darmpermeabilität in Verbindung gebracht wurde (Carrageenan ist jedoch in der Lebensmittelindustrie nicht nur in Sojamilch verbreitet).
Einige Experten äußerten auch Bedenken hinsichtlich des Sojakonzentrats an Phytinsäure, einem in Nüssen und Samen enthaltenen „Anti-Nährstoff“, der es dem Körper möglicherweise erschwert, lebenswichtige Nährstoffe aufzunehmen und zu verdauen.
Das größte Problem im Zusammenhang mit Soja ist jedoch möglicherweise die Wirkung auf Östrogen.
Soja ist das Nahrungsmittel mit dem größten bekannten Isoflavon-Gehalt; Die Studie hebt diese pflanzlichen Nährstoffe für ihre krebsbekämpfenden Eigenschaften hervor. Isoflavone können jedoch auch die Produktion von Östrogen stimulieren. In einer Studie aus dem Nutrition Journal aus dem Jahr 2008 wird sogar darauf hingewiesen, dass aufgrund der krebsbekämpfenden Eigenschaften von Isoflavonen mit der Modulation von Östrogen Frauen mit Brustkrebsrisiko anfälliger werden können auf die Krankheit bei der Erhöhung ihres Isoflavonverbrauchs. Der Verbrauch großer Mengen Sojamilch war auch in einer Studie zur Umweltforschung 2017 mit der frühen Pubertät verbunden.
Milch bekommen? (Sicher, in Moderation)
Die Prämisse der Studie ist jedoch sehr verfälscht: Bei der Einstufung von Milchersatzstoffen nach Nährstoffgehalt gehen die Autoren der Studie davon aus, dass die Menschen Milchprodukte zu den Raten einnehmen, die die Bundesregierung empfiehlt. Ab 2015 empfehlen die Ernährungsrichtlinien des Bundes weiterhin, dass Erwachsene täglich zwei bis drei Portionen Milch trinken. Die meisten Ernährungsexperten sind sich jedoch einig, dass dies bei weitem nicht der beste Weg ist, um Nährstoffe zu erhalten.
„Milchprodukte sind ein Wachstumshormon“, erklärt die Naturheilkundlerin Serena Goldstein. Erwachsene, die Milchprodukte konsumieren, könnten am Ende Gewicht, Blutzucker und Hautprobleme aufgrund dieser Hormone bekommen. “Wir verlieren auch unsere Fähigkeit, Molkereiprodukte zu tolerieren, nachdem wir zwei Jahre alt sind. Daher ist es ein Faktor, der die Darmgesundheit stört, die mit schlechter Laune, Herz-Kreislauf-Erkrankungen, hormonellen Problemen usw. in Verbindung gebracht wurde.”
Selbst wenn ein Erwachsener sich dafür entscheidet, Kuhmilch in seine Ernährung aufzunehmen, sollte er sparsam konsumiert werden, was bedeutet, dass er sich auf andere Quellen für die mit Milch verbundenen Nährstoffe wie Kalzium, Eiweiß und bestimmte Vitamine verlassen muss. und Milch – egal, ob sie von einer Kuh oder einer Pflanze stammt – sollte „manchmal“ Nahrung sein.
„Alles in allem ist ein bisschen ungesüßte Bio-Sojamilch ohne Carrageen oder Gerstenmalz in Ordnung, sollte aber kein Grundnahrungsmittel sein“, sagt Hyman. „Wenn Sie es in Ihren Kaffee geben wollen, ist es in Ordnung. Wenn Sie jeden Tag einen großen Sojalatte trinken, ist das wahrscheinlich keine gute Idee. “
Also, welche Milch soll ich trinken?
Hyman und Goldstein bevorzugen beide Kokosnuss- oder Nussmilch; Goldstein merkt an, dass sie in der Regel vorschlägt, dass ihre Kunden Kokosnussmilch, Mandelmilch oder Hanfmilch wählen, da sie gute Quellen für gesunde Fette sind, was bedeutet, dass sie ein wenig mehr Durchhaltevermögen haben und weniger wahrscheinlich Ihren Blutzucker ansteigen lassen , wie Reismilch kann.
Für welche Milch Sie sich auch entscheiden, Sie sollten unbedingt sicherstellen, dass sie aus einer sauberen Quelle stammt: Kokosnussmilch in Dosen ohne Zusatzstoffe oder hausgemachte Nussmilch ist eine ausgezeichnete Wahl für Ihren Morgenkaffee.
Die Post Ist Sojamilch die gesündeste pflanzliche Milch? erschien zuerst bei Health Beauty ABC.
The post Ist Sojamilch die gesündeste pflanzliche Milch? appeared first on Natürliche Alternative Heilmittel - Körper | Geist | Zuhause.
Networked Fabrication for Urban Provocations.
Shifting Paradigms from Mass Production to Mass Customization
Computational architecture and design course
Conventional construction methods all depart from the basic premises of mass production: standardization, modulation and a production line. What these systems developed during the last two centuries fail to take into account are the evolutionary leaps and bounds the manufacturing industry has taken over the last decades. With the introduction of CNC technologies and rapid prototyping machines have altered the paradigms of fabrication forever. It is due to these new tools that it is now possible to create (n) amount of completely unique and different pieces with the same amount of energy and material that is required to create (n) identical pieces. The possibilities for implementation of new forms, textures, materials and languages are infinite due to the versatility that these new tools offer a growing network of architects, designers, fabricators that are integrating them into their professional practices to generate unique and precise objects that respond to countless data and real-life conditions.
Instructors:
Monika Wittig [ LaN, IaaC ]
Shane Salisbury [ LaN, IaaC ]
Filippo Moroni [ SOLIDO, Politecnico di Milano ]
MS Josh Updyke [ Advanced Manufacturing Institute, KSU, Protei ]
Aaron Gutiérrez Cortes [ Amorphica ]
Basically, the Ekdahl Moisturizer is a spring reverb where the springs are exposed so they can be played/hit/fiddled with. As well as being capable of creating sound in itself, you can of course also play sound through the springs like a regular spring reverb - this makes for happy-fun-time finger-modulation of the reverb on whatever audio that's going through it. On top of this there's an analog multimode filter that can be used to attenuate or exaggerate certain frequencies in the sound, this is real handy while playing the springs as you can - for instance - cut all the highs and just make thunderous doomy sounds or do the opposite; cut all the lows and make that ear piercing high frequency special love. Also, it incorporates an LFO that's internally routable to the filter and that also has some external routing-stuff. The Ekdahl Moisturizer has tons of CV / Expression pedal options on the back for even more hillarious moments. The Moisturizer is a mono unit.
The Moisturizer was developed with the help of Jason Willett (Half Japanese, Leperchaun Catering), Martin Schmidt (Matmos, Instant Coffee), Joshua Atkins (Polygons, Major Powers), mom & dad and many more
An inspirational Tejano song with strong tropical flavors and a hot Spanish lead guitar.
Accordion - Lee Fitzsimmons * Lead Spanish guitar - Lee Fitzsimmons * Sparkly keyboards, Organ, and Classic analog sounds - Lee Fitzsimmons * Ibanez electric bass guitar - Lee Fitzsimmons * Drums, chime tree, shakers, and (it needs more) cowbell - Lee Fitzsimmons
This inspirational song features a very relaxing groove that is in no hurry, yet is still packed with a sheer intensity that drives it right along at a sure and steady pace. There are two main sections of the piece. The A section features a very identifiable melodic hook played on accordion and organ that instantly makes the listener pay attention and want to sing along. The B section provides nice contrasting relief by presenting a two part melodic figure played on Spanish guitar and analog keyboard. The B section is further empowered by syncopated chordal accents supplied by the rest of the ensemble.
At the bridge, a live Spanish guitar takes a quick lead and then sets up a tremendous modulation that presents the main theme that has been modulated up a whole step, as the Spanish guitar continues to dance around nimbly, cleverly weaving in and out between the nooks and crannies of the primary accordion melody. After a quick, yet effective coda, the piece ends...
Title: Concha Renaissance San Juan Resort
Other title: Concha
Creator: Toro, Osvaldo 1914-1995; Ferrer, Miguel, 1915-2004; Salvadori, Mario George, 1907-1997; Marvel & Marchand Architects
Creator role: Architect
Date: 1958 (original) 2008 (renovation)
Current location: San Juan, Puerto Rico
Description of work: Renaissance Hotels tasked architect Jose R. Marchand and interior designer Jorge Rossello with renovating and saving this beachside landmark. "[B]y the mid-1990s the venerable La Concha hotel had been shuttered, abandoned and left to rot...Originally designed by Osvaldo Toro and Miguel Ferrer, with an eccentric but utterly loveable seashell-shaped restaurant by Mario Salvatori [sic], La Concha was a beautifully massed, expertly sited, vividly inventive building perfectly in sync with its time. Closely attuning the hotel to its sun-swept setting, the architects created deep-shading overhangs, open corridors, windows and doors that gave onto lush interior courtyards and provided cross ventilation, and beautifully lacy quiebra-sol (their take on a brise-soleil) for further modulation of the light and heat" (Frank, Michael. "La Concha Revival". Architectural Digest. Aug 2009, p. 103-104. Print).
Description of view: Detail view of the outdoor showers with a large tiled curved wall.
Work type: Architecture and Landscape
Style of work: Modern: International Style
Culture: Puerto Rican
Materials/Techniques: Concrete
Wood
Trees
Source: Pisciotta, Henry (copyright Henry Pisciotta)
Date photographed: May 13, 2008
Resource type: Image
File format: JPEG
Image size: 2304H X 3072W pixels
Permitted uses: This image is posted publicly for non-profit educational uses, excluding printed publication. Other uses are not permitted. For additional details see: alias.libraries.psu.edu/vius/copyright/publicrightsarch.htm
Collection: Worldwide Building and Landscape Pictures
Filename: WB2010-0282 Concha.JPG
Record ID: WB2010-0282
Sub collection: resorts
Copyright holder: Copyright Henry Pisciotta
My MXR M169 CARBON COPY ANALOG DELAY PEDAL!
The MXR Carbon Copy Analog Delay features an entirely analog audio path, delivering rich, warm delay using old-school bucket brigade technology. The Carbon Copy boasts 600ms of delay time, with optional modulation via a top-mounted switch, and its simple three-knob layout gives you complete control over Delay Time, Mix (dry/wet blend), and Regeneration (delay repeats) - all in one incredibly compact pedal! For even more tonal options, you can also adjust width and rate control of the modulation via two internal trim pots. Giving you everything from crisp "bathroom" slap echoes to epic delays, all with the simple twist of a knob, stage-worthy blue LEDs and 9-volt operation round out this MXR Carbon Copy Analog Delay!
If you're asking what's all that? Take a look...
www.youtube.com/watch?v=FiZ95CXnPrA
Out of the box, this baby oozes great tone, and creates warm, silky-smooth repeats as you’d expect from an analog and importantly it doesn’t turn your tone overly dark as analog delays are apt to do. The Mod button adds a cool and super-subtle modulation similar to chorus, to smooth out the tone even more.
Title: Concha Renaissance San Juan Resort
Other title: Concha
Creator: Toro, Osvaldo 1914-1995; Ferrer, Miguel, 1915-2004; Salvadori, Mario George, 1907-1997; Marvel & Marchand Architects
Creator role: Architect
Date: 1958 (original) 2008 (renovation)
Current location: San Juan, Puerto Rico
Description of work: Renaissance Hotels tasked architect Jose R. Marchand and interior designer Jorge Rossello with renovating and saving this beachside landmark. "[B]y the mid-1990s the venerable La Concha hotel had been shuttered, abandoned and left to rot...Originally designed by Osvaldo Toro and Miguel Ferrer, with an eccentric but utterly loveable seashell-shaped restaurant by Mario Salvatori [sic], La Concha was a beautifully massed, expertly sited, vividly inventive building perfectly in sync with its time. Closely attuning the hotel to its sun-swept setting, the architects created deep-shading overhangs, open corridors, windows and doors that gave onto lush interior courtyards and provided cross ventilation, and beautifully lacy quiebra-sol (their take on a brise-soleil) for further modulation of the light and heat" (Frank, Michael. "La Concha Revival". Architectural Digest. Aug 2009, p. 103-104. Print).
