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Using awake and freely behaving mice, this study employs a high-throughput in vivo RNA-seq approach to identify odorant receptor repertoires. The authors find sets of odorant receptors for two odorants encompassing 69 odorant receptor-odor pairs and develop models to predict receptor activation. The mammalian olfactory system uses a large family of odorant receptors (ORs) to detect and discriminate amongst a myriad of volatile odor molecules. Understanding odor coding requires comprehensive mapping between ORs and corresponding odors. We developed a means of high-throughput in vivo identification of OR repertoires responding to odorants using phosphorylated ribosome immunoprecipitation of mRNA from olfactory epithelium of odor-stimulated mice followed by RNA-Seq. This approach screened the endogenously expressed ORs against an odor in one set of experiments using awake and freely behaving mice. In combination with validations in a heterologous system, we identified sets of ORs for two odorants, acetophenone and 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), encompassing 69 OR-odorant pairs. We also identified shared amino acid residues specific to the acetophenone or TMT receptors and developed models to predict receptor activation by acetophenone. Our results provide a method for understanding the combinatorial coding of odors in vivo .

Background Community Advisory Boards (CABs) have been frequently used to engage diverse partners to inform research projects. Yet, evaluating the quality of engagement has not been routine. We describe a multi-method ethnographic approach documenting and assessing partner engagement in two “virtual” CABs, for which we conducted all meetings remotely. Methods Two research projects for increasing equitable COVID-19 testing, vaccination, and clinical trial participation for underserved communities involved remote CAB meetings. Thirty-three partners representing 17 community groups participated in 15 sessions across the two CABs facilitated by a social change organization. We developed ethnographic documentation forms to assess multiple aspects of CAB member engagement (e.g., time spent speaking, modality used, types of interactions). Documenters were trained to observe CAB sub-groups via virtual sessions. Debriefing with the documentation team after CAB meetings supported quality assurance and process refinement. CAB members completed a brief validated survey after each meeting to assess the quality and frequency of engagement. Content and rapid thematic analysis were used to analyze documentation data. Quantitative data were summarized as frequencies and means. Qualitative and quantitative findings were triangulated. Results A total of 4,540 interactions were identified across 15 meetings. The most frequent interaction was providing information (44%), followed by responding (37–38%). The quality and frequency of stakeholder engagement were rated favorably (average 4.7 of 5). Most CAB members (96%) reported good/excellent engagement. Specific comments included appreciation for the diversity of perspectives represented by the CAB members and suggestions for improved live interpretation. Debriefing sessions led to several methodological refinements for the documentation process and forms. Conclusion We highlight key strategies for documenting and assessing community engagement. Our methods allowed for rich ethnographic data collection that refined our work with community partners. We recommend ongoing trainings, including debriefing sessions and routinely reviewed assessment of data to strengthen meaningful community engagement.

BackgroundHypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) caused by repeated exposure to inhaled antigens, leading to small airway and parenchymal inflammation. Diagnosis is based on a detailed clinical history, chest imaging and invasive tests such as bronchoalveolar lavage. Distinguishing HP from other ILDs is challenging. Respiratory oscillometry, a novel pulmonary function test (PFT), is highly sensitive to small airway abnormalities. Oscillometry measurement of reactance is strongly correlated with gender-age-physiology score, a prognostic tool used to predict mortality and disease severity in idiopathic pulmonary fibrosis (IPF).ObjectiveTo determine if oscillometry and standard PFT patterns are different in HP and IPF.Methods39 HP (79.5% with fibrotic HP) were enrolled from October 2022 to December 2023 for oscillometry before clinically-indicated standard PFTs and compared with 39 age-matched and sex-matched patients with IPF who also had same day oscillometry and standard PFTs. The main oscillometry metrics of interest were R5-19 (the difference in resistance from 5 to 19 Hz, a metric of small airway function and ventilatory inhomogeneity that increases with worsening respiratory mechanics), X5 (reactance at 5 Hz) which primarily reflects respiratory elastance and AX (area of reactance), a summative measure of the respiratory system stiffness across a range of frequencies, that behaves similarly but in opposite direction to X5.ResultsPatients with HP exhibited higher residual volume/total lung capacity (RV/TLC), lower per cent predicted (%) forced expiratory volume in 1 s (FEV1) and % predicted forced vital capacity (FVC) than IPF (p<0.05) while FEV1/FVC and %TLC were similar. Oscillometry showed higher R5-19 in HP. RV/TLC ratio correlated with AX (r2=0.72), X5 (r2=0.66) and R5-19 (r2=0.64).ConclusionGas trapping (RV/TLC>0.40) is a feature of HP not observed in IPF. The strong correlations of RV/TLC with AX, X5 and R5-19 suggest that oscillometry can provide non-invasive markers of small airway obstruction in HP that can differentiate it from IPF.

The use of face masks or respirators (N95/KN95) is recommended to reduce transmission of SARS-CoV-2, the virus that causes COVID-19 (1). Well-fitting face masks and respirators effectively filter virus-sized particles in laboratory conditions (2,3), though few studies have assessed their real-world effectiveness in preventing acquisition of SARS-CoV-2 infection (4). A test-negative design case-control study enrolled randomly selected California residents who had received a test result for SARS-CoV-2 during February 18-December 1, 2021. Face mask or respirator use was assessed among 652 case-participants (residents who had received positive test results for SARS-CoV-2) and 1,176 matched control-participants (residents who had received negative test results for SARS-CoV-2) who self-reported being in indoor public settings during the 2 weeks preceding testing and who reported no known contact with anyone with confirmed or suspected SARS-CoV-2 infection during this time. Always using a face mask or respirator in indoor public settings was associated with lower adjusted odds of a positive test result compared with never wearing a face mask or respirator in these settings (adjusted odds ratio [aOR] = 0.44; 95% CI = 0.24-0.82). Among 534 participants who specified the type of face covering they typically used, wearing N95/KN95 respirators (aOR = 0.17; 95% CI = 0.05-0.64) or surgical masks (aOR = 0.34; 95% CI = 0.13-0.90) was associated with significantly lower adjusted odds of a positive test result compared with not wearing any face mask or respirator. These findings reinforce that in addition to being up to date with recommended COVID-19 vaccinations, consistently wearing a face mask or respirator in indoor public settings reduces the risk of acquiring SARS-CoV-2 infection. Using a respirator offers the highest level of personal protection against acquiring infection, although it is most important to wear a mask or respirator that is comfortable and can be used consistently.

