Search

Abstract Background Primary thyroid lymphoma (PTL) is a rare cancer accounting for approximately 5% of thyroid malignancies. Historically, incisional biopsy has been the gold standard for definitive diagnosis of PTL, however, the use of cell block as an adjunct to fine needle aspiration (FNA) provides a high sensitivity and specificity for diagnosis and classification. Methods Three patients presented with a symptomatic enlarging thyroid mass. Patient 1 underwent incisional biopsy under general anesthesia, Patient 2 underwent core needle biopsy to avoid high risk intubation, and Patient 3 underwent fine needle aspiration alone with the use of cell block. Results All patients were diagnosed with a fully classified non-Hodgkin’s lymphoma using immunohistochemistry, flow cytometry, and fluorescence in situ hybridization (FISH) analysis. Conclusions FNA for diagnosis of some subtypes of PTL is feasible and preferred in cases that are particularly high risk for general anesthesia. This minimally invasive technique is safe and cost effective as it avoids expenses associated with operative intervention.

The ability of Mycobacterium tuberculosis to derive lipids from the host, store them intracellularly, and then break them down into energy requires a battery of serine hydrolases. Serine hydrolases are a large, diverse enzyme family with functional roles in dormant, active, and reactivating mycobacterial cultures. To rapidly measure substrate-dependent shifts in mycobacterial serine hydrolase activity, we combined a robust mycobacterial growth system of nitrogen limitation and variable carbon availability with nimble in-gel fluorogenic enzyme measurements. Using this methodology, we rapidly analyzed a range of ester substrates, identified multiple hydrolases concurrently, observed functional enzyme shifts, and measured global substrate preferences. Within every growth condition, mycobacterial hydrolases displayed the full, dynamic range of upregulated, downregulated, and constitutively active hydrolases independent of the ester substrate. Increasing the alkyl chain length of the ester substrate also allowed visualization of distinct hydrolase activity likely corresponding with lipases most responsible for lipid breakdown. The most robust expression of hydrolase activity was observed under the highest stress growth conditions, reflecting the induction of multiple metabolic pathways scavenging for energy to survive under this high stress. The unique hydrolases present under these high-stress conditions could represent novel drug targets for combination treatment with current front-line therapeutics. Combining diverse fluorogenic esters with in-gel activity measurements provides a rapid, customizable, and sensitive detection method for mycobacterial serine hydrolase activity.

The preparation and processing of rodent brains for evaluation by immunohistochemistry is time-consuming. A large number of mouse brains are routinely used in experiments in neuroscience laboratories to evaluate several models of human diseases. Thus, methods are needed to reduce the time associated with processing brains for histology. A scalable method was developed to embed, section, and stain multiple mouse brains using supplies found in any common histology laboratory. Section collection schemes can be scaled to provide identical bregma locations between adjacent sections for immunohistochemistry, facilitating comprehensive, high-quality immunohistochemistry. As a result, sectioning and staining times are considerably reduced as sections from multiple blocks are stained simultaneously. This method improves on previous procedures and allows multiple embedding and subsequent immunostaining of brains easily with a dramatically reduced time requirement. Furthermore, we expand this method for use in numerous mouse tissues, rat brain tissue, and post-mortem human brain and arterial tissues. In summary, this procedure allows the processing of many rodent or human tissues from perfusion through microscopy in 10 days or less.

The extent to which semi-quantitative antibody levels confer protection against SARS-CoV-2 infection in populations with heterogenous immune histories is unclear. Two nested case-control studies were designed within the multisite HEROES/RECOVER prospective cohort of frontline workers to study the relationship between antibody levels and protection against first-time post-vaccination infection and reinfection with SARS-CoV-2 from December 2021 to January 2023. All participants submitted weekly nasal swabs for rRT-PCR testing and blood samples quarterly and following infection or vaccination. Cases of first-time post-vaccination infection following a third dose of monovalent (origin strain WA-1) mRNA vaccine (n = 613) and reinfection (n = 350) were 1:1 matched to controls based on timing of blood draw and other potential confounders. Conditional logistic regression models were fit to estimate infection risk reductions associated with 3-fold increases in end titers for receptor binding domain (RBD). In first-time post-vaccination and reinfection study samples, most were female (67%, 57%), non-Hispanic (82%, 68%), and without chronic conditions (65%, 65%). The odds of first-time post-vaccination infection were reduced by 21% (aOR = 0.79, 95% CI = [0.66-0.96]) for each 3-fold increase in RBD end titers. The odds of reinfection associated with a 3-fold increase in RBD end titers were reduced by 23% (aOR = 0.77, 95% CI = [0.65-0.92] for unvaccinated individuals and 58% (aOR = 0.42, 95% CI = [0.22-0.84]) for individuals with three mRNA vaccine doses following their first infection. Frontline workers with higher antibody levels following a third dose of mRNA COVID-19 vaccine were at reduced risk of SARS-CoV-2 during Omicron predominance. Among those with previous infections, the point estimates of risk reduction associated with antibody levels was greater for those with three vaccine doses compared to those who were unvaccinated.

