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Lymphoid follicles (LFs) are responsible for generation of adaptive immune responses in secondary lymphoid organs and form ectopically during chronic inflammation. A human model of ectopic LF formation will provide a tool to understand LF development and an alternative to non‐human primates for preclinical evaluation of vaccines. Here, it is shown that primary human blood B‐ and T‐lymphocytes autonomously assemble into ectopic LFs when cultured in a 3D extracellular matrix gel within one channel of a two‐channel organ‐on‐a‐chip microfluidic device. Superfusion via a parallel channel separated by a microporous membrane is required for LF formation and prevents lymphocyte autoactivation. These germinal center‐like LFs contain B cells expressing Activation‐Induced Cytidine Deaminase and exhibit plasma cell differentiation upon activation. To explore their utility for seasonal vaccine testing, autologous monocyte‐derived dendritic cells are integrated into LF Chips. The human LF chips demonstrate improved antibody responses to split virion influenza vaccination compared to 2D cultures, which are enhanced by a squalene‐in‐water emulsion adjuvant, and this is accompanied by increases in LF size and number. When inoculated with commercial influenza vaccine, plasma cell formation and production of anti‐hemagglutinin IgG are observed, as well as secretion of cytokines similar to vaccinated humans over clinically relevant timescales. Primary human lymphocytes taken from blood are reprogrammed into lymphoid follicles (LF) by superfusion in an organ chip device. These ectopic LFs express AID and can be induced to form plasma cells and antigen‐specific antibodies upon activation with different stimuli including adjuvants and seasonal influenza vaccines.

Organ‐on‐a‐Chip A microfluidic organ‐on‐a‐chip model of the human lymphoid follicle that recapitulates vaccination responses in vitro. Blood‐derived cells self assemble into germinal centers in a matrix gel in the lower channel when nutrient medium is flowed through the upper channel. Antigen‐specific antibodies and cytokines are secreted in response to seasonal influenza vaccination that mirror responses observed in patients. More details can be found in article number 2103241 by Donald E. Ingber and co‐workers.

SARS-CoV-2 infection and COVID-19 disease vary with respect to viral variant and host vaccination status. However, how vaccines, emergent variants, and their intersection shift host responses in the human nasal mucosa remains uncharacterized. We and others have shown during the first SARS-CoV-2 wave that a muted nasal epithelial interferon response at the site of infection underlies severe COVID-19. We sought to further understand how upper airway cell subsets and states associate with COVID-19 phenotypes across viral variants and vaccination. Here, we integrated new single-cell RNA-sequencing (scRNA-seq) data from nasopharyngeal swabs collected from 67 adult participants during the Delta and Omicron waves with data of 45 participants collected during the original (Ancestral) wave from our prior study. By characterizing detailed cellular states during infection, we identified changes in epithelial and immune cells that are both unique and shared across variants and vaccination status. By defining SARS-CoV-2 RNA+ cells for each variant, we found that Delta samples had a marked increase in abundance of viral RNA+ cells. Despite this dramatic increase in viral RNA+ cells, the nasal cellular landscapes of Delta and Omicron exhibit greater similarity, driven partly by myeloid subsets, than the Ancestral landscapes associated with specialized epithelial subsets. We found that vaccination was surprisingly associated with nasal macrophage recruitment and activation rather than adaptive immune cell signatures. While patients with severe disease caused by Ancestral or Delta variants had muted interferon responses, Omicron-infected patients had equivalent interferon responses regardless of disease severity. Our study defines the evolution of cellular targets and signatures of disease severity in the upper respiratory tract across SARS-CoV-2 variants, and suggests that intramuscular vaccines shape myeloid responses in the nasal mucosa upon SARS-CoV-2 infection.