Description of view: Detail view of the southeast portion of the lounge and pool area located in the center of the hotel.
Work type: Architecture and Landscape
Style of work: Modern: International Style
Culture: Puerto Rican
Materials/Techniques: Concrete
Plants
Source: Pisciotta, Henry (copyright Henry Pisciotta)
Date photographed: May 13, 2008
Resource type: Image
File format: JPEG
Image size: 2304H X 3072W pixels
Permitted uses: This image is posted publicly for non-profit educational uses, excluding printed publication. Other uses are not permitted. For additional details see: alias.libraries.psu.edu/vius/copyright/publicrightsarch.htm
Collection: Worldwide Building and Landscape Pictures
Filename: WB2010-0239 Concha.JPG
Record ID: WB2010-0239
Sub collection: resorts
Copyright holder: Copyright Henry Pisciotta
Brug verbindingsdam naar Javaeiland en KNSM-eiland
Build in 1995. Architect Hans van Heeswijk
The Verbindingsdam in the Eastern Docklands of Amsterdam was the railroad link between manmade harbour islands and a vast switchyard. For this reason, the dam and bridge traverses the water obliquely instead of going straight across.
The islands and railway yard have been redeveloped into residential areas. The railroad became tramway and capacity for other forms of traffic had to be increased. The islands had to remain accessible at all times, so the design of the bridge is in two parts to allow phased construction. To emphasize the “bridge” character, the original flat girders were replaced by arches.
Compared to its span, the bridge is extremely wide. Separating the deck into three parts provides a spatial modulation. The bridge deck is supported by beams that are suspended from above with cables running through the slits in the deck.
By night the road is illuminated from above. Spotlights from underneath cast a glow on the white painted steel construction.
Last week a co-worker said, "I have never in my life felt more like a widget than I do at this place."
Thanks, Wave Of Modulation, for the assist.
Blacktron Gold - Listening and Assault Unit
Spacecraft equipped with:
- stereo cockpit
- optoechoic head
- white noise generator
- modulation metronome
- dual megabass cannon
- large aperture antenna with phrase scanning
- dual IR (iridium) jam-session-er
- powerful pro-tone torpedo
- dual frequency Hi-Fi-per sonic missiles
7/16 (L29) is one kind of thread coupling RF coaxial connector, characteristic impedance is 50ohm. The characteristics of Huajian Electronics connector are its big power, low VSWR,less attenuation, low inter modulation, excellent nature of airtight. Our products are used by ZTE,China Mobile and China Telecom. They are used in connection with feeder cables in broadcast, television, ground launch system, monitoring of radar, microwave communication fields etc. Our company also produces many kinds of 7/16 cable assembly in mass scale, which can reduce your cost.
Material:
Center Contacts: Phosphor bronze, Silver plated
Bodies and Other Metal Parts: Brass, Ni plated
Insulator: PTFE
Seal Rings: Silicone Rubber
Gasket: Silicone Rubber
Technical Specifications:
Characteristic Impedance: 50Ω
Frequency Range: 0～11GHz
Contact Resistance:
Center Conductor: ≤ 1.5mΩ
Outer Conductor: ≤ 0.2mΩ
Insulator Resistance: ≥5000MΩ
Insulator Withstanding Voltage: 1500V
VSWR: ≤1.15
Connector Durability: 500cycles
Applicable Standard: MIL-C-39012
Brand: Huajian
Color: Silver
Size: 50.3mm
"iSwarm is a swarm of luminous “sea creatures” that interact with passers-by. Subtle and hardly visible by day, iSwarm comes alive at night. As daylight fades, the cells of iSwarm illuminate the waters of Marina Bay with fluorescent light reminiscent of natural phenomena such as bioluminescent algae or the Aurora Borealis. iSwarm reacts to groups of visitors by detecting human presence and greeting them with subtle modulation of its light patterns."
Connected Vehicle SafetyCars that look out for each other
With a little warning, many traffic accidents can be avoided altogether. Enabling cars and scooters to communicate and work together may be the first step to avoid collisions and other incidents. To do this, fast and reliable communication amongst vehicles is critical, even on crowded city streets. Intel Labs, through the Intel Collaborative Research Institute for Connected Context Computing, is exploring visible light from tail lights to support high-speed data transmission over the short distances between vehicles. The technology uses direct modulation of LED tail lights to encode data in the visible spectrum, while maintaining a constant ambient lighting state. At almost no
Networked Fabrication for Urban Provocations.
Shifting Paradigms from Mass Production to Mass Customization
Computational architecture and design course
amorphica.com/networked.html
Conventional construction methods all depart from the basic premises of mass production: standardization, modulation and a production line. What these systems developed during the last two centuries fail to take into account are the evolutionary leaps and bounds the manufacturing industry has taken over the last decades. With the introduction of CNC technologies and rapid prototyping machines have altered the paradigms of fabrication forever. It is due to these new tools that it is now possible to create (n) amount of completely unique and different pieces with the same amount of energy and material that is required to create (n) identical pieces. The possibilities for implementation of new forms, textures, materials and languages are infinite due to the versatility that these new tools offer a growing network of architects, designers, fabricators that are integrating them into their professional practices to generate unique and precise objects that respond to countless data and real-life conditions.
Instructors:
Monika Wittig [ LaN, IaaC ]
Shane Salisbury [ LaN, IaaC ]
Filippo Moroni [ SOLIDO, Politecnico di Milano ]
MS Josh Updyke [ Advanced Manufacturing Institute, KSU, Protei ]
Aaron Gutiérrez Cortes [ Amorphica ]
Here's some spec's on this sweet system. It's a "Matrix" system, meaning that it has the ability to change all of it's routings on every preset.
Instead of being tied to one signal flow you can have any signal flow you want, when you want. Which is pretty handy for score music composer & guitar instrumental musician who has to constantly change the signal flow.
The switcher has a software interface that allows you to create an icon for each device and it's corresponding input(s) & Output(s), then using the mouse, connect the rig you want to have at that moment with no extra devices connected to the signal path for the cleanest path possible from pick ups to speakers.
A matrix switcher has 16x Inputs & 16x Outputs, so we decided to put 5 switchers in this system, connected them to each other & bunch of other cool gear. Each switcher has a "Group" responsibility:
1. "Master" - Magnetic & Piezo Inputs + 4x Amplifiers + 1 Axe FX ("Front End" of 4 Wire Config) + Multiple Connections to the other Switchers
2. "Harmonics" - Octave, Fuzz & Overdrive devices.
3. "Dynamics" - Compressors, EQ's Filters, Synthesizers.
4. "Modulations" - Chorus, Phaser, Flanger, UniVibe, & Tremolo.
5. "Time" - Delays & Reverbs + Axe FX ("Back End") for Reverb, Delay & Looper.
Any order & combination of series & parallel is possible, the possibilities for signal routings are only limited by the player's imagination...
Prague Castle (Pražský hrad)
For more than a thousand years, has the Prague Castle been an important symbol of the Czech state. Founded in the 9th century, it became the permanent seat of the Czech rulers and, most recently, also of the Presidents. One of the largest castle complexes in the world consists of palaces, offices, churches and fortification buildings, gardens and picturesque corners. The castle covers an area of 45 hectares. The unique view to the Prague Castle is one of the most amazing panorama views in the world.
Prague Castle is the most important folk-cultural and historical monument, and is the symbol of the more than one thousand years of development of the Czech and all-Czech states. It is a monumental symbol of the palace, church, fortification, official and residential buildings which represent very valuable monuments, included in all style epochs. It covers an area of 45 hectares, was the seat of the Bohemian princes, kings and emperors, and since the Republic was founded in 1918, it was also the residence of the presidents. Since 1962, the Prague Castle has been known for its archaeological discoveries.
History
The initial phases of the Prague Castle are connected with the first historically documented Přemyslid Bořivoj (Bořivoj I (Czech pronunciation: [ˈbɔr̝ɪvɔj], Latin: Borzivogius, c. 852 – c. 889) was the first historically documented Duke of Bohemia from about 870 and progenitor of the Přemyslid dynasty.] The Duchy of Bohemia was at those times subordinated to Great Moravia.). This one transferred in the 80s of the 9th century his original seat from Levý Hradec to the place where on the raised spot above the river Vltava/Moldau already existed a Slavic castle and was very well situated.
The first princely palace apparently only consisted of wood. The first stone building and the oldest Christian sanctuary was the Virgin Mary Church. Its remains have been found between the Second Courtyard and the Bastion garden (original name of the garden: Na Baště). This Bořivoj church was soon reconstructed by the prince Spytihněv I, who was buried here in 915. The second church in the castle was the St. George Basilica founded by Prince Vratislaus I. The next Přemyslide, Prince Wenceslas (Saint), the third sanctuary - the St Veit Rotunda - in the twenties of the 10th century nearby had built which in the 11th century by Prince Spytihnev II was transformed into a huge basilica.
In 973, when the bishopric was established in Prague, the castle was not only the seat of the head of state, but also the seat of the Prague bishop, the highest representative of the church. At the same time arose the first monastery in Bohemia at St. George's basilica.
In the 10th century the castle occupied an area of about 6 ha. In the Romanesque epoch the former fortress, especially after the year 1135 thanks to Soběslaus I, as the stony princely palace and the new masonry fortified with some towers were erected, was turned into a fortified medieval castle. Of the towers is the eastern blacktower best preserved.
Very significantly the Gothic period in the appearance of Prague Castle intervened, most of all Charles IV (1346 - 1378), who, with his father, John of Luxemburg (1310 - 1346), obtained from the pope the promotion of the Prague bishopric to the archbishopric and laid the foundations for the construction of St. Vitus Cathedral. Under Charles IV, the castle for the first time was turned into the imperial residence. Charles IV the defense of the Prague Castle had consolidated, the Royal Palace with the Chapel of All Saints he rebuilt generously. The roofs he had covered with gilded plates, which were the foundation for the binding of words "Golden Prague". Since 1382, Bohemian rulers ceased to occupy the Prague Castle for more than 100 years. The royal court was moved to the place of today's Community hall and back to the Prague castle it came only in 1483 under Wladislaus from the Jagiellonian dynasty.
Although the ruler already in 1490 moved to Ofen (Buda), he had the Prague castle renovated in the late Gothic style under the supervision of Benedikt Ried. He was the master builder of the magnificent Vladislav Hall, the largest secular vaulted room of the then Europe, with which the first Renaissance signs came to Prague. He carried out major construction works, including the construction of a new masonry, the defensive towers and the expansion of the Royal Palace. At his time, the Gothic died away and a new architectural style, the Renaissance, gradually prevailed.
The direct influence of the Italian art on the new style was most frequently observed in Prague under the reign of Ferdinand I (von Habsburg) and after his departure from Prague under the influence of the governor Ferdinand of Tyrol. At that time, the medieval castle was converted into a comfortable Renaissance castle with gardens. The typical Italian architecture of the Royal Pleasure palace arose in the northern King's garden.
For a large building activity in 1541 contributed a fire devastating the castle objects as well as the surrounding area quite a lot. Within the framework of the restoration, both the housing estates and the church buildings were rebuilt. Under the reign of the first Habsburgs, nobility palaces were added to the castle grounds (for example, the Pernstein Palace - later Lobkowicz Palace, Rosenberg Palace and others). Horse stable buildings were built in the north-west.
Under the reign of the Emperor Rudolph II (1576 - 1611), the Renaissance and Mannerism transformation of the castle, which for the second time became the center of the empire, and especially the center of European culture and science, reached its peak. On the second courtyard, new rooms were built for the collections of Rudolph - the new (now Spanish) hall and the Rudolph gallery. Also arose the connection tract between the northwestern and the southwestern part of the castle. Just here the famous Kunstkammer (Art chamber) and other rooms for Rudolph's collective activities were located. Additionally further horse stable properties were built for his rare Spanish horses. During the Rudolph times also the foundation stone of the famous Golden Alley was laid. Laboratories of the Rudolph-Alchymists were supposed to have been in the Powder tower above the Hirschgraben (Deer's ditch). The castle suffered again considerable damages when it was occupied by the Saxon army in 1631 and by the Swedes in 1648 not only was occupied but also plundered. After the Thirty Years' War, the Habsburgs did not care too much about the Prague royal seat.