Measurements of chemical abundances in high- z star-forming (SF) galaxies place important constraints on the enrichment histories of galaxies and the physical conditions in the early Universe. The James Webb Space Telescope (JWST) is beginning to enable direct chemical abundance measurements in galaxies at z > 2 via the detection of the faint T _e -sensitive auroral line [O iii ] λ 4364. However, abundances of other elements (e.g., S and Ar) in high- z galaxies remain unconstrained owing to a lack of T _e data and wavelength coverage. Here we present multiple direct abundances in Q2343-D40, a galaxy at z = 2.9628 ± 0.0001 observed with JWST/NIRSpec as part of the CECILIA program. We report the first simultaneous measurement of T _e [O iii ] and T _e [S iii ] in a high- z galaxy, finding good agreement with the temperature trends in local SF systems. We measure a gas-phase metallicity of 12+log(O/H) = 8.07 ± 0.06, and the N/O abundance, log(N/O) = −1.37 ± 0.21, is indicative of primary nucleosynthesis. The S/O and Ar/O relative abundances, log(S/O) = −1.88 ± 0.10 and log(Ar/O) = −2.80 ± 0.12, are both >0.3 dex lower than the solar ratios. However, the relative Ar ^2+ /S ^2+ abundance is consistent with the solar ratio, suggesting that the relative S-to-Ar abundance does not evolve significantly with redshift. Recent nucleosynthesis models find that significant amounts of S and Ar are produced in Type Ia supernovae, such that the S/O and Ar/O abundances in Q2343-D40 could be the result of predominantly core-collapse supernova enrichment. Future JWST observations of high- z galaxies will uncover whether S/O and Ar/O are sensitive to the timescales of these different enrichment mechanisms.

The development and validation of the recombinant 9E1 monoclonal antibody against channel catfish IgM is described. The variable heavy and light chain domains of the 9E1 hybridoma were cloned into murine IgG1 and IgK expression vectors. These expression plasmids were co-transfected into 293F cells and mature IgG was purified from culture supernatant. It is demonstrated that the recombinant 9E1 monoclonal antibody binds to soluble IgM in ELISA and ELISPOT assays and to membrane-bound IgM by immunofluorescence with different B-cell types. The recombinant 9E1 monoclonal antibody will be a valuable tool in the continued examination of the channel catfish adaptive immune system

Summary: Hepcidin is the master hormone governing systemic iron homeostasis. Iron regulates hepcidin by activating bone morphogenetic protein (BMP)6 expression in liver endothelial cells (LECs), but the mechanisms are incompletely understood. To address this, we performed proteomics and RNA-sequencing on LECs from iron-adequate and iron-loaded mice. Gene set enrichment analysis identified transcription factors activated by high iron, including Nrf-2, which was previously reported to contribute to BMP6 regulation, and c-Jun. Jun (encoding c-Jun) knockdown blocked Bmp6 but not Nrf-2 pathway induction by iron in LEC cultures. Chromatin immunoprecipitation of mouse livers showed iron-dependent c-Jun binding to predicted sites in Bmp6 regulatory regions. Finally, c-Jun inhibitor blunted induction of Bmp6 and hepcidin, but not Nrf-2 activity, in iron-loaded mice. However, Bmp6 and iron parameters were unchanged in endothelial Jun knockout mice. Our data suggest that c-Jun participates in iron-mediated BMP6 regulation independent of Nrf-2, though the mechanisms may be redundant and/or multifactorial.

Epithelial Na+ channels (ENaCs) control extracellular fluid volume by facilitating Na+ absorption across transporting epithelia. In vitro studies showed that Cys-palmitoylation of the γENaC subunit is a major regulator of channel activity. We tested whether γ subunit palmitoylation sites are necessary for channel function in vivo by generating mice lacking the palmitoylated cysteines (γC33A,C41A) using CRISPR/Cas9 technology. ENaCs in dissected kidney tubules from γC33A,C41A mice had reduced open probability compared with wild-type (WT) littermates maintained on either standard or Na+-deficient diets. Male mutant mice also had higher aldosterone levels than WT littermates following Na+ restriction. However, γC33A,C41A mice did not have reduced amiloride-sensitive Na+ currents in the distal colon or benzamil-induced natriuresis compared to WT mice. We identified a second, larger conductance cation channel in the distal nephron with biophysical properties distinct from ENaC. The activity of this channel was higher in Na+-restricted γC33A,C41A versus WT mice and was blocked by benzamil, providing a possible compensatory mechanism for reduced prototypic ENaC function. We conclude that γ subunit palmitoylation sites are required for prototypic ENaC activity in vivo but are not necessary for amiloride/benzamil-sensitive Na+ transport in the distal nephron or colon.