Abstract The ability to monitor anti-tumor CD8+ T cell responses in the blood has tremendous therapeutic potential. Here, we used paired single-cell RNA sequencing and T cell receptor (TCR) sequencing to detect and characterize “tumor matching” (TM) CD8+ T cells in the blood of mice with MC38 tumors and melanoma patients using the TCR as a molecular barcode. TM cells showed increased activation compared to non-matching T cells in blood, and appeared less exhausted than matching counterparts in tumor. Importantly, PD-1, which has been used to identify putative circulating anti-tumor CD8+ T cells, showed poor sensitivity for identifying TM cells. By leveraging the transcriptome we identified candidate cell surface marker panels for TM cells in mice and melanoma patients, and validated NKG2D, CD39, and CX3CR1 in mice. These data demonstrate that the TCR can be used to identify tumor-relevant populations for comprehensive characterization, reveal unique transcriptional properties of TM cells, and develop marker panels for tracking and analysis of these cells. Summary Using single-cell RNA-sequencing coupled with TCR sequencing, we detected CD8+ T cell clones shared between blood and tumor in mice and melanoma patients, characterized these matching clones in blood and tumor, and identified potential biomarkers for their isolation in blood. Competing Interest Statement The authors declare the enclosed potential conflicts of interest. M.D.R. is a founder of TRex Bio and Sitryx Bio and receives research funding from Abbvie, LEO Pharma, and TRex bio. A.I.D. has funds from Merck, Oncosec, BMS, Roche, Genentech, Pfizer, Incyte, Novartis and Checkmate, is on advisory boards for Xencor, Pfizer, Array, has stock in TRex, SQZ bio., and patents with Oncosec on Gene Therapy of melanoma. A.H.S. has patents on the PD-1 pathway licensed by Roche/Genentech and Novartis, consults for Novartis, is on the scientific advisory boards for Surface Oncology, Sqz Biotech, Elstar Therapeutics, Elpiscience, Selecta and Monopteros, and has research funding from Merck, Novartis, Roche, and Quark Ventures. K.K.T discloses institutional research funding from Array/Pfizer, BMS, Oncosec, Regeneron, and Replimune. From August 4th 2020, MS is an employee of Guardant Health. The authors have no additional financial conflicts of interest to disclose. Footnotes * ↵+ co-first authors

SARS-CoV-2 infection and COVID-19 disease vary with respect to viral variant and host vaccination status. However, how vaccines, emergent variants, and their intersection shift host responses in the human nasal mucosa remains uncharacterized. We and others have shown during the first SARS-CoV-2 wave that a muted nasal epithelial interferon response at the site of infection underlies severe COVID-19. We sought to further understand how upper airway cell subsets and states associate with COVID-19 phenotypes across viral variants and vaccination. Here, we integrated new single-cell RNA-sequencing (scRNA-seq) data from nasopharyngeal swabs collected from 67 adult participants during the Delta and Omicron waves with data from 45 participants collected during the original (Ancestral) wave in our prior study. By characterizing detailed cellular states during infection, we identified changes in epithelial and immune cells that are both unique and shared across variants and vaccination status. By defining SARS-CoV-2 RNA+ cells for each variant, we found that Delta samples had a marked increase in the abundance of viral RNA+ cells. Despite this dramatic increase in viral RNA+ cells in Delta cases, the nasal cellular compositions of Delta and Omicron exhibit greater similarity, driven partly by myeloid subsets, than the Ancestral landscapes associated with specialized epithelial subsets. We found that vaccination prior to infection was surprisingly associated with nasal macrophage recruitment and activation rather than adaptive immune cell signatures. While patients with severe disease caused by Ancestral or Delta variants had muted interferon responses, Omicron-infected patients had equivalent interferon responses regardless of disease severity. Our study defines the evolution of cellular targets and signatures of disease severity in the upper respiratory tract across SARS-CoV-2 variants, and suggests that intramuscular vaccines shape myeloid responses in the nasal mucosa upon SARS-CoV-2 infection.