Only Maria Theresia carried out an extensive reconstruction of the Prague Castle from 1755 - 1775 into a representative castle complex. The reason for the massive construction action were war damages, caused by the intense bombing of the castle during war conflicts at the beginning of her reign. The reconstruction was designed by the Viennese architect Nicolo Pacassi, who also planned the first courtyard with the monumental entrance gate. From the time of the Theresian reconstruction stems also the chapel of the Holy Cross on the 2nd castle forecourt and other buildings, especially the noblewomen institute. The south wing he imprinted the uniform monumental late Baroque facade of a representative seat. His plans influenced by Viennese Rococo and French Classicism the builders Anselmo Lurago, Anton Kunz and Anton Haffenecker brought into life.
In the 19th century, the castle fell into ruin, in several objects after the Josephine reforms the army settled. In connection with the stay of Ferdinand I the Good in the castle after his abdication in 1848 and further in connection with the preparation for the coronation of Franz Joseph I in the sixties it came to building modifications of several objects. After 1859, when the community for the completion of St Veit cathedral emerged, began first the repair, and then, under the influence of the architect Joseph Mocker, the work on the actual completion of St Veit's cathedral was started, completed in 1929.
In the years 1920 - 35, carried out extensive regulations of the Prague Castle as the seat of the Czechoslovak President the great Slovenian architect Josip Plečnik, who masterfully combined the valuable historical space with modern civilization claims. His modifications mainly concerned the 1st and 3rd court, the southern gardens of the castle, the fourth forecourt with the Bastion garden as well as numerous interiors. He created e.g. the pillared hall, private rooms of the presidential residence, including the Masaryk workroom. His pupil, Otto Rothmayer, brought to an end the incomplete solutions of some castle interior spaces after the Second World War in comparable quality.
In 1936, Pavel Janák and after him, in 1959, Jaroslav Fragner became castle architect.
After the year of change of 1989, the Prague Castle was opened to the public in many places. During the term of President Havel, at the castle it came to modulations of the interiors and to the expansion of two new entrances into the second courtyard after the project of the creator and designer Bořek Šípek. The puncture through the rampart of the Powder bridge in Hirschgraben was rewarded with a significant prize (Arch. Josef Pleskot). Also interesting is the modern greenhouse of the world-famous architect Eva Jiřičná. The Georgian Square (Jiřské náměstí) was re-paved and modulated. The Mosaic of the Last Judgment was renovated in collaboration with the specialists from the Getti Institute. In 1990, the Prague Castle was solemnly illuminated and this situation lasts from dusk to midnight until today. In the main tourist season, the lighting time even lasts an hour longer until 1 o'clock. The tradition of electric lighting, but on a much smaller scale, began in 1928, when the lamps were installed for the 10th anniversary of the elevation to a Republic. A little bit the present daylight resembles of those from the end of the sixties, but today it is much more detailed and in communist times it was only switched on at solemn occasions. At that time, illuminative days were state holidays or significant day of republic, which, however, did not lack recognition from the communist point of view.
In recent years the reconstruction and renovation work has been developed in many buildings of the castle and a considerable attention has been devoted to the archaeological investigation, which has been going on since 1925 and has brought many insights into the history of the castle. The investigation as well as the renovation of the individual rooms and objects is motivated by the idea of invigorating them as much as possible by making them accessible to the public.
Prager Burg (Pražský hrad)
Die Prager Burg ist seit über tausend Jahren ein bedeutendes Symbol des tschechischen Staates. Gegründet im 9. Jahrhundert wurde sie zum ständigen Sitz der tschechischen Herrscher und zuletzt auch der Präsidenten. Einer der größten Burgkomplexe weltweit setzt sich aus Palästen, Amts-, Kirchen- und Fortifikationsgebäuden, aus Gärten und malerischen Ecken zusammen. Die Burg erstreckt sich auf einer Fläche von 45 Hektar. Der alleinige Blick auf die Prager Burg stellt einen der überwältigendsten Panoramablicke der Welt dar.
Die Prager Burg ist das bedeutendste Volkskultur- und Historiedenkmal, sie ist das Symbol der mehr als eintausendjährigen Entwicklung des böhmischen sowie gesamttschechischen Staats. Es ist ein monumentales Symbol der Palast-, Kirchen-, Fortifikations-, Amts- und Wohngebäude, die sehr wertvolle Denkmäler darstellen, einbezogen auf alle Stilepochen. Sie erstreckt sich auf einer Fläche von 45 ha, war der Sitz der böhmischen Fürsten, Könige und Kaiser und seit der Republikentstehung im Jahre 1918 war sie auch die Residenz der Präsidenten. Seit 1962 steht die Prager Burg mit ihren archäologischen Funden als bekanntester.
Geschichte
Die Anfangszeiten der Prager Burg sind mit dem ersten historisch belegten Přemysliden Bořivoj verbunden. Dieser übertrug in den 80er Jahren des 9. Jahrhunderts seinen ursprünglichen Sitz von Levý Hradec an den Ort, wo auf der erhabenen Stelle über der Moldau eine slawische Burgstätte bereits bestand und sehr gut gelegen war.
Der erste Fürstenpalast bestand offenbar aus Holz. Der erste Steinbau und das älteste christliche Heiligtum war die Jungfrau Maria Kirche. Ihre Reste wurden zwischen dem II. Vorhof und dem Basteigarten (Originalname des Gartens: Na Baště) gefunden. Diese Bořivoj-Kirche wurde durch den hier im Jahre 915 beigesetzten Fürsten Spytihněv I. bald umgebaut. Die zweite Kirche im Burgraum war die vom Fürsten Vratislaus I. gegründete St. Georg Basilika. Der nächste Přemyslide, der Fürst Wenzel (der Heilige), ließ in der Nähe in den 20er Jahren des 10. Jahrhunderts das dritte Heiligtum - die St. Veit Rotunde - bauen, die im 11. Jahrhundert vom Fürsten Spytihněv II. zu einer gewaltigen Basilika umgebaut wurde.
Im Jahre 973, als in Prag das Bistum gegründet wurde, war die Burg nicht nur der Sitz des Staatsoberhaupts, sondern auch der Sitz des Prager Bischofs, des höchsten Repräsentanten der Kirche. Zu demselben Zeitpunkt entstand an der St. Georg Basilika das erste Kloster in Böhmen.
Im 10. Jahrhundert nahm die Burg eine Fläche von ca. 6 ha in Anspruch. In der romanischen Epoche wurde die einstige Burgstätte, insbesondere nach dem Jahr 1135 dank Soběslaus I., als der steinige Fürstenpalast und das neue mit einigen Türmen verstärkte Mauerwerk aufgebaut wurden, zu einer festen mittelalterlichen Burg umgebaut. Von den Türmen ist der östliche Schwarzturm am besten erhalten.
Sehr bedeutend griff ins Aussehen der Prager Burg die Gotikzeit ein, insbesondere Karl IV. (1346 - 1378), der mit seinem Vater Johann von Luxemburg (1310 - 1346) vom Papst die Beförderung des Prager Bistums zum Erzbistum erwirkte und den Grundstein für den Bau der St. Veit Kathedrale legte. Unter Karl IV. wurde die Burg zum ersten Mal zur Kaiserlichen Residenz. Karl IV. ließ die Verschanzung der Prager Burg festigen, den Königspalast mit der Kapelle Aller Heiligen baute er großzügig um. Die Dächer ließ er mit vergoldeten Blechen decken, die das Fundament für die Wörterbindung „Goldenes Prag“ darstellten. Seit 1382 hörten böhmische Herrscher auf, die Prager Burg für mehr als 100 Jahre zu bewohnen. Der Königshof wurde an den Ort des heutigen Gemeindehauses umgezogen und zurück auf die Prager Burg kehrte er erst im Jahre 1483 unter Wladislaus aus der Jagiellonen-Dynastie.
Obwohl der Herrscher bereits 1490 nach Ofen (Buda) umsiedelte, ließ er die Prager Burg im spätgotischen Stil unter der Bauleitung von Benedikt Ried umbauen. Er war der Baumeister des großartigen Wladislaus-Saals, des größten weltlichen gewölbten Raums des damaligen Europas, mit dem die ersten Renaissancezeichen nach Prag kamen. Er führte großartige Bauregelungen einschließlich des Ausbaus eines neuen Mauerwerks, der Wehrtürme und der Erweiterung des Königspalastes durch. Zu seiner Zeit klang die Gotik aus und es setzte sich allmählich ein neuer Baustil durch, die Renaissance.
Der direkte Einfluss der italienischen Kunst des neuen Stils wurde in Prag unter der Regierung von Ferdinand I. (von Habsburg) und nach seinem Weggang von Prag unter der Wirkung des Statthalters Ferdinand von Tirol am meisten beobachtet. Damals wurde die mittelalterliche Burg in ein bequemes Renaissanceschloss mit Gärten umgewandelt. Im nördlichen Königsgarten entstand die typisch italienische Architektur des Königlichen Lustschlosses.
Zu einer großen Bauaktivität trug im Jahre 1541 ein Brand bei, der die Burgobjekte sowie die Umgebung ziemlich viel kaputt machte. Im Rahmen der Wiederherstellung wurden sowohl die Wohnräume als auch die Kirchenobjekte umgebaut. Unter der Regierung der ersten Habsburger kamen ins Burggelände auch Adelspaläste dazu (zum Beispiel der Pernstein-Palast - später Lobkowicz-Palast, Rosenberg-Palast und weitere). Im Nordwesten wurden Pferdestallgebäude erbaut.
Unter der Regierung des Kaisers Rudolph II. (1576 - 1611) erreichte der Renaissance- und Manierismusumbau der Burg, die zum zweiten Mal zum Zentrum des Reiches und insbesondere zum Zentrum der europäischen Kultur und Wissenschaft wurde, seinen Gipfel. Auf dem II. Vorhof wurden neue Räume für die Sammlungen Rudolphs erbaut - der Neue (heute Spanische) Saal und die Rudolph-Galerie. Es entstand auch der Verbindungstrakt zwischen dem Nordwest- und dem Südwestteil der Burg. Eben hier befanden sich die berühmte Kunstkammer und weitere Räume für die Sammeltätigkeit Rudolphs. Es wurden auch weitere Pferdestallobjekte für seine seltenen spanischen Pferde aufgebaut. Während der Rudolph-Zeiten wurde auch der Grundstein der berühmten Goldenen Gasse gelegt. Laboratorien der Rudolph-Alchymisten sollen im Pulverturm über dem Hirschgraben gewesen sein. Die Burg erlitt erneut erhebliche Schäden, als sie 1631 vom sächsischen Heer und 1648 von den Schweden besetzt und ausgeplündert wurde. Nach dem Dreißigjährigen Krieg kümmerten sich die Habsburger um den Prager königlichen Sitz nicht allzu sehr.
Erst Maria Theresia führte in den Jahren 1755 - 1775 einen umfangreichen Umbau der Prager Burg zu einem repräsentativen Schlosskomplex durch. Der Grund für die massive Bauaktion waren Kriegsschäden, verursacht durch die intensive Bombardierung der Burg bei Kriegskonflikten zu Beginn ihrer Regierung. Den Umbau entwarf der Wiener Architekt Nicolo Pacassi, der auch den I. Vorhof mit dem monumentalen Eingangstor projektierte. Aus der Zeit des theresianischen Umbaus stammt auch die Kapelle des Heiligen Kreuzes auf dem II. Burgvorhof und weitere Gebäude, insbesondere die Edeldamenanstalt. Dem Südflügel prägte er die einheitliche monumentale Spätbarockfassade eines Repräsentationssitzes ein. Seine durch das Wiener Rokoko und den französischen Klassizismus beeinflussten Pläne brachten die Baumeister Anselmo Lurago, Anton Kunz und Anton Haffenecker zustande.
Im 19. Jahrhundert verfiel die Burg, in mehreren Objekten ließ sich nach den josephinischen Reformen das Heer nieder. Zu Bauregelungen einiger Objekte kam es im Zusammenhang mit dem Aufenthalt von Ferdinand I. dem Guten auf der Burg nach seiner Abdikation im Jahre 1848 und weiter im Zusammenhang mit der Vorbereitung auf die vorgesehene Krönung von Franz Joseph I. in den 60er Jahren. Nach 1859, als die Gemeinde für die Fertigstellung der St. Veit Kathedrale entstand, begann zuerst die Reparatur und anschließend unter der Wirkung des Architekten Joseph Mocker wurde die Arbeit an der eigentlichen Fertigstellung der St. Veit Kathedrale aufgenommen, abgeschlossen im Jahre 1929.