There is a need to identify predictive biomarkers to guide treatment strategies in stage III non-small cell lung cancer (NSCLCs). In this multi-institutional cohort of 197 patients with stage III NSCLC treated with concurrent chemoradiation (cCRT) and durvalumab consolidation, we identify that low tumor aneuploidy is independently associated with prolonged progression-free survival (HR 0.63; p=0.03) and overall survival (HR 0.50; p=0.03). Tumors with high aneuploidy had a significantly greater incidence of distant metastasis and shorter median distant-metastasis free survival (p=0.04 and p=0.048, respectively), but aneuploidy level did not associate with local-regional outcomes. Multiplexed immunofluorescence analysis in a cohort of NSCLC found increased intratumoral CD8-positive, PD-1-positive cells, double-positive PD-1 CD8 cells, and FOXP3-positive T-cell in low aneuploid tumors. Additionally, in a cohort of 101 patients treated with cCRT alone, tumor aneuploidy did not associate with disease outcomes. These data support the need for upfront treatment intensification strategies in stage III NSCLC patients with high aneuploid tumors and suggest that tumor aneuploidy is a promising predictive biomarker.

Background: Prenatal selective serotonin reuptake inhibitor (SSRI) exposure has been inconsistently linked to depression, and little is known about neural correlates. We examined whether prenatal SSRI exposure is associated with depressive symptoms and brain structure during middle childhood. Methods: Prenatal SSRI exposure (retrospective caregiver report), depressive symptoms (caregiver-reported Child Behavior Checklist), and brain structure (magnetic resonance imaging–derived subcortical volume; cortical thickness and surface area) were assessed in children (analytic ns = 5420–7528; 235 with prenatal SSRI exposure; 9–10 years of age) who completed the baseline Adolescent Brain Cognitive Development Study session. Linear mixed-effects models nested data. Covariates included familial, pregnancy, and child variables. Matrix spectral decomposition adjusted for multiple testing. Results: Prenatal SSRI exposure was not independently associated with depression after accounting for recent maternal depressive symptoms. Prenatal SSRI exposure was associated with greater left superior parietal surface area (b = 145.3 mm2, p = .00038) and lateral occipital cortical thickness (b = 0.0272 mm, p = .0000079); neither was associated with child depressive symptoms. Child depression was associated with smaller global brain structure. Conclusions: Our findings, combined with adverse outcomes of exposure to maternal depression and the utility of SSRIs for treating depression, suggest that risk for depression during middle childhood should not discourage SSRI use during pregnancy. Associations between prenatal SSRI exposure and brain structure were small in magnitude and not associated with depression. It will be important for future work to examine associations between prenatal SSRI exposure and depression through young adulthood, when risk for depression increases.

In a cohort of essential workers in the United States previously infected with SARS-CoV-2, risk factors for reinfection included being unvaccinated, infrequent mask use, time since first infection, and being non-Hispanic Black. Protecting workers from reinfection requires a multipronged approach including up-to-date vaccination, mask use as recommended, and reduction in underlying health disparities.

Abstract Autoantibodies to desmoglein-2 have been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) in people. ARVC is a common disease in the Boxer dog. The role of anti-desmoglein-2 antibodies in Boxers with ARVC and correlation with disease status or severity is unknown. This prospective study is the first to evaluate dogs of various breeds and cardiac disease state for anti-desmoglein-2 antibodies. The sera of 46 dogs (10 ARVC Boxers, 9 healthy Boxers, 10 Doberman Pinschers with dilated cardiomyopathy, 10 dogs with myxomatous mitral valve disease, and 7 healthy non-Boxer dogs) were assessed for antibody presence and concentration via Western blotting and densitometry. Anti-desmoglein-2 antibodies were detected in all dogs. Autoantibody expression did not differ between study groups and there was no correlation with age or body weight. In dogs with cardiac disease, there was weak correlation with left ventricular dilation (r = 0.423, p = 0.020) but not left atrial size (r = 0.160, p = 0.407). In ARVC Boxers there was strong correlation with the complexity of ventricular arrhythmias (r = 0.841, p = 0.007) but not total number of ectopic beats (r = 0.383, p = 0.313). Anti-desmoglein-2 antibodies were not disease specific in the studied population of dogs. Correlation with some measures of disease severity requires further study with larger populations.