JWST has revealed a population of compact and extremely red galaxies at z ≳ 4, which likely host active galactic nuclei (AGNs). We present a sample of 434 “little red dots” (LRDs), selected from the 0.54 deg2 COSMOS-Web survey. We fit galaxy and AGN spectral energy distribution models to derive redshifts and physical properties; the sample spans z ∼ 5–9 after removing brown dwarf contaminants. As a thought experiment, we consider two extreme physical scenarios: either LRDs are all AGNs, and their continuum emission is dominated by the accretion disk, or they are all compact star-forming galaxies, and their continuum is dominated by stars. If LRDs are AGN-dominated, our sample exhibits bolometric luminosities ∼1045−47 erg s−1, spanning the gap between JWST AGNs in the literature and bright, rare quasars. We derive a bolometric luminosity function (LF) ∼ 100 times the (UV-selected) quasar LF, implying a nonevolving black hole accretion density of ∼10−4M⊙ yr−1 Mpc−3 from z ∼ 2–9. By contrast, if LRDs are dominated by star formation, we derive stellar masses ∼108.5−10 M⊙. MIRI/F770W is key to deriving accurate stellar masses; without it, we derive a mass function inconsistent with Λ cold dark matter. The median stellar mass profile is broadly consistent with the maximal surface densities seen in the nearby Universe, though the most massive objects exceed this limit, requiring substantial AGN contribution to the continuum. Nevertheless, stacking all available X-ray, mid-IR, far-IR/submillimeter, and radio data yields nondetections. Whether dominated by dusty AGNs or compact star-formation, the high masses/luminosities and remarkable abundance of LRDs implies a dominant mode of early galaxy/SMBH growth.

Background Providing sterile drug smoking materials to people who use drugs can prevent the acquisition of infectious diseases and reduce overdose risk. However, there is a lack of understanding of how these practices are being implemented and received by people who use drugs globally. Methods A systematic review of safer smoking practices was conducted by searching PubMed, PsycInfo, Embase for relevant peer-reviewed, English-language publications from inception or the availability of online manuscripts through December 2022. Results Overall, 32 peer-reviewed papers from six countries were included. 30 studies exclusively included people who use drugs as participants ( n  = 11 people who use drugs; generally, n  = 17 people who smoke drugs, n  = 2 people who inject drugs). One study included program staff serving people who use drugs, and one study included staff and people who use drugs. Sharing smoking equipment (e.g., pipes) was reported in 25 studies. People who use drugs in several studies reported that pipe sharing occurred for multiple reasons, including wanting to accumulate crack resin and protect themselves from social harms, such as police harassment. Across studies, smoking drugs, as opposed to injecting drugs, were described as a crucial method to reduce the risk of overdose, disease acquisition, and societal harms such as police violence. Ten studies found that when people who use drugs were provided with safer smoking materials, they engaged in fewer risky drug use behaviors (e.g., pipe sharing, using broken pipes) and showed improved health outcomes. However, participants across 11 studies reported barriers to accessing safer smoking services. Solutions to overcoming safer smoking access barriers were described in 17 studies and included utilizing peer workers and providing safer smoking materials to those who asked. Conclusion This global review found that safer smoking practices are essential forms of harm reduction. International policies must be amended to help increase access to these essential tools. Additional research is also needed to evaluate the efficacy of and access to safer smoking services, particularly in the U.S. and other similar countries, where such practices are being implemented but have not been empirically studied in the literature.