In den Jahren 1920 - 35 führte ausgedehnte Regelungen der Prager Burg als des Sitzes des tschechoslowakischen Präsidenten der bedeutende slowenische Architekt Josip Plečnik durch, der den wertvollen historischen Raum mit modernen Zivilisationsansprüchen meisterlich zusammenfügte. Seine Regelungen betrafen vor allem den 1. und 3. Vorhof, die Südgärten der Burg, den 4. Vorhof mit dem Basteigarten sowie zahlreiche Innenräume. Er schuf z.B. die Säulenhalle, Privaträume der Präsidentenwohnung einschließlich des Arbeitszimmers Masaryks. Sein Schüler Otto Rothmayer brachte die unvollendeten Lösungen einiger Burginnenräume nach dem 2. Weltkrieg in vergleichbarer Qualität zu Ende.
Im Jahre 1936 ist Pavel Janák und nach ihm seit 1959 Jaroslav Fragner Burgarchitekt geworden.
Nach dem Wendejahr 1989 wurde die Prager Burg an vielen Stellen für die Öffentlichkeit geöffnet. Während der Amtszeit des Präsidenten Havel kam es auf der Burg zu Regelungen der Innenräume und zum Ausbau zweier neuer Eingänge in den 2. Vorhof nach dem Projekt des Bildners und Designers Bořek Šípek. Mit einem bedeutenden Preis wurde der Durchstich durch den Wall der Pulverbrücke im Hirschgraben belohnt (Arch. Josef Pleskot). Interessant ist auch das moderne Gewächshaus der weltberühmten Architektin Eva Jiřičná. Der Georg-Platz (Jiřské náměstí) wurde neu bepflastert und geregelt. In Zusammenarbeit mit den Fachleuten aus dem Getti-Institut wurde die Mosaik „des Letzten Gerichts“ renoviert. Im Jahre 1990 wurde die Prager Burg feierlich beleuchtet und dieser Zustand dauert von der Dämmerung bis zur Mitternacht bis heute. In der touristischen Hauptsaison dauert die Beleuchtungszeit sogar eine Stunde länger, bis 1 Uhr. Die Tradition der elektrischen Beleuchtung, jedoch im viel kleineren Umfang, begann im Jahre 1928, als die Lampen zum 10. Jubiläum der Republikentstehung installiert wurden. Ein wenig ähnelte die heutige feierliche Beleuchtung jener aus dem Ende der 60er Jahren, heute ist sie allerdings viel detaillierter und in den Kommunistenzeiten wurde sie nur bei feierlichen Gelegenheiten angemacht. Beleuchtungswürdige Tage waren damals Staatsfeiertage oder bedeutende Republiktage, denen allerdings aus der kommunistischen Sicht die Anerkennung nicht fehlte.
In den letzten Jahren entwickelte sich die Umbau- bzw. Renovierungstätigkeit in vielen Objekten der Burg und eine erhebliche Aufmerksamkeit wurde der archäologischen Untersuchung gewidmet, die bereits seit 1925 läuft und viele Erkenntnisse über die Burggeschichte brachte. Die Untersuchung sowie die Renovierung der einzelnen Räume und Objekte ist von der Idee motiviert, sie dadurch, dass sie der Öffentlichkeit zugänglich gemacht werden, möglichst viel zu beleben.
Title: Concha Renaissance San Juan Resort
Other title: Concha
Creator: Toro, Osvaldo 1914-1995; Ferrer, Miguel, 1915-2004; Salvadori, Mario George, 1907-1997; Marvel & Marchand Architects
Creator role: Architect
Date: 1958 (original) 2008 (renovation)
Current location: San Juan, Puerto Rico
Description of work: Renaissance Hotels tasked architect Jose R. Marchand and interior designer Jorge Rossello with renovating and saving this beachside landmark. "[B]y the mid-1990s the venerable La Concha hotel had been shuttered, abandoned and left to rot...Originally designed by Osvaldo Toro and Miguel Ferrer, with an eccentric but utterly loveable seashell-shaped restaurant by Mario Salvatori [sic], La Concha was a beautifully massed, expertly sited, vividly inventive building perfectly in sync with its time. Closely attuning the hotel to its sun-swept setting, the architects created deep-shading overhangs, open corridors, windows and doors that gave onto lush interior courtyards and provided cross ventilation, and beautifully lacy quiebra-sol (their take on a brise-soleil) for further modulation of the light and heat" (Frank, Michael. "La Concha Revival". Architectural Digest. Aug 2009, p. 103-104. Print).
Description of view: Distant view of the north and west facade from the nearby park area la Ventana al Mar.
Work type: Architecture and Landscape
Style of work: Modern: International Style
Culture: Puerto Rican
Materials/Techniques: Concrete
Trees
Masonry
Source: Pisciotta, Henry (copyright Henry Pisciotta)
Date photographed: May 13, 2008
Resource type: Image
File format: JPEG
Image size: 2304H X 3072W pixels
Permitted uses: This image is posted publicly for non-profit educational uses, excluding printed publication. Other uses are not permitted. For additional details see: alias.libraries.psu.edu/vius/copyright/publicrightsarch.htm
Collection: Worldwide Building and Landscape Pictures
Filename: WB2010-0251 Concha.JPG
Record ID: WB2010-0251
Sub collection: resorts
fountains
Copyright holder: Copyright Henry Pisciotta
Assembled. The orange backdrop is the cutdown parachute =)
Using full power (10mW) MSK modulation at 915Mhz with a bitrate of 250 kbps I was able to get over 1000ft of line-of-sight range. I have since changed this to 2-FSK at 38.4kbps which should give me another 12dB of range. I'll test this again once I get real antennas.
(le français suit l’anglais)
AM Clock Radio
Model: D-25
Manufacturer: Crosley Radio and Television Ltd.,
Toronto, Ontario
ca. 1951/52
Artifact no. pending
Made of green Bakelite, this 1950’s era clock radio takes its design queues from automobiles of the era. It featured 5 tubes, received in the AM band only, and has a clock with five functions which still works. To blend with décor, the D-25 series was available in six colours.
Canada Science and Technology Museums Corporation
www.technomuses.ca/our_corporation/index_e.asp
Photo: CSTMC/2014
____________________________
Radio-Horloge AM
Modèle : D-25
Manufacturier : Crosley Radio and Television Ltd.,
Toronto (Ontario)
ca. 1951/52
No. d'artefact : en attente
Fait de bakélite verte, le design de cette radio des années 1950 prend sont inspiration des automobiles de l'époque. Elle contient 5 tubes, reçoit dans la bande AM seulement, et dispose d'une horloge avec cinq fonctions qui fonctionne encore. Pour se fondre dans le décor, la série D-25 était disponible en six couleurs.
Société des musées de sciences et technologies du Canada
www.sciencetech.technomuses.ca/francais/index.cfm
SMSTC/2014
A closeup of the controls- all the original button openings were used for the theremin controls and output jacks (except one, for future use.)
The PAiA Theremax circuit used in this project provides control-voltage outputs for pitch and volume, which allows the instrument to control outboard equipment. This capability is easily exploited to allow the theremin to be used as a very responsive gestural controller. Interfacing with a microcontroller is a snap ;)
The oscillator inductors are exposed for tuning and you can also see the touch strips we added for manually applying 'modulation', along the top edge of the opening. More pics in the set: www.flickr.com/photos/imajilon/sets/72157629518599040/
Nolita, Manhattan, New York City, New York
Corners of Houston, Lafayette, Mulberry and Jersey, Nolita
The Puck Building, originally the home of Puck magazine, is one of the great surviving buildings from New York's old publishing and printing district.
The red-brick round-arched structure occupies the entire block bounded by East Houston, Lafayette, Mulberry and Jersey Streets, and has been one of the most prominent architectural presences in the area since its construction one hundred years ago. The building is further distinguished by the large statue of Puck at the building's East Houston and Mulberry Street corner; this is among the city 's most conspicuous pieces of architectural sculpture.
Puck was, from its founding in 1876 until its demise in 1918, the city's and one of the country's best-known humor magazines. Published in both English and German-language editions , Puck satirized most of the public events of the day. The magazine featured color lithographic cartoons produced by the J. Ottman Lithographic Company, largest in the country, which shared the Puck Bllilding space.
The current building is the result of three stages of construction, all supervised by architect Albert Wagner; the building and its additions read as a single unified composit ion. The style is an adaptation of the Romanesque
Revival, which had reached great popularity in the 1880s through the works of H. H. Richardson. Wagner's Romanesque, however, was not Richardsonian. A German-born architect, Wagner had worked in New York for Prague-trained Leopold Eidlitz, and his version of the Romanesque appears to reflect the round-arched Gernan "Rundbogenstil" that Eidlitz had brought to New York several decades earlier.
The Puck Building remains one of the most striking 19th-century industrial buildings in lower Manhattan. The comic magazine was founded by Joseph Keppler (1838-1894) and Adolph Schwarzman first appeared in German in 1876. Puck's attitude varied from d humor to merciless satire. Politicallv, in Keppler's time, supported the Democratic Party, but it was never a partisan magazine. It ridiculed poiitical corruption, monopolies, labor unions, suffragism, and all forms of graft, extravagance, and unjustice. It reviewed theater and musical performances. It laughed at fashions and different fads.
In March 1885, with the magazine's circulation and success on the rise, Keppler, Schwarzmann and Ottman purchased property on the southwest corner of East Houston and Mulberry Streets to be the site of a building to house both Puck and the Ottman company. The location was at the fringes of what was then New York's printing district, whose -center was the Astor Library on Lafayette Street (then Lafayette Place). The authors of a Puck supplement issued on the occasion of its tenth anniversary wrote that "Houston street marks the southernmost boundary of a region much affected by large publishing houses."
Publishing houses, periodicals, and printers were located throughout the neighborhood during the 1880s and 1890s, and it was a natural choice for Puck. The original building was erected in 1885-86 to the designs of Albert Wagner, but went through several additions and alterations. In August 1890, spurred by the continuing growth of the magazine, Keppler, Schwarzann, and J. Ottman's heirs bought the adjoining property to the south at 281 Mulberry Street and erected an addition to the Puck Building in 1892-93, again to Albert Wagner's design. The two-year delay was caused by uncertainty in 1890, about the potential route of a proposed new rapid transit line.
Although the Puck Building is too late to be considered part of the Rundbogenstil, it appears to show the influence of Wagner's earlier experience with it. Such a connection would help explain both the references to the style as "Renaissance," and its dissimilarity to the then more popular Richardsonian version of the Romanesque.
The enormous red brick structure has been a commanding presence in the neighborhood since the time of its construction. Its identity was further announced by the statue of Puck at the Houston and Mulberry Street corner of the building, where the two main entrances originally met, one on either street. There is also a smaller statue over the Lafayette Street entrance. The larger '"Puck" on East Houston Street was apparently designed by Henry Baerer, the sculptor of the bust of Beethoven in Central Park. The designer of the smaller "Puck" is not known.
The Puck Building today comprises the original 1885-86 structure and the 1892 addition, less the western portion of each removed in 1898; the Lafayette Street elevation dates from the latter alteration, but duplicates the earlier design. The building occupies an irregular lot bounded by East Houston Street on the north, Mulberry Street on the east, Jersey Street on the south, and Lafayette Street on the west.43 Despite the complexity of its building history, the Puck reads as a single structure retaining the integrity of its original design. The original portion is seven stories high, and the addition nine, but otherwise they are practically identical in design and material.
The building's architectural effects derive from the rhythms set up by arches of varying width, within bays of equal width, and from an adept use of red brick which creates the modulations in the piers, the definition of the arches, and the corbeling of the cornice. Cast-iron window enframements, statuary, and wrought-iron entrance gates, and the cast-iron and glass vault-lighting, provide the necessary contrast in materials.