Larval zebrafish are subjected to ototoxic compounds to evaluate their impact on rheotaxis, and compound-specific behaviour profiles reveal unique effects on zebrafish rheotaxis behavior.

Abstract Background Hepatitis C (HCV) poses a major public health problem in the USA. While early identification is a critical priority, subsequent linkage to a treatment specialist is a crucial step that bridges diagnosed patients to treatment, cure, and prevention of ongoing transmission. Emergency departments (EDs) serve as an important clinical setting for HCV screening, although optimal methods of linkage-to-care for HCV-diagnosed individuals remain unknown. In this article, we describe the rationale and design of The Determining Effective Testing in Emergency Departments and Care Coordination on Treatment Outcomes (DETECT) for Hepatitis C (Hep C) Linkage-to-Care Trial. Methods The DETECT Hep C Linkage-to-Care Trial will be a single-center prospective comparative effectiveness randomized two-arm parallel-group superiority trial to test the effectiveness of linkage navigation and clinician referral among ED patients identified with untreated HCV with a primary hypothesis that linkage navigation plus clinician referral is superior to clinician referral alone when using treatment initiation as the primary outcome. Participants will be enrolled in the ED at Denver Health Medical Center (Denver, CO), an urban, safety-net hospital with approximately 75,000 annual adult ED visits. This trial was designed to enroll a maximum of 280 HCV RNA-positive participants with one planned interim analysis based on methods by O’Brien and Fleming. This trial will further inform the evaluation of cost effectiveness, disparities, and social determinants of health in linkage-to-care, treatment, and disease progression. Discussion When complete, the DETECT Hep C Linkage-to-Care Trial will significantly inform how best to perform linkage-to-care among ED patients identified with HCV. Trial registration ClinicalTrials.gov ID: NCT04026867 Original date: July 1, 2019 URL: https://clinicaltrials.gov/ct2/show/NCT04026867

Abstract Background Guidelines‐driven screening protocols for early cancer detection in dogs are lacking, and cancer often is detected at advanced stages. Hypothesis/Objectives To examine how cancer typically is detected in dogs and whether the addition of a next‐generation sequencing‐based “liquid biopsy” test to a wellness visit has the potential to enhance cancer detection. Animals Client‐owned dogs with definitive cancer diagnoses enrolled in a clinical validation study for a novel blood‐based multicancer early detection test. Methods Retrospective medical record review was performed to establish the history and presenting complaint that ultimately led to a definitive cancer diagnosis. Blood samples were subjected to DNA extraction, library preparation, and next‐generation sequencing. Sequencing data were analyzed using an internally developed bioinformatics pipeline to detect genomic alterations associated with the presence of cancer. Results In an unselected cohort of 359 cancer‐diagnosed dogs, 4% of cases were detected during a wellness visit, 8% were detected incidentally, and 88% were detected after the owner reported clinical signs suggestive of cancer. Liquid biopsy detected disease in 54.7% (95% confidence interval [CI], 49.5%‐59.8%) of patients, including 32% of dogs with early‐stage cancer, 48% of preclinical dogs, and 84% of dogs with advanced‐stage disease. Conclusions/Clinical Importance Most cases of cancer were diagnosed after the onset of clinical signs; only 4% of dogs had cancer detected using the current standard of care (i.e., wellness visit). Liquid biopsy has the potential to increase detection of cancer when added to a dog's wellness visit.

Abstract Background Adherence to antiretroviral treatment (ART) remains the cornerstone of optimal HIV outcomes, including viral suppression (VS), immune recovery, and decreased transmission risk. For many people with HIV (PWH), particularly those with early-acquired HIV, structural, behavioral, and cognitive barriers to adherence and competing priorities related to life events may be difficult to overcome, resulting in nonadherence. Long-acting injectable antiretroviral therapies (LAI-ART) may be a useful strategy to overcome some of these barriers. However, to date, the approved LAI-ART strategies (e.g., cabotegravir and rilpivirine (CAB/RPV)) have targeted those who have already attained viral suppression, precluding their use in the 40% of adolescents and young adults (AYA) that VS has eluded. Case presentation Ms. X is a 30-year-old woman with perinatally-acquired HIV and barriers to adherence. Despite many interventions, she remained persistently viremic, with resultant immune suppression and multiple comorbid opportunistic conditions, and viral load (VL) > 10,000,000 copies/ml. Given her longstanding history of poor adherence to an oral regimen, a switch to monthly intramuscular (IM) injections and biweekly infusions of ibalizumab were initiated leading to decreased viral load to 8,110 copies/ml within two weeks. Ms. H is a 33-year-old woman with cognitive limitations due to childhood lead poisoning. Her viral load trajectory took a downward turn, precipitated by various life events, remaining elevated despite intensive case management. Initiation of LAI-ART (CAB/RPV) in this patient led to an undetectable VL ( 5 years. She received a 1-month oral lead-in (OLI) of cabotegravir/rilpivirine, followed by the injectable loading dose. She has since adhered to all her monthly dosing appointments, sustained VS, and transitioned to a bi-monthly injection schedule. Conclusion These three individuals with HIV (perinatally and non-perinatally acquired) with longstanding nonadherence and persistent viremia were successfully initiated on LAI-ART through the process of care coordination and the collective efforts of the care team, highlighting the barriers, challenges, and the multidisciplinary coordination needed to assure successful implementation of this strategy for the most vulnerable of patients.