A complete census of dusty star-forming galaxies (DSFGs) at early epochs is necessary to constrain the obscured contribution to the cosmic star formation rate density (CSFRD); however, DSFGs beyond z ∼ 4 are both rare and hard to identify from photometric data alone due to degeneracies in submillimeter photometry with redshift. Here, we present a pilot study obtaining follow-up Atacama Large Millimeter Array (ALMA) 2 mm observations of a complete sample of 39 850 μm-bright dusty galaxies in the SSA22 field. Empirical modeling suggests 2 mm imaging of existing samples of DSFGs selected at 850 μm—1 mm can quickly and easily isolate the “needle in a haystack” DSFGs that sit at z > 4 or beyond. Combining archival submillimeter imaging with our measured ALMA 2 mm photometry (1σ ∼ 0.08 mJy beam−1 rms), we characterize the galaxies’ IR spectral energy distributions (SEDs) and use them to constrain redshifts. With available redshift constraints fit via the combination of six submillimeter bands, we identify 6/39 high-z candidates each with >50% likelihood to sit at z > 4, and find a positive correlation between redshift and 2 mm flux density. Specifically, our models suggest the addition of 2 mm to a moderately constrained IR SED will improve the accuracy of a millimeter-derived redshift from Δz/(1 + z) = 0.3 to Δz/(1 + z) = 0.2. Our IR SED characterizations provide evidence for relatively high-emissivity spectral indices (〈β〉 = 2.4 ± 0.3) in the sample. We measure that especially bright (S 850μ m > 5.55 mJy) DSFGs contribute ∼10% to the cosmic-averaged CSFRD from 2 < z < 5, confirming findings from previous work with similar samples.

JWST has enabled detecting and spatially resolving the heavily dust-attenuated stellar populations of submillimeter galaxies, revealing detail that was previously inaccessible. In this work, we construct a sample of 289 submillimeter galaxies with joint Atacama Large Millimeter/submillimeter Array (ALMA) and JWST constraints in the COSMOS field. Sources are originally selected using the SCUBA-2 instrument and have archival ALMA observations from various programs. Their JWST NIRCam imaging is from COSMOS-Web and PRIMER. We extract multiwavelength photometry in a manner that leverages the unprecedented near-infrared (NIR) spatial resolution of JWST, and we fit the data with spectral energy distribution models to derive photometric redshifts, stellar masses, star formation rates, and optical attenuation. The sample has an average 〈z〉=2.6−0.8+1.0 , 〈AV〉=2.5−1.0+1.5 , 〈SFR〉=300−200+400M⊙yr−1 , and 〈log(M*/M⊙)〉=11.1−0.5+0.3 . There are 81 (30%) galaxies that have no previous optical/NIR detections, including 75% of the z > 4 subsample (n = 28). The faintest observed NIR sources have the highest redshifts and largest AV = 4 ± 1. In a preliminary morphology analysis we find that ∼10% of the members of our sample exhibit spiral arms and 5% host stellar bars, with one candidate bar found at z > 3. Finally, we find that the clustering of JWST sources within 10″ of a submillimeter galaxy is a factor of 2 greater than what is expected based on either random clustering or the distribution of sources around any red galaxy irrespective of a submillimeter detection.

We report the identification of 15 galaxy candidates at z ≥ 9 using the initial COSMOS-Web JWST observations over 77 arcmin2 through four Near Infrared Camera filters (F115W, F150W, F277W, and F444W) with an overlap with the Mid-Infrared Imager (F770W) of 8.7 arcmin2. We fit the sample using several publicly available spectral energy distribution (SED) fitting and photometric redshift codes and determine their redshifts between z = 9.3 and z = 10.9 (〈z〉 = 10.0), UV magnitudes between M UV = −21.2 and −19.5 (with 〈M UV〉 = −20.2), and rest-frame UV slopes (〈β〉 = −2.4). These galaxies are, on average, more luminous than most z ≥ 9 candidates discovered by JWST so far in the literature, while exhibiting similar blue colors in their rest-frame UV. The rest-frame UV slopes derived from SED fitting are blue (β ∼ [−2.0, −2.7]) without reaching extremely blue values as reported in other recent studies at these redshifts. The blue color is consistent with models that suggest the underlying stellar population is not yet fully enriched in metals like similarly luminous galaxies in the lower-redshift Universe. The derived stellar masses with 〈log10( M ⋆/M ⊙)〉 ≈ 8–9 are not in tension with the standard Lambda cold dark matter (ΛCDM) model, and our measurement of the volume density of such UV-luminous galaxies aligns well with previously measured values presented in the literature at z ∼ 9–10. Our sample of galaxies, although compact, is significantly resolved.