The original section now comprises four bays on Lafayette Street, three bays on East Houston, and six bays on Mulberry. On Mulberry, the bays are defined by large brick piers that run the full height of the building. Each pier is actually in two sections: a wider pier at the first and second stories, and a narrower pier above. Each pier has a small brownstone base and rests on a five-foot high block of polished gray granite; each is banded in projecting brick. Within each bay at the first and second stories is a double-story brick arch, with projecting brick edges. Ihthin the arch, each bay consists of an upper arched lunette and a lower rectangle, separated by a cast-iron transom. The lunette contains a central double-hung one-over-one window, flanked on either side by a swing window topped by a quarter-arch pane. Beneath the spandrel are three large rectangular windows with transoms above and six-paned basement windows below.
The second and fourth bays south of East Houston Street contain secondary storefront entrances; the door replaces the central rectangular window of each storefront. The first and second stories are set off from those above by a brownstone stringcourse, beneath which is a band of corbeling.
The second section of pier, running from the third story to the seventh story, is narrower than the lower section; each is banded and adorned with an elegant iron ornamental tie-rod end at the fourth story, and a smaller one at the top. At the third and fourth story each bay comprises a pair of two-story arches, each half the width of the arches below. These arches rest on small brick piers with patterned brick "capitals." Within each arch are a pair of four-over-four doublehung windows above the brick spandrel, and a similar pair below the spandrel; each window in the pair is separated from the one next to it by a slender cast-iron pier with neo-Grec detailing. The third and fourth story bay is topped by corbeling and a brownstone sillcourse above.
- From the 1983 NYCLPC Landmark Designation report
The layering corresponds to Milankovitch cycle
Graham P. Weedon:
"The 21 000 year (21 ka) precession cycle was detected in all three cases, the 100 ka eccentricity cycle in two cases and the 41 ka obliquity cycle in one. Filtering revealed that the supposed 21 ka sedimentary cycles are grouped into packets of four or five small and large amplitude cycles. The packets reflect the 100 ka modulation of the 21 ka precession cycle. Local disruption of the packaging can be used to locate hiatuses in pelagic strata."
source: jgs.lyellcollection.org/cgi/content/abstract/ 146/1/133
My 1/35 scale AFV Club Stryker M1126 8X8 infantry combat vehicle is done! Much to my surprise, this kit went together with only a couple minimal fit issues, self induced! I had expected it to be a bit on the iffy side as the kit has been in my stash for many years now, and older kits tend to be less engineered than recent ones, but it turned out to be an enjoyable build.
I decided to to it as a vehicle that has been in the field for a while during the summer, perhaps on maneuvers in a training facility, so the weathering is not that heavy. I did use burnt sienna oils with mineral spirits (my first use of this thinner with oils as I usually use the less odorous Turpenol) to do some of the filtering and dirtying but the majority of the modulation is done using the usual black undercoat with white accent under main color coat method.
I also used a very light coat of Tamiya buff thinned way down and sprayed on at a foot or so from the model to create a light dusty look as well. That especially worked well on the tires, which are vinyl mounted to plastic hubs (really nicely detailed tires I might add). I did do some panel accenting with Tamiya Black Panel Liner around the raised hull elements. I sanded the tire treads to make them look worn which really brought out that detail, in my opinion.
The decals went on quite easily and released from their carrier sheet with little to no time needed, not like the previous couple of kits i have worked on…a very delightful development! I did use the Micro Set and Sol method to embed them, but the vehicle numbers all silvered on me (think I should have used more gloss under them to relieve this issue). I am still ok with that as you can always weather to compensate after the fact. Prior to weathering, everything was clear coated with Testor’s Dull Coat…still my favorite flat coat.
For once I have few criticisms of the kit and am delighted to add it to my ever growing shelf of diverse armor builds. Definitely a fun build!
At the Cluny Museum, medieval culture showcases its ancestral knowledge. It took five centuries to discover that the thymus and the genitals are connected, as seen in this statue of the first man to experience desire, through a dream about a mythical serpent.....
Within the thymus, regulation of the cellular crosstalk directing T cell development depends on spatial interactions within specialized niches. To create a spatially defined map of tissue niches guiding human postnatal T cell development, we employed the multidimensional imaging platform co-detection by indexing (CODEX) as well as cellular indexing of transcriptomes and epitopes sequencing (CITE-seq) and assay for transposase accessible chromatin sequencing (ATAC-seq). We generated age-matched 4- to 5-month-old human postnatal thymus datasets for male and female donors, identifying significant sex differences in both T cell and thymus biology. We demonstrate a possible role for JAG ligands in directing thymic-like dendritic cell development, identify important functions of a population of extracellular matrix (ECM)− fibroblasts, and characterize the medullary niches surrounding Hassall’s corpuscles. Together, these data represent an age-matched spatial multiomic resource to investigate how sex-based differences in thymus regulation and T cell development arise, providing an essential resource to understand the mechanisms underlying immune function and dysfunction in males and females.
The thymus is the primary organ responsible for the generation and selection of mature, functional, and self-tolerant T cells.1 Effective T cell development is a critical component of our immune system’s ability to accurately and exclusively identify and kill foreign entities such as pathogens. During early postnatal T cell development—the period in life when T cell development is most active2—thymic seeding progenitors migrate to the thymus and mature into thymocytes. Thymic architecture is highly organized to provide spatially defined, stage-specific signaling cues to migrating thymocytes that guide development toward functional mature T cells.3,4,5,6
Recent single-cell sequencing resources demonstrating the diversity of human thymus tissue are incongruous with our current framework of thymus structure and organization,7,8,9,10,11,12,13,14,15,16,17,18,19 which describe a general migratory path thymocytes take through the cortex and medulla during conventional αβT cell development. Spatial transcriptomic sequencing of human thymus has demonstrated a deeper granularity of thymic niches and their evolution during fetal development to support different waves of non-conventional T cells.19,20 However, our understanding of how human postnatal thymus niches support conventional and non-conventional T cell development, T-lineage branching, and alternative lineage development remains limited.3,4,6 T cells generated at this stage of postnatal human development will become the foundation of our immune system, patrolling the body for decades.21 Thus, insights into early postnatal thymus niche biology are crucial to understand how our adaptive immune system is built and how perturbations in postnatal T cell development may emerge as immune dysfunction later in life.
To create a spatially defined map of tissue niches guiding human postnatal T and alternative lineage cell development, we employed multi-dimensional spatial proteomic imaging using co-detection by indexing (CODEX),22,23 single-cell transcriptomic-proteomic profiling using cellular indexing of transcriptomes and epitopes sequencing (CITE-seq),24 and single-cell assay for transposase accessible chromatin sequencing (ATAC-seq).25 Given the emerging recognition of sex differences in thymus gene expression and function,26,27,28,29,30,31 we collected and analyzed samples from male and female donors. Our analysis identifies significant sex differences during early postnatal development that affect T cell and thymus biology through common and cell type-specific mechanisms. Additionally, we highlight key cell types contributing to thymic involution that exhibit sex-based differences in thymic growth and early transition toward adipogenesis. These data suggest that kinetic differences in thymic involution are present between sexes and, importantly, that mechanisms driving thymic involution begin early in life. Altogether, these data represent a powerful age-matched spatial multiomic resource to investigate how sex-based differences in thymus biology and T cell development arise, and how they contribute to sex differences in diseases caused by immune dysfunction.
Results
Spatial multiomic profiling of human postnatal thymus identifies sex-based differences in T cells and thymus biology
We performed single-cell CITE-seq, ATAC-seq, and CODEX imaging on 4–33 months human postnatal thymuses, including 6 (3 female and 3 male) 4- to 5-month-old age-matched samples (Table S1). Each donor sample was processed simultaneously for CODEX imaging and sequencing (Figure 1A). We included a comprehensive 137 antibody panel (Data S1), allowing us to compare epigenomic, transcriptomic, and proteomic expression kinetics across developing thymocytes and enabling direct comparison of cells identified via phenotypic expression in CODEX with cells captured via CITE-seq. Prior to sequencing, we enriched CD45− non-hematopoietic cells and CD25+CD8− regulatory T (Treg) cells to ensure coverage of low-abundance cell types. After quality control and computational merging of individually sequenced patient datasets, we obtained a total of 74,334 cells with CITE-seq, including 19,434 non-T-lineage cells, and captured 25,717 nuclei with ATAC-seq. Importantly, cell proximity in CODEX tissue niches was used to screen predicted receptor-ligand interactions.
Figure 1 Spatial multiomic analysis identifies sex-biased characteristics of thymic niches
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CITE-seq cells were clustered based on transcriptional expression and annotated based on marker gene and surface protein expression (Figure S1A; Table S2).7,8 ATAC-seq clusters were computationally labeled using CITE-seq reference cluster labels, which identified 34 ATAC-seq cluster transfer labels for dataset integration (Figures 1B and S1B). We captured 54,900 thymocytes spanning development from early thymic progenitors (ETPs) to mature single positive (SP) T cells, immature innate cells, innate-like cells, and Tregs. We identified three Treg populations expressing canonical lineage markers, namely Treg progenitors (Pro-Tregs), thymic Tregs (tTregs), and recirculating/resident Tregs (rrTregs).32 We also identified antigen-presenting cells, including B cells, mast cells, monocytes, and six populations of dendritic cells (DCs).33 In addition to the activated DCs (aDCs), plasmacytoid DCs (pDCs), DC1, and DC2/3 populations described by Park et al.,7 we found proliferating populations of pDCs and DC1. We also captured 7,093 epithelial cells, including cortical epithelial cells (cTECs), medullary epithelial cells (mTECs), activated mTECs, and mimetic TECs.
Importantly, we captured 7,721 mesenchymal cells, which contribute to negative selection and thymic involution.9,19,34,35,36 Subclustering identifies important mesenchymal cell types, including two populations of endothelial cells (ECs) defined by differential expression of Notch ligands (ECs, ECs (Notch)). Additionally, we identified lymphatic ECs (LECs), pericytes, vascular smooth muscle cells (VSMCs), and five distinct fibroblast cell types, including DPP4+ capsular fibroblasts (DPP4+ capFibs), capsule fibroblasts (capFibs), medullary fibroblasts (mFibs), KRT+ fibroblasts (KRT+ Fibs), and proliferating fibroblasts (Fibs (P)).
We imaged each tissue sample with a custom 48 antibody CODEX panel to study the architecture and function of niches guiding thymocyte development, aiming to define the niche characteristics guiding T-lineage branch points. Stage-specific thymocyte phenotyping markers (CD62L, CCR7, CD1A, CD5, CD7, CD4, CD8, CD3, CD45RO, CD45RA, FOXP3, and SATB1) identified CD3+ double positive cells (DPs) undergoing T-lineage commitment toward CD4 or CD8 T cells. Phenotyping markers for non-T-lineage hematopoietic cells (CD19, CD11c, CD11b, and CD68), epithelial cells (EPCAM and KRT5/8), mural cells (MCAM and SMA), ECs (CD31), and fibroblasts (PDGFRA) identified the remaining major cell types defining thymic niche architecture. Finally, we included functional markers to define patterns of antigen presentation (CD86), human leukocyte antigen (HLA) class I and II expression (HLA-ABC and HLA-DR,DP,DQ), adhesion ligands (ICAM and VCAM), Notch ligands (DLL1, DLL4, JAG1, and JAG2), T cell activation (PD-1), self-tolerance (PD-L1), proliferation (Ki67), and enzymatic regulation (15-PDGH). In sum, our CODEX panel enabled investigation of spatially regulated mechanisms directing human T cell development.
Using neural-network-driven cell segmentation and Leiden-based clustering,23 we identified individual cells within thymic tissue for each sample (Figure S1C). We annotated cell types based on tissue location and phenotypic expression compared with CITE-seq clusters (Figure 1C), performed proximity-based neighborhood clustering to identify niches,23 and annotated niches based on location and cell type composition (Figure 1D; Figure S1D). This analysis quantified proximity-based cell-cell interactions (Figure S1E) and served as a platform to interrogate spatially defined thymic niche biology via integrated sequencing-imaging analysis.