Summary: Retinal ganglion cell (RGC) degeneration drives vision loss in blinding conditions. RGC death is often triggered by axon degeneration in the optic nerve. Here, we study the contributions of dynamic and homeostatic Ca2+ levels to RGC death from axon injury. We find that axonal Ca2+ elevations from optic nerve injury do not propagate over distance or reach RGC somas, and acute and chronic Ca2+ dynamics do not affect RGC survival. Instead, we discover that baseline Ca2+ levels vary widely between RGCs and predict their survival after axon injury, and that lowering these levels reduces RGC survival. Further, we find that well-surviving RGC types have higher baseline Ca2+ levels than poorly surviving types. Finally, we observe considerable variation in the baseline Ca2+ levels of different RGCs of the same type, which are predictive of within-type differences in survival.

“Star” survey designs have become an increasingly popular alternative to parallel line designs in fisheries-independent sampling of areas with isolated fish aggregations, such as artificial reefs, seamounts, fish aggregating devices, and spawning aggregation sites. In this study, we simulated three scenarios of fish aggregating around a feature of interest with variations in the size and complexity of aggregations as well as their location relative to the habitat feature. Simulated and empirical data representing goliath grouper (Epinephalus itajara) spawning aggregations at artificial reefs were utilized as a case study, and scenarios were generated in relation to both a single habitat feature and a reef complex with multiple structures. Seven variations of survey design using both star and parallel transects were examined and compared by geostatistical and generalized additive models (GAMs) to identify the most robust approach to quantify fish aggregations in each scenario. In most scenarios, precision in the mean and variability of backscatter estimates is not significantly affected by the number of transects passing over the habitat feature as long as at least one pass is made. Estimation error is minimized using the GAM approach, and is further reduced when sampling variance is high, which was better accomplished by parallel designs overall. These results will help inform surveyors on the best overall approach to improve precision in quantifying fish aggregations given basic knowledge of their behavior around an established habitat feature and help them to adapt their survey designs based on common difficulties in sampling these populations simulated below.

Objective: The gut microbiome has been associated with visceral fat (VAT) in European and Asian populations; however, associations with VAT and with ectopic fats among African-ancestry individuals are not known. Our objective was to investigate cross-sectional associations of fecal microbiota diversity and composition with VAT and ectopic fat, as well as body mass index (BMI), among middle-aged and older African Caribbean men. Methods: We included in our analysis n = 193 men (mean age = 62.2 ± 7.6 years; mean BMI = 28.3 ± 4.9 kg/m2) from the Tobago Health Study. We assessed fecal microbiota using V4 16s rRNA gene sequencing. We evaluated multivariable-adjusted associations of microbiota features (alpha diversity, beta diversity, microbiota differential abundance) with BMI and with computed tomography-measured VAT and ectopic fats (pericardial and intermuscular fat; muscle and liver attenuation). Results: Lower alpha diversity was associated with higher VAT and BMI, and somewhat with higher pericardial and liver fat. VAT, BMI, and pericardial fat each explained similar levels of variance in beta diversity. Gram-negative Prevotellaceae and Negativicutes microbiota showed positive associations, while gram-positive Ruminococcaceae microbiota showed inverse associations, with ectopic fats. Conclusions: Fecal microbiota features associated with measures of general adiposity also extend to metabolically pernicious VAT and ectopic fat accumulation in older African-ancestry men.