To describe the implementation of a test-negative design case-control study in California during the Coronavirus Disease 2019 (COVID-19) pandemic. Test-negative case-control study. Between February 24, 2021 - February 24, 2022, a team of 34 interviewers called 38,470 Californians, enrolling 1,885 that tested positive for SARS-CoV-2 (cases) and 1,871 testing negative for SARS-CoV-2 (controls) for 20-minute telephone survey. We estimated adjusted odds ratios for answering the phone and consenting to participate using mixed effects logistic regression. We used a web-based anonymous survey to compile interviewer experiences. Cases had 1.29-fold (95% CI: 1.24-1.35) higher adjusted odds of answering the phone and 1.69-fold (1.56-1.83) higher adjusted odds of consenting to participate compared to controls. Calls placed from 4pm to 6pm had the highest adjusted odds of being answered. Some interviewers experienced mental wellness challenges interacting with participants with physical (e.g., food, shelter, etc.) and emotional (e.g., grief counseling) needs, and enduring verbal harassment from individuals called. Calls placed during afternoon hours may optimize response rate when enrolling controls to a case-control study during a public health emergency response. Proactive check-ins and continual collection of interviewer experience(s) and may help maintain mental wellbeing of investigation workforce. Remaining adaptive to the dynamic needs of the investigation team is critical to a successful study, especially in emergent public health crises, like that represented by the COVID-19 pandemic.

Slapps--strategic lawsuits against public participation--are a type of legal action not undertaken to be won but to intimidate defendants into silence or inaction. They are most often used by powerful actors (corporations, public officials, high-profile businesspeople) in an attempt to stop individuals or organizations from expressing critical views on issues of public interest. They imperil not only independent journalism but academia, activism and other forms of civic engagement. And they seem to be becoming more common around the world. Here, Mhainin highlights the 'Breaking the Silence', a report published by Index that looks at the legal measures that will help give journalists back their voices.

Topography, or depth variation, of certain interfaces in the solid Earth can provide important insights into the dynamics of our planet interior. Although the intermediate- and long-range topographic variation of the 660-kilometer boundary between Earth’s upper and lower mantle is well studied, small-scale measurements are far more challenging. We found a surprising amount of topography at short length scale along the 660-kilometer boundary in certain regions using scattered P′P′ seismic waves. Our observations required chemical layering in regions with high short-scale roughness. By contrast, we did not see such small-scale topography along the 410-kilometer boundary in the upper mantle. Our findings support the concept of partially blocked or imperfect circulation between the upper and lower mantle.

Beyond the canonical K48-linked homotypic polyubiquitination for proteasome-targeted proteolysis, K11/K48-branched ubiquitin (Ub) chains are involved in fast-tracking protein turnover during cell cycle progression and proteotoxic stress. Here, we report cryo-EM structures of human 26S proteasome in a complex with a K11/K48-branched Ub chain. The structures revealed a multivalent substrate recognition mechanism involving a hitherto unknown K11-linked Ub binding site at the groove formed by RPN2 and RPN10 in addition to the canonical K48-linkage binding site formed by RPN10 and RPT4/5 coiled-coil. Additionally, RPN2 recognizes an alternating K11-K48-linkage through a conserved motif similar to the K48-specific T1 binding site of RPN1. The insights gleaned from these structures explain the molecular mechanism underlying the recognition of the K11/K48-branched Ub as a priority signal in the ubiquitin-mediated proteasomal degradation. K11/K48 branched ubiquitin chains regulate protein degradation and cell cycle progression. Here, the authors report the structural basis of how such a branched ubiquitin chain is recognized by the human 26S proteasome, revealing a multivalent binding mode that underlies selective recognition.

Hydrogel materials have emerged as versatile platforms for various biomedical applications. Notably, the engineered nanofiber-hydrogel composite (NHC) has proven effective in mimicking the soft tissue extracellular matrix, facilitating substantial recruitment of host immune cells and the formation of a local immunostimulatory microenvironment. Leveraging this feature, here we report an mRNA lipid nanoparticle (LNP)-incorporated NHC microgel matrix, termed LiNx, by incorporating LNPs loaded with mRNA encoding tumour antigens. Harnessing the high transfection efficiency of LNPs in antigen-presenting cells, LiNx demonstrates substantial levels of immune cell recruitment, antigen expression and presentation, and cellular interaction. These attributes collectively create an immunostimulating microenvironment and yield a potent immune response with a single dose at a level comparable to the conventional three-dose LNP immunization protocol. Further investigation reveals that the LiNx generates not only high levels of Th1 and Th2 responses, but also a distinct Type 17 T helper cell response critical for bolstering antitumour efficacy. Our findings elucidate the mechanism underlying LiNx’s role in potentiating antigen-specific immune responses, presenting a strategy for cancer immunotherapy. Hydrogel materials have emerged as versatile platforms for biomedical applications. Here this group reports an mRNA lipid nanoparticle-incorporated microgel matrix for immune cell recruitment/antigen expression and presentation/cellular interaction thereby eliciting antitumor efficacy with a single dose.