Because of known sex differences in thymus and T cell gene expression,31 we compared our age-matched male and female samples separately. In line with prior reports of sex-biased gene expression on autosomes,37,38,39,40 only 2% of male differentially expressed genes (DEGs) were found on the Y chromosome and 0.3% of female DEGs were found on the X chromosome (Tables S3 and S4). Gene set enrichment analysis (GSEA) on male vs. female cells for each cell type identified pathways commonly upregulated in either sex (Figure 1E; Data S1). Pathways differentially regulated across hematopoietic, epithelial, and stromal cells represent cell-intrinsic sex-based differences. Female cells have higher gene expression of transcription, energy regulation, and antigen presentation. Male cells, by contrast, have increased gene expression of proinflammatory signaling, amino acid metabolism, and G protein-coupled receptors (GPCR) signaling. The top differentially expressed energy regulation and metabolism pathways were similarly sex-biased in human kidney,41 suggesting multiple organs show consistent sex-biased enrichment of pathways linked to metabolism and energy production. Our data align with sex-biased trends identified in human induced pluripotent stem cell (iPSC) lines42 and other human organs,43 indicating these pathways often differ between male and female cells across various cell types.
By contrast, some pathways showed cell type-specific sex-biased enrichment. Female T and hematopoietic cells showed enrichment of interferon signaling, and female fibroblast and perivascular cells were enriched in extracellular matrix (ECM)-centric pathways (Figure 1E). Our dataset also identified differential sex-specific pathway enrichment between cell types. Gene expression indicated higher cytokine signaling in T cells and hematopoietic cells in females and in epithelial and mesenchymal cells in males (Figure 1E). These data show significant gene expression differences in male and female thymic cells. To demonstrate sex differences at the proteomic level, we identified genes with a log fold change greater than 1 that contributed to increased chemokine signaling in male T cells. CXCR4, an important chemokine receptor in thymocyte migration and development, had increased expression in male progenitor T (pro-T) cells, which we confirmed via flow cytometry (3 male, 3 female; p = 0.03; Figure S1F). As higher levels of cytokine and interferon signaling have been previously shown to influence thymus and T cell biology,44,45 our data suggest male and female T cells develop in different signaling environments and may respond differently to cytokine stimuli.
Next, we quantified cell type abundance within male and female tissues, demonstrating differences in cortical and medullary cell distributions between sexes. When normalized to the total number of cells per lobe, female thymus lobes contained significantly more DPs (p = 0.011) and cTECs (p = 0.0023). In males, we found significantly more SPs (p = 4.2 × 10−4), CD3+ DPs (p = 9.9 × 10−4), activated mTECs (p = 0.0014), and VSMCs (p = 2.4 × 10−6) (Figure 1F). Given that thymus lobules with more DPs and cTECs would have a greater proportion of cells undergoing positive selection and lobules with more medullary cells would have more cells undergoing negative selection, these data suggest that sex differences in cell type abundance may influence the resources directed toward specific stages of thymocyte selection. Alternatively, these results may suggest that male and female thymuses are developmentally asynchronous, with males exhibiting faster growth and involution kinetics, resulting in decreased cortical-to-medullary ratios even in early neonatal stages. We focused further analyses on sequential developmental niches, including analysis of sex differences in cell types and niches at each stage.
JAG1 skews ETP development toward thymic DCs
We first analyzed the cortico-medullary junction (CMJ) where cells home to the thymus (Figure 2A). This region recruits and supports ETPs10 and is composed of ECs, VSMCs, and pericytes expressing the Notch ligand JAG1 (Figures 2B and 2C). CITE-seq demonstrated that the cell adhesion molecule used by ETPs to enter the thymus, CD62L, is quickly downregulated upon CMJ entrance through the vasculature (Figure S2A). However, recently immigrated CD62L+ double negative cells are frequently located in the subcapsular zone (Figure S2B), suggesting that ETPs enter the thymus and rapidly migrate to a subcapsular niche where DLL4, a more potent Notch ligand, is highly expressed on fibroblasts and subcapsular epithelial cells (Figures 2D and S2C). However, the concentrated presence of JAG1 at the entry point indicates that ETPs are first exposed to this Notch ligand.
Figure 2 Thymic progenitors entering via the corticomedullary junction are exposed to a gradient of Notch ligands, which influence lineage specification
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CellChat46 pathway analysis showed that JAG1-NOTCH1 interactions between endothelial and perivascular cells are enriched with ETPs (Figure 2E), while JAG1-NOTCH2 and JAG1-NOTCH3 interactions are enriched with DC1, DC1 (P), DC2/3, and aDCs (Figures 2E–2G). These data suggest that JAG1 could induce commitment toward other hematopoietic lineages, such as pDCs, conventional DCs (cDCs), or macrophages, which are known to develop within the thymus.10 As JAG ligands induce weaker Notch induction,47,48,49,50 we hypothesized that early contact with ETPs could maintain T-lineage potential while cells migrate toward DLL4 in the subcapsular niche.
We first analyzed the ability of the four thymic Notch ligands to induce T-lineage commitment or alternative lineage development from cord-blood-derived CD34+ hematopoietic stem and progenitor cells (HSPCs) in a defined, feeder-free culture system44 (Figure 2H). We included titrated concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF), which is produced by mast cells at the CMJ, to support DC development.51 We found that only DLL1 and DLL4 ligands induce T-lineage commitment, whereas JAG ligands or no ligand controls supported myeloid cell development and did not induce T-lineage commitment (Figure S2D). Specifically, JAG ligands with GM-CSF skewed CD68+ DC development toward CD14− DC1 cells, while no ligand controls skewed CD68+ DC development toward CD14+ DC2/3 cells (Figures 2I and S2E).
Next, to test our hypothesis that Notch signals via JAG1 ligands could act as a bridge toward later DLL4 interactions, we analyzed cells grown on JAG1 for 3, 5, or 7 days prior to DLL4 transfer (Figure 2J). We found that cells cultured on JAG ligands or no ligands for 3 days maintained reduced T-lineage commitment compared with DLL1 or DLL4 cells (pJAG1 = 0.033; pJAG2 = 0.017), whereas cells cultured on JAG ligands for longer than 3 days lost T-lineage potential (Figure 2K), indicating that JAG ligands could not support T-lineage potential.
We next analyzed the contribution of different Notch ligands to the development of male and female ETPs (Figures S2F and S2G). Our data suggest that JAG ligand interactions are more abundant and diverse in females, with JAG1-NOTCH1 interactions enriched in female ETPs and DLL4 interactions enriched in male ETPs.
Together, these data suggest that timely migration from the CMJ to DLL4 ligands at the subcapsular zone is critical for T-lineage commitment, and exposure to JAG ligands at the CMJ can guide alternative lineage development toward thymic-derived DCs. Our data further demonstrate previously unrecognized sex-biased regulation by Notch ligands.
Analysis of the subcapsular zone identifies sex-based differences in fibroblast regulation of DP development and thymus growth
From the CMJ, ETPs migrate to the subcapsular zone via a CCL25-CCR9 chemokine gradient established by cTECs and directed to pro-T, DP (P), and DP2 (Q), but not DP1 (Q) cells (Figure 3A; Figure S3A). The subcapsular niche consists of JAG1+ VCAM1+ DCs, cTECs, capsular fibroblasts, DPP4+ capsular fibroblasts, and proliferating fibroblasts, which secrete and maintain spatially regulated ECM ligands to support sequential thymocyte development (Figures 3B and 3C; Figure S3B and S3C).
Figure 3 Fibroblasts in the subcapsular zone contribute to regulation of thymus biology and T cell progenitor development
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GSEA showed that DPP4+ capsule fibroblasts were enriched in HSP90 chaperone cycle for steroid hormone receptors (padjusted = 0.0065; 18/52 pathway genes significantly upregulated) (Data S1), suggesting an enhanced response to steroid hormones and supporting their role in sex hormone-based thymic involution.9 By contrast, capFibs were enriched for genes related to cytokine (interleukin [IL]-33, padjusted = 1.50 × 10−6; IL-34, padjusted = 3.56 × 10−7) and chemokine signaling (CCL2, padjusted = 5.10 × 10−40; CXCL3, padjusted = 0.020; CXCL12, padjusted = 1.78 × 10−8; CXCL14, padjusted = 3.63 × 10−15), functions previously attributed to TECs. Furthermore, CellChat identified cortical fibroblasts as major contributors to insulin growth factor (IGF) signaling through predicted signaling to cTECs, which are found in close proximity in the cortex (Figure S3D), via IGF2-IGF1R and IGF1-IGF1R axes, and to ETPs and β-selection cells, which were found under the capsule (Figure S2B), via an IGF2-IGF2R axis (Figures 3D–3F).
We next explored the role of proliferating fibroblasts. GSEA comparisons between capFibs and Fibs (P) showed marked differences in signal transduction pathways. CapFibs resembled traditional fibroblasts, which upregulate tyrosine kinase, angiogenesis, and ECM regulation and deposition pathways, whereas Fib (P) upregulates WNT signaling and cell sensing pathways, including genes involved in transient receptor potential (TRP) channels in the stimuli sensing channels pathway and taste receptors (TASRs) (Figure 3G; Data S1). Interestingly, CODEX images identified ECM− PDGFRa+ fibroblasts lacking extra domain A fibronectin (EDA-FN) expression, indicating that Fibs (P) are not involved in fibrotic matrix deposition unlike capFibs (Figure 3H; Figure S3B). Fibs (P) form a network of PDGFRa+ cells throughout the cortex that does not overlap with the cTEC network, yet maintain cell-cell contact in specific niches and often localize near cortical capillaries (Figure S3D).
We found sex-specific differences in vascular endothelial growth factor A (VEGFA) signaling within ECM− fibroblasts (Fib (P)) and other mesenchymal cells. Although all thymic fibroblasts produce the angiogenesis growth factor VEGFA, male fibroblasts express more than female cells (Fibs (P): padjusted = 0.0306; DPP4+ capFibs: padjusted = 0.0318; mFibs: padjusted = 1.85 × 10−6) (Figure 3I). Given that postnatal male thymuses are larger than female thymuses in humans and primates26 (Figure S3E), male fibroblasts may provide increased VEGFA to support angiogenesis and rapid thymic growth observed during postnatal development.52 Additionally, male mFibs have higher expression of FGF7 (padjusted = 0.0154), which regulates thymus size.53 CellChat predicts that male Fibs (P) are enriched in FGF10 compared with females, which supports cTEC proliferation and vascular growth,53,54 and only male VSMCs express FGF18 (Figures S3F–S3H). These sex biases in fibroblast growth factor (FGF) gene expression may contribute to the larger size of early postnatal male thymuses by stimulating epithelial and EC growth and proliferation.
Comparison of DEGs between male and female mesenchymal cells found increased expression of adipogenesis, cytokine, and GPCR signaling pathways in DPP4+ capFibs (Figure 3J). We also found increased expression of APOD, a gene associated with androgen, estrogen, progesterone, and glucocorticoid signaling,55,56 across male fibroblast populations (Fibs (P): padjusted = 2.18 × 10−26, mFibs: padjusted = 8.45 × 10−32) (Figure S3I). Given the association of hormone signaling with thymic involution,29,52,57 these findings suggest early initiation of thymic involution in postnatal males.
In sum, we identified three roles for fibroblasts within the subcapsular niche: maintaining tissue structure and organization via ECM and chemokine signaling, directly regulating cTEC maintenance and expansion, and potentially coordinating T cell development directly through growth factors and cell-cell interactions.
Human postnatal thymocytes may self-select in the cortex to support positive selection of conventional αβT cells
Upon exiting the subcapsular zone, DPs migrate into the inner cortex toward the medulla, where they receive positive selection signals that guide T-lineage branching toward CD4 or CD8 SP cells (Figure 4A). For DPs to transition toward the CD4 lineage, cells must receive T cell receptor (TCR) stimulation through HLA class II interactions, yet previous mouse studies have shown transcriptional downregulation of HLA class I and II in DPs.58,59 Low transcriptional expression is hypothesized to prevent thymocyte-thymocyte self-selection during positive selection, necessitating DP interactions with cTECs to receive positive selection signals.