Abstract Background Sampling from a peripheral intravenous catheter (PIVC) might be a more efficient and less traumatic collection of blood for serum biochemistry (SB) or CBC than direct venipuncture (DV). Agreement between results of samples obtained by these methods has not been evaluated in dogs. Objectives The primary objectives were to determine whether sampling from PIVC could be used in place of DV for dogs. We hypothesized DV and PIVC samples would have clinically equivalent SB and CBC results. Animals Sixty‐one client‐owned dogs were included in each study arm. Methods This was a partially randomized method‐comparison study. Paired DV and PIVC samples obtained within 1 to 2 minutes after, or approximately 24 hours after, placement of a PIVC in a cephalic vein were evaluated for agreement and bias using percentage difference plots (with a priori application of consensus total allowable error), Bland‐Altman analysis, Passing‐Bablok regression analysis, Wilcoxon signed rank test, and McNemar's test. Results There was statistically and clinically acceptable agreement and no bias between sampling methods for the majority of results. Analytes with the most frequent disagreement were aspartate aminotransferase, total bilirubin, potassium, bicarbonate, and leukocyte differential counts, as well as red blood cell count, hemoglobin, hematocrit, and packed cell volume in the hospitalized PIVC sampling group. Few observed differences would change clinical decision making. Conclusions and Clinical Importance PIVC sampling can provide generally acceptable SB and CBC results for most dogs, but clinicians should be aware of a few values for which disparate results might occasionally be obtained.

Abstract Background Emerging RNA viruses that target the central nervous system (CNS) lead to cognitive sequelae in survivors. Studies in humans and mice infected with West Nile virus (WNV), a re-emerging RNA virus associated with learning and memory deficits, revealed microglial-mediated synapse elimination within the hippocampus. Moreover, CNS-resident memory T (TRM) cells activate microglia, limiting synapse recovery and inducing spatial learning defects in WNV-recovered mice. The signals involved in T cell-microglia interactions are unknown. Methods Here, we examined immune cells within the murine WNV-recovered forebrain using single-cell RNA sequencing to identify putative ligand-receptor pairs involved in intercellular communication between T cells and microglia. Clustering and differential gene analyses were followed by protein validation and genetic and antibody-based approaches utilizing an established murine model of WNV recovery in which microglia and complement promote ongoing hippocampal synaptic loss. Results Profiling of host transcriptome immune cells at 25 days post-infection in mice revealed a shift in forebrain homeostatic microglia to activated subpopulations with transcriptional signatures that have previously been observed in studies of neurodegenerative diseases. Importantly, CXCL16/CXCR6, a chemokine signaling pathway involved in TRM cell biology, was identified as critically regulating CXCR6 expressing CD8+ TRM cell numbers within the WNV-recovered forebrain. We demonstrate that CXCL16 is highly expressed by all myeloid cells, and its unique receptor, CXCR6, is highly expressed on all CD8+ T cells. Using genetic and pharmacological approaches, we demonstrate that CXCL16/CXCR6 not only is required for the maintenance of WNV-specific CD8 TRM cells in the post-infectious CNS, but also contributes to their expression of TRM cell markers. Moreover, CXCR6+CD8+ T cells are required for glial activation and ongoing synapse elimination. Conclusions We provide a comprehensive assessment of the role of CXCL16/CXCR6 as an interaction link between microglia and CD8+ T cells that maintains forebrain TRM cells, microglial and astrocyte activation, and ongoing synapse elimination in virally recovered animals. We also show that therapeutic targeting of CXCL16 in mice during recovery may reduce CNS CD8+ TRM cells.

Abstract It is difficult to identify people with nonalcoholic fatty liver disease (NAFLD) who are at high risk for developing hepatocellular carcinoma (HCC). A polygenic risk score (PRS) for hepatic fat (HFC‐PRS) derived from non‐Asians has been reported to be associated with HCC risk in European populations. However, population‐level data of this risk in Asian populations are lacking. Utilizing resources from 24,333 participants of the Singapore Chinese Health Study (SCHS), we examined the relationship between the HFC‐PRS and HCC risk. In addition, we constructed and evaluated a NAFLD‐related PRS (NAFLD‐PRS) with HCC risk in the SCHS. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of HCC incidence with both HFC‐PRS and NAFLD‐PRS. The HFC‐PRS and NAFLD‐PRS were highly correlated (Spearman r = 0.79, p

Social science research has long recognized the relevance of socioeconomic background for mobility and inequality. In this article we interrogate how and why working-class and first-generation backgrounds are especially meaningful and take as our case in point the professoriate and the discipline of sociology, – i.e., a field that intellectually prioritizes attention to group inequality and that arguably offers a conservative empirical test compared to other academic fields. Our analyses, which draw on unique survey items and open-ended qualitative materials from nearly 1,000 academic sociologists, reveal significant background divergences in academic job attainment, tied partly to educational background. Moreover, and especially unique and important, findings demonstrate significant consequences across several dimensions of inequality including compensation and economic precarity, professional visibility, and isolation at departmental, college or university, and professional levels. We conclude by highlighting how our discussion and results contribute in important ways to broader sociological concerns surrounding mobility, group disadvantage, and social closure.