Figure 4 HLA class I and II interactions may support thymocyte positive selection in the inner cortical zone
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Analogous to mouse literature, quiescent human DPs do not express HLA class II transcripts and have closed CIITA promoters (Figures 4B and 4C). Despite the lack of class II mRNA, thymocytes express low levels of HLA class II protein throughout development (Figure 4B). Additionally, in contrast to mouse data, we observe constitutive class I mRNA expression, which increased as cells transitioned toward SPs (Figure 4D). This is consistent with ATAC-seq data demonstrating that the B2M promoter is open throughout thymocyte development (Figure 4E). We confirmed HLA expression via flow cytometry and found that approximately 25% of DPs express both class I and II, and over 65% of DPs are class I+ (Figure S4A). Thus, thymocyte self-selection within the cortex could support positive selection. In support of this notion, CODEX enabled us to identify locations within the cortex devoid of epithelial, fibroblast, endothelial, or DCs but packed with DPs expressing class II+ molecules concentrated at cell junctions (Figure 4F). We confirmed the absence of spindle-like cTEC projections in this niche via confocal imaging (Figure 4G). Additionally, we quantified cell-cell interactions and identified a niche (positive selection niche 1) consisting of class II+ DPs and CD3+ DPs and a niche (self-selection niche) containing mainly class II+ DPs (Figure 1D). Finally, we sorted thymocytes to isolate immature DPs (CD4+CD8+CD3−TCR−) and mature DPs (CD4+CD8+CD3+TCR+) from three donors and cultured them for 7 days in a feeder-free assay. In the absence of epithelial cells, both immature and mature DPs upregulate HLA class II proteins (Figure 4H), and immature DPs continue to mature along their developmental pathway, as indicated by increased percentage of CD27+ DPs in culture after 7 days (Figure 4I).
Next, we identified a niche that directs T-lineage commitment toward CD4 or CD8SPs. We performed differential gene expression analysis on clusters representing this lineage branch point to identify markers for our CODEX panel (Figure S4B). We found SATB1 expression increased as DPs transitioned toward SPs (Figure S4C), and compared with CD8SP transition cells, CD4SP transition cells had higher expression of this master transcription factor60 (Figures S4D and S4E). Imaging analysis confirmed increased SATB1 expression coincides with CD3 upregulation, consistent with a role in late DP development and lineage branching (Figure 4J).7 Neighborhood analysis identified a niche enriched for mature CD3+ DPs in the inner cortex, suggesting that there either exists a niche specifically for late DP development and CD4 lineage transition or that cells are pre-disposed to CD4 lineage development through their TCR and migrate as clonal populations after proliferation at the outer cortex.
We compared cortical niche organization between sexes and found differences in niche organization supporting conventional T cell development, self-selection, and cross presentation. Females showed increased neighborhood interactions between the cortical DC niche containing JAG1+ VCAM+ DCs and the mature DP niche containing CD3+ DPs, the positive selection niche 1 containing class II+ DP cells and CD3+ DP cells, and the positive selection niche 3 containing DCs and DPs (Figure S4F) as well as increased cell-cell interactions between cTECs and class II+ DPs (Figures S4G and S4H). Conversely, males had increased cell-cell interactions between cTECs and CD3+ DPs (Figures S4G and S4H). These data suggest that the proportionally larger female cortex could increase cross presentation from DCs and cTECs to class II+ DPs, possibly facilitating greater use of self-selection as an alternative mechanism for positive selection.
Taken together, spatial multiomic analysis of the inner cortex identified cortical niches supporting specific stages of DP development, including three positive selection niches, a specialized niche for self-selection, and a mature DP niche thymocytes migrate through prior to entering the medulla.
Spatial multiomics identifies key mechanisms regulating negative selection niches in the medulla
Mature DPs enter the medulla, an environment specialized for negative selection, and transition toward CD4 or CD8 lineages (Figure 5A). Within the medulla, cells specialized for negative selection localize around keratinized structures called Hassall’s corpuscles (HCs).61 HCs appear during late prenatal development and are abundant in human postnatal thymuses but rare in mice.62 Here, we demonstrate that HCs can be divided into three major components: an external epithelial border of highly keratinized cells, an inner border of cells expressing prostaglandin-degrading enzyme 15-PGDH (HPGD), and a central PDGFRa+ mass (Figure 5B). HCs produce thymic stromal lymphopoietin (TSLP),61 an analog of IL-7, which activates DCs to increase expression of class II and co-stimulatory molecules CD80 and CD86. Importantly, subclustering stromal populations identified a population of KRT+ fibroblasts resembling cells undergoing epithelial-to-mesenchymal transition (EMT)63 (Figures S5A and S5B). CITE-seq identified TSLP and 15-PGDH mRNA expression in KRT+ Fibs, mFibs, mTECs, activated mTECs, and aDCs (Figure 5C), implicating these cell types as potential contributors to the function of HCs. Finally, given the inner layer of 15-PGDH+ cells, we explored the role of prostaglandin signaling regulation within the medulla. We found that DC1 cells express high levels of PGE2, whereas DC2/3 cells and monocytes express the PTGER2 and PTGER4 receptors, and aDCs express the PTGER3 receptor (Figure 5C), suggesting prostaglandin signaling is a major regulator of DC activity near HCs.
Figure 5 HCs represent scalable organizing centers for negative selection in the neonatal thymic medulla
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CODEX imaging suggests HCs act as sub-medullary organizational centers to segregate the inner medulla into specialized niches for negative selection. CD86+ APCs, a subset of which express the co-stimulatory ligand CD40, localize near HCs and in direct contact with CD45RA+ mature SPs (Figure 5D; Figure S5C). In addition, approximately 30% of medullary area is composed of CD19+ B cells,64 which cluster into niches surrounding HCs (Figure S5D). These B cells are found in close contact with—and are often enveloped within—mTECs, potentially facilitating cross presentation with epithelial cells (Figure 5E). These results suggest thymic B cells may comprise an important source of antigen presentation for negative selection.64,65 We quantified medullary neighborhoods and identified six niches, including an mTEC maturation niche, a cross-presentation niche, and four niches specialized for negative selection, which vary in relative location to HCs or the CMJ, as well as their composition of APCs, epithelial, and T cells (Figure 1D; Figure S1D).
Negative selection niches surrounding HCs play a key role in conventional T cell and tTreg development.61 We enriched CD25+ cells for sequencing and found a population of CD25hi pro-Tregs expressing canonical Treg markers CTLA-4, TNFRSF1B (TNFR2), and TNFRSF4 (OX40); positive/negative selection markers (ITM2A, RANBP1, NCL, NME1, MIF, and ATP5G1); Treg developmental long non-coding RNA (MIR155HG)66,67,68,69; and other markers described in mice (Figure S5E). Whereas pro-Tregs expressed high levels of pro-apoptotic gene BCL2L11, mature tTreg subsets expressed the anti-apoptotic gene BCL2. Gene network reconstruction via SCENIC70 identified transcription factor networks activated during pro-Treg to tTreg transition (Figure 5F).
The thymus also contains mature, highly activated Tregs, labeled as rrTregs, believed to have recirculated from the periphery.71,72 rrTregs lack expression of CCR7 or thymic egress markers (KLF2 and S1PR1) but express IL1R2 (Figure S5F), which sequesters the inflammatory cytokine IL-1β to reduce local concentrations.73 CODEX imaging identified tTregs and rrTregs dispersed throughout the medulla, with rrTregs primarily adjacent to CD68+ DCs (Figure 5G). CellChat supported the potential of rrTregs to sequester inflammatory cytokines through interactions with DC2/3 via an IL-1β-IL-1R2 axis (Figure S5G). rrTregs also exhibited a tissue resident Treg phenotype (BATFhigh CCR8+) associated with wound healing and tissue regeneration function,74 and expressed remodeling and tissue repair-related genes such as matrix metalloproteinase enzymes (MMP25 and ADAM19) (Figure S5H). Overall, these findings illustrate Treg diversity in the thymus with their developmental trajectories and functions yet to be elucidated.
Comparisons of male and female rrTregs showed that male rrTregs had higher expression of IL-4 and IL-13, heat shock factor protein 1 (HSF1), and IL-1 signaling pathways (Figure 5H), suggesting rrTreg-mediated regulation of IL-1R2-mediated anti-inflammatory feedback checkpoints is a more prominent mechanism in male tTreg development in early postnatal thymus. Notably, male-activated mTECs have higher expression of CD40 and tumor necrosis factor (TNF) inflammatory pathways than females, possibly resulting in higher rrTreg activity (Figure S5I).
Finally, as Tregs have been shown in mouse to contribute to thymic involution through JAG1,75 we explored sex-based differences in tTreg gene expression. GSEA showed male rrTregs and tTregs have higher expression of adipogenesis pathways (Figures 5H and 5I). Given the presence of cells undergoing EMT, our data underlie the aggressive timeline of thymic involution and suggest that sex-based differences in thymus functional decline begin early in life.
Our detailed examination of the medulla identifies several niches specialized for negative selection, cross presentation, and mTEC maturation around HCs and demonstrates sex biases in inflammatory pathways and thymic involution kinetics within these niches.
Discussion
We performed spatial multiomics to construct a tissue atlas of niches guiding T cell development in early human postnatal thymus. These datasets characterize how key developmental niches drive lineage branch decisions, identify a possible mechanism for conventional αβT cell development through self-selection, and suggest additional functions for mesenchymal cell types governing thymus biology. Furthermore, we discovered several sex-specific differences in thymus cell and niche biology. As T cell development is a dynamic migratory process, knowledge of cell position in combination with proteomic, transcriptomic, and epigenomic sequencing data provides an invaluable resource to predict niche-specific signaling cues directing T cell development, and mechanisms responsible for maintaining tissue structure and directing thymic involution.
We describe an approach to sequencing analysis using multidimensional imaging to establish benchmarks for the location, ligand expression, and composition of key niches in T cell development. This enables us to analyze cell-cell interactions guided by niche composition, identifying physiologically relevant ligand-receptor interactions based on cell proximity within the tissue. Ultimately, this approach maps epigenomic, transcriptomic, and proteomic data to distinct tissue niches at single-cell resolution. Furthermore, we included equal numbers of male and female age-matched thymus samples, enabling comparison between sexes across platform modalities. Our analysis of sex-matched human early postnatal thymus demonstrates the highly plastic nature of thymus lobule organization and resource dedication. Each niche responds to sex-biased developmental kinetics, supporting robust T cell development to ultimately produce functional immune systems in different manners (Figure 6). The findings herein describe only a subset of the data, and we encourage the community to capitalize on this resource to provide further insight into sex differences and targeted niche-specific inquiries.
Figure 6 The human early postnatal thymus lobule is spatially organized into sex-biased niches to support stage-specific T cell development
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In our analysis of Notch ligands, we complemented our in silico approach with in vitro analysis. Our analysis suggests that JAG1 at the CMJ cannot support T-lineage commitment as cells migrate toward the subcapsular zone but instead skew alternative lineage development toward a CD14− DC1 subset (Figure 6). CD14 expression on DCs is linked with increased inflammatory cytokine production,76 suggesting that JAG ligands promote non-inflammatory DC phenotypes. These results highlight the importance of precise Notch signaling strength and timing in the thymus and emphasize the need for strict spatial control of different Notch ligands within thymic niches. Our observation of high JAG1 expression in the medulla and decreased DLL4 expression on cTECs outside the subcapsular zone aligns with previous studies on human postnatal thymus.77
In the subcapsular zone, we characterize the important roles of specialized fibroblasts. DPP4+ capFibs, described in mouse as cells with progenitor and anti-fibrotic potential,78,79,80,81,82 are observed as a fibroblast subset responsive to changes in systemic hormone levels. Since thymic function and involution are regulated by sex hormone levels,57,83,84,85 DPP4+ capFibs likely control these processes and are potential targets for addressing age-related thymic involution.86 Previously, only medullary fibroblasts were linked to thymocyte development and selection in the medulla.82 We demonstrate that capFibs may directly support thymocyte development in the cortex by producing growth factors like IGF2 (Figure 6). Blocking IGF2 signaling arrests thymocytes at the double negative stage,87 and our data identify capFibs as the IGF2 source, suggesting capFibs as an additional cell source of cytokines and growth factors for in vitro developmental systems. Finally, we demonstrate that ECM profiles of thymic fibroblasts are tightly regulated based on spatial localization. Future work should characterize how tissue stiffness changes as thymocytes migrate through developmental thymic niches to improve biomaterial strategies for in vitro T cell development.88
Furthermore, we identify a population of ECM− cortical fibroblasts that are enriched in cell sensing pathways, such as TASRs and TRP channels. Interestingly, TASRs regulate cell responses to local soluble substances, such as glucose, modulating release of hormones and other signaling molecules.89 Similarly, TRP channels play roles in cell sensing, such as pheromone signaling, nociception, temperature sensation, and osmoregulation.90 Given the proximity of these cells to vasculature in the cortex, Fibs (P) may play a critical role as regulatory cells by sensing environmental changes and modulating thymus size (Figure 6). Their lack of ECM production and network-like structure resemble fibroblast reticular cells (FRCs) in the lymph node, which rapidly proliferate and remodel the cortex during infection.91 Our data are generated from early postnatal thymus samples, an age with active T cell development, suggesting these fibroblasts expand the thymic cortex similarly to FRCs during infection, signaling through FGF and IGF to stromal and epithelial cells to orchestrate remodeling.