Summary: Background: Understanding the usefulness of additional COVID-19 vaccine doses—particularly given varying disease incidence—is needed to support public health policy. We characterize the benefits of COVID-19 booster doses using number needed to vaccinate (NNV) to prevent one COVID-19-associated hospitalization or emergency department encounter. Methods: We conducted a retrospective cohort study of immunocompetent adults at five health systems in four U.S. states during SARS-CoV-2 Omicron BA.1 predominance (December 2021–February 2022). Included patients completed a primary mRNA COVID-19 vaccine series and were either eligible to or received a booster dose. NNV were estimated using hazard ratios for each outcome (hospitalization and emergency department encounters), with results stratified by three 25-day periods and site. Findings: 1,285,032 patients contributed 938 hospitalizations and 2076 emergency department encounters. 555,729 (43.2%) patients were aged 18–49 years, 363,299 (28.3%) 50–64 years, and 366,004 (28.5%) ≥65 years. Most patients were female (n = 765,728, 59.6%), White (n = 990,224, 77.1%), and non-Hispanic (n = 1,063,964, 82.8%). 37.2% of patients received a booster and 62.8% received only two doses. Median estimated NNV to prevent one hospitalization was 205 (range 44–615) and NNV was lower across study periods for adults aged ≥65 years (110, 46, and 88, respectively) and those with underlying medical conditions (163, 69, and 131, respectively). Median estimated NNV to prevent one emergency department encounter was 156 (range 75–592). Interpretation: The number of patients needed to receive a booster dose was highly dependent on local disease incidence, outcome severity, and patient risk factors for moderate-to-severe disease. Funding: Funding was provided by the Centers for Disease Control and Prevention though contract 75D30120C07986 to Westat, Inc. and contract 75D30120C07765 to Kaiser Foundation Hospitals.

Introduction Although SARS-CoV-2 vaccines were first approved under Emergency Use Authorization by the Food and Drug Administration in late 2020 for adults, authorisation for young children 6 months to 6 months and adults aged

Background: Glioblastoma is the most aggressive and common primary brain tumor. Patients usually present with a short clinical history that often includes focal neurological deficits. Historically 1- and 5-year survival of patients with this disease has been low. There are now increasing reports of patients living longer, making it important to understand the clinical progression of the disease to predict patient needs. Methods: Patients ≥ 18 years who were enrolled in the central nervous system (CNS) tumor registry at HonorHealth in Scottsdale, Arizona between April 7, 2017 and February 5, 2020 were included. Demographic data and data on adverse events were collected from the CNS tumor registry. The data was analyzed and reported as means and standard deviations. Results: 12 male and 7 female patients were included in the study. The average time to follow-up was 15.12 months and patients experienced the onset of psychiatric/neurological adverse events an average of 3.29 months after surgery, cardiovascular/respiratory adverse events 3.42 months after surgery, and general adverse events 3.71 months after surgery. Additionally, 63.2% of patients experienced a seizure with an average time to onset of 6.75 months after surgery. Conclusions: Patients with glioblastoma experience psychiatric/neurological adverse events first, followed by cardiovascular/respiratory adverse events, and finally followed by general adverse events. Most patients will experience at least one seizure.

Summary: Shared decision making for infant feeding in the context of HIV in high-resourced settings is necessary to acknowledge patient autonomy, meet increasing patient requests and address the changing reality of perinatal HIV care. In low-to middle-income countries (LMIC), where the majority of individuals living with HIV reside, persons with HIV are recommended to breastfeed their infants. In the setting of maternal anti-retroviral therapy (ART) use throughout pregnancy, viral suppression and appropriate neonatal post-exposure prophylaxis (PEP) use, updated information indicates that the risk of HIV transmission through breastmilk may be between 0.3 and 1%. While not endorsing or recommending breastfeeding, the United States’ DHHS perinatal guidelines are similarly pivoting, stating that individuals should “receive patient-centred, evidence-based counselling on infant feeding options.” Similar statements appear in the British, Canadian, Swiss, European, and Australasian perinatal guidelines. We assembled a multi-disciplinary group at our institution to develop a structured shared decision-making process and protocol for successful implementation of breastfeeding. We recommend early and frequent counselling about infant feeding options, which should include well known benefits of breastfeeding even in the context of HIV and the individual’s medical and psychosocial circumstances, with respect and support for patient’s autonomy in choosing their infant feeding option.