While the dogma in thymocyte positive selection suggests that DPs downregulate class II RNA to prevent self-selection and force interactions with cTECs,58,59 several studies suggest that T-lineage cells can select off each other to support CD4 T cell development.20,92,93,94 Here, we describe an inner cortical niche where class II+ DPs reside that may support positive selection via DP-DP self-selection (Figure 6). We show that immature DPs cultured without epithelial cells upregulate HLA class II and continue to mature and receive positive selection signals. Additionally, upregulated SATB1 expression identifies mature DPs in an inner cortical niche and the CD4 branch of their progeny, suggesting it may determine early lineage specificity. Future work should investigate critical features of this niche and SATB1’s role in thymocyte development.
Within the medulla, we identified a niche adjacent to HCs specialized for negative selection and highlighted the role of rrTregs in modulating the medullary inflammatory environment (Figure 6). The abundance of HCs in human but not mouse, and their proximity to negative selection niches, suggests these structures evolved to provide niche-level organization within the larger human medulla or to regulate negative selection more stringently in longer-lived species.
Comparing male and female tissue showed sex differences in both T cell and thymus biology. Studies on post-pubertal males and females show that sex hormones differentially regulate thymic involution between sexes,26,27,28,29,30,52,57,84,86 and that androgen blockers increase FOXN1 expression, thymic involution, and increased rejuvenation.29,30,52,84,86 Additionally, older males produce fewer recent thymic emigrants and have smaller thymuses compared with females.26,28 Some studies describe decreased numbers of AIRE+ mTECs with age and in females,95 potentially predisposing females who maintain greater thymic function later in life to autoimmune disease.29 These studies also observe less interlobular fat in young female thymus,26 suggesting differences in thymic involution kinetics begin pre-puberty. However, current literature has not addressed transcript-level sex differences underlying functional differences in thymic and immune function. Our analysis uncovers that female thymic cells upregulate energy regulation, transcription, and antigen-presentation pathways, whereas male cells increase proinflammatory signaling, amino acid metabolism, and GPCR signaling. These cell metabolic differences align with transcript-level sex differences in other organs41,42,43 and highlight the need for sex-based cell culture optimization in in vitro T cell culture systems.
In addition to changes common to other organs,40,41 we identify thymus-specific differences affecting key processes in thymocyte development and training. Females have a larger proportion of cortical cells per lobule, aligning with lower thymic involution rates and a larger cortex/medulla ratio.26,27,52 ETPs have enriched interactions with JAG1 as they migrate away from the CMJ, suggesting increased JAG1 interactions could skew ETP lineage commitment toward less inflammatory DC phenotypes (Figure 6). In the female cortex, we observe increased cTEC and class II+ DP interactions and increased interactions between cortical DC and positive selection niches, suggesting thymocyte self-selection may play a larger role during positive selection (Figure 6). Conversely, the female medulla shows decreased inflammatory pathway activation and fewer medullary cells. These data suggest females prioritize generating a larger repertoire of DPs over deleting autoreactive cells through negative selection, potentially contributing to sex differences in autoimmune disease prevalence in females.96
In males, we observe enriched DLL4 interactions with ETPs, which aligns with previous data demonstrating that androgen levels positively correlate with DLL4 on cTECs.29 The male cortex shows increased interactions with mature CD3+ DPs and cTECs, suggesting male thymocytes may have lower proliferation rates post β-selection, allowing sufficient space for positive selection. In the medulla, male-activated mTECs exhibit increased inflammatory pathway markers, and male Tregs exhibit higher inflammatory modulation and activate thymic involution pathways.75 Upregulation of inflammatory modulation by male rrTregs may regulate the higher proinflammatory signaling in male cells (Figure 6). Interestingly, post-pubertal males have more Tregs and fewer CD4 T cells than females, possibly due to a more inflammatory medullary environment skewing CD4 development toward the Treg lineage.31
We further explore sex differences in thymus size control mechanisms. Among fibroblast populations, we find significant differences in expression of growth and angiogenesis factors, such as VEGFA and FGFs, potentially contributing to the size difference in male and female thymuses at this age (Figure 6). These data align with and extend known sex differences in growth factor expression, including sex-biased expression of growth hormone and IGF-1 in regulating size of different tissues.97,98 Importantly, these results indicate sex-specific differences in early thymus structure maintenance and growth, which could skew T cell development. We also establish an early transition toward an adipogenic environment in males. These observations align with findings in model organisms, where young male rats exhibit higher rates of thymic involution52 and early postnatal male primates have a larger interlobular fat area.26 Together, these factors define two possible mechanisms contributing to a male-female difference in thymus size and involution kinetics.
Future studies should test how sex differences at the transcript, niche, and organ level impact differential T cell production and quality as well as explore how sex differences in other organs contribute to known differences in immune responses. Defined in vitro and organoid culture systems replicating the thymic microenvironment present powerful platforms to test if the cell type-specific and sex-specific differences identified here lead to increased autoimmune disease incidence among females and increased infection susceptibility in males. Furthermore, given the surprising sex-based differences at this early postnatal stage, future work should examine aged thymus to investigate how cellular level differences in thymic involution kinetics may translate to larger impacts on our immune system later in life.
Limitations of the study
Our analysis of intra-sex variation is limited by access to patient samples as well as the inability to conduct mechanistic experiments in the context of a whole organism. There is an opportunity for future work to further validate and expand on predicted ligand-receptor interactions.
The thymic epithelium is responsible for the secretion of thymic peptides, which intervene in some steps of intra- and extrathymic T cell differentiation. Recent data suggest that thymic hormone secretion is modulated by the neuroendocrine network, comprising thyroid, adrenals, and gonads. However, the role of the pituitary gland in this regulation is still poorly understood. In the present paper we studied the in vivo and in vitro influences of PRL on the secretion of thymulin, one of the chemically defined thymic hormones, by thymic epithelial cells (TEC). When injected daily (20-100 micrograms/20 g) in young or old C57BL/6 mice, PRL induced a specific increase in thymulin synthesis and secretion, respectively, measured by the number of thymulin-producing cells in the thymus and the peripheral levels of the hormone. This stimulation was dose dependent and reversible after the end of treatment. Similar findings have been made in animals with pituitary dwarfism, known to have low levels of circulating thymulin. This stimulatory effect was also observed in primary cultures of human and mouse TEC when PRL (10(-7) to 10(-8) M) was applied to culture supernatants, thus suggesting that PRL could act directly on TEC. In addition, we induced in vivo experimental hypoprolactinemia, treating mice with bromocriptine, a dopamine receptor agonist that inhibits pituitary PRL secretion. Bromocriptine treatment (100-200 micrograms/20 g) yielded a significant decrease in thymulin secretion that could be reversed by coincident treatment with PRL. In the light of previous observations that bovine GH can also increase thymulin production in aged dogs, we performed a series of experiments in vitro to evaluate whether GH has a direct effect on TEC. We observed that only human GH preparations that are known to have a PRL-like effect were efficient in stimulating thymulin biosynthesis and release into the culture supernatants. The effects of PRL on TEC were not restricted to thymic hormone production. We observed that TEC proliferation, as well as the numbers of a TEC subset defined by the expression of cytokeratins 3 and 10, could also be increased by PRL treatment. All these findings show that the pituitary gland directly affects TEC in terms of cytoskeletal and secretory protein expression as well as cell cycle.. This paper reviews the mechanism of sex hormone actions on the thymus, presenting mainly our data obtained at the cellular and molecular levels. First, data supporting the "genomic" action via the nuclear sex hormone receptor complexes are as follows: 1) sex hormone receptors and the thymic factor (thymulin) are co-localized in thymic epithelial cells, but not in T cells; 2) production/expression of thymic factors (thymulin, thymosin alpha 1) are remarkably inhibited by sex hormone treatment; 3) sex hormones cause changes in T cell subpopulations in the thymus; and 4) sex hormones strongly influence the development of thymus tumors in spontaneous thymoma BUF/Mna rats through their receptor within the tumor cells. Secondly, data indicating the "non-genomic" action of sex hormones via a membrane signal-generating mechanism are as follows: 1) the proliferation/maturation of thymic epithelial cells is mediated through protein kinase C activity introduced by sex hormones; 2) sex hormones directly influence DNA synthesis and cdc2 kinase (cell cycle-promoting factor) activity..
pubmed.ncbi.nlm.nih.gov/2737149/
www.cell.com/developmental-cell/fulltext/S1534-5807(24)00539-2
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Golobulus: Your appearance has changed, but it is impossible not to recognize the Time Lord within.
The Doctor and Golobulus approach each other. The Emperor of Cobra-La stretches his snake-body to rise above the Time Lord in an act of intimidation.
Doctor: 'And I see you're looking well Golobby old boy!'
Golobulus: 'You might want to cast aside the pleasantries, Time Lord. You are far from welcome here.'
The Emperor of Cobra La menaces the Doctor.
Doctor: 'Then you may choose to dispense with the psychological tactics, Golobulus. You know that never works on me.'
Golobulus: 'So what brings you to my Valley, Doctor?'
The Doctor looks straight into the grotesque eyes of the Emperor of Cobra La.
Doctor: 'I need your help.'
Golobulus's expression does not change. The Doctor continues.
Doctor: "The Decepticons and Cobra are tampering with time-travel technology. In fact, a Cobra-made Decepticon named Meantime already has time-control capabilities...'
Golobulus interrupts.
Golobulus: 'I am aware, Doctor. I am aware of everything.'
Doctor: 'So you keep insisting. Tell me then, you must be aware of the full scope of damage potential this act could have, not just on the local area, but the entire planet!'
Golobulus considers for a heartbeat.
Golobulus: 'The future is always in motion.'
The Doctor waves off Golobulus' comment, immediately deeming it useless.
Doctor: 'Don't give me that nonsense, Golobulus. You're smarter than that. Just because the future is in motion doesn't mean that a clear trail of events can not lead to a overtly predictable conclusion! One plus one will always equal two. no matter how far after the fact you add the pair together! The repairs to the Time Vortex from the damage caused by The Time Disturbance are too vulnerable. The wounds to the walls of time and space are not yet fully healed. Any time travel or time-tampering of any sort by unskilled hands could lead to the wounds opening again! Only this time, the all time-parallels will converge and implode! The very nature of existence will disappear! There will be nothing but the Void!'
Golobulus closes his eyes.
Golobulus: 'What do you need from me?'
Doctor: 'I need a seismic crystal.'
Golobulus: 'What?'
The Doctor looks over his shoulder to his companions, waving Golobulus quiet. The others did not seem to hear the latter's outburst.
Doctor: 'I need a seismic crystal.'
Golobulus: 'Are you aware of what you're asking, Doctor?'
Doctor: 'I am perfectly aware and believe me, if I had any other choice I would take it. I don't have the luxury of choice. I need a crystal.'
Golobulus: 'For what purpose? seismic crystals are not easy to manipulate. They are even less easy to control.'
Doctor: 'They can be controlled, Golobulus. They can be manipulated and controlled with tremendous accuracy.'
Golobulus: 'Not by human hands.'
Doctor: 'Not by hands at all. They can be controlled with precise harmonic frequency modulation.'
Golobulus: 'That is absurd!'
Doctor: 'It's the truth, Golobulus. I need a seismic crystal and I need it now. You can surrender one to me and play a part in saving every single universe, or you an make a significant and insane contribution to the end of all things. Make your choice.'
Golobulus glares in silence, mistaking the Doctor's pause for the end of his argument. The Doctor's eyes then turn stone cold.
Doctor: 'Either way, I will acquire a seismic crystal. Choose to be an ally, Emperor. Don't make the mistake of becoming my enemy.'