Urine marking, aggression, and other behavioral concerns are common reasons for cat owners to seek veterinary care. Empiric treatment for lower urinary tract disease or primary behavior disorders are commonly pursued, especially in those cases with normal routine laboratory evaluations. Herein, we report the clinicopathologic findings in eight sexually altered cats that were diagnosed with androgen-secreting adrenocortical tumors. Nearly all cats (n = 7) initially were evaluated for inappropriate urination and pungent urine, with additional behavioral concerns including aggression (n = 3) and excess vocalization (n = 4) commonly reported. Penile barbs (n = 5) were identified in all five male cats, and an enlarged clitoris was observed in one female cat. Testing of serum androgen concentrations revealed abnormally high androstenedione (n = 1) or testosterone (n = 7) concentrations. In the five cases with available adrenal tissue, histopathologic evaluation identified either an adrenocortical adenoma (n = 3) or adrenocortical carcinoma (n = 2). Hormonal abnormalities resolved and clinical signs improved in the four cats that underwent surgical adrenalectomy, with each of these cats surviving >1 year. However, clinical signs were minimally impacted with medical treatments, including one cat in which trilostane treatment failed to improve clinical signs or testosterone concentrations. This collection of cases underscores the importance of a detailed physical examination as well as the consideration of endocrine disturbances in cats undergoing evaluation for inappropriate urination or aggression. Furthermore, this report adds to the growing body of evidence that sex-hormone secreting adrenal tumors in cats may be an under-recognized syndrome.

The activity of PD-1 blockade in patients with sarcoma has been modest so far. Here, the authors report the results of a pilot clinical trial to assess the efficacy and safety of bempegaldesleukin, a CD122-preferential interleukin-2 (IL-2) pathway agonist, in combination with the PD1 blockade (nivolumab) in patients with locally advanced or metastatic high-grade sarcoma.

Abstract Background The East Nusa Tenggara province, Indonesia, contributed to 5% of malaria cases nationally in 2020, with other mosquito-borne diseases, such as dengue and filariasis also being endemic. Monitoring of spatial and temporal vector species compositions and bionomic traits is an efficient method for generating evidence towards intervention strategy optimization and meeting disease elimination goals. Methods The impact of a spatial repellent (SR) on human biting mosquitoes was evaluated as part of a parent cluster-randomized, double-blinded, placebo-controlled trial, in Sumba, East Nusa Tenggara. A 10-month (June 2015–March 2016) baseline study was followed by a 24-month intervention period (April 2016 to April 2018)—where half the clusters were randomly assigned either a passive transfluthrin emanator or a placebo control. Results Human-landing mosquito catches documented a reduction in landing rates related to the SR. Overall, there was a 16.4% reduction (21% indoors, and 11.3% outdoors) in human biting rates (HBR) for Anopheles. For Aedes, there was a 44.3% HBR reduction indoors and a 35.6% reduction outdoors. This reduction was 38.3% indoors and 39.1% outdoors for Armigeres, and 36.0% indoors and 32.3% outdoors for Culex species. Intervention impacts on the HBRs were not significant and are attributed to large inter-household and inter cluster variation. Anopheles flavirostris, Anopheles balabacensis and Anopheles maculatus individually impacted the overall malaria infections hazard rate with statistically significance. Though there was SR-based protection against malaria for all Anopheles species (except Anopheles sundaicus), only five (Anopheles aconitus, Anopheles kochi, Anopheles tessellatus, An. maculatus and An. sundaicus) demonstrated statistical significance. The SR numerically reduced Anopheles parity rates indoors and outdoors when compared to the placebo. Conclusion Evidence demonstrating that Anopheles vectors bite both indoors and outdoors indicates that currently implemented indoor-based vector control tools may not be sufficient to eliminate malaria. The documented impact of the SR intervention on Aedes, Armigeres and Culex species points to its importance in combatting other vector borne diseases. Studies to determine the impact of spatial repellents on other mosquito-borne diseases is recommended.

Abstract Background Liver disease is frequently cited as a cause of gastroduodenal ulceration (GDU) in dogs but studies regarding GDU and liver disease are limited. Objectives To document the presence of GDU in dogs with liver disease. Animals Forty dogs that underwent liver biopsy, computed tomographic (CT) angiography or both at the University of Florida Small Animal Hospital to diagnose congenital or acquired liver disease. Methods Cross‐sectional study. Dogs had gastroduodenoscopy performed with photographic and video documentation in a standardized fashion. Lesions (hemorrhage, erosions, ulcers) in the esophagus, stomach, and duodenum were scored based on a grading scale. Presence of esophageal varices was recorded. Dogs were categorized into 4 groups according to cause of liver disease (inflammatory disease, cirrhosis, congenital, other). Presence or absence of ulcers, erosions or both as well as total endoscopic scores were compared among groups. Results Forty dogs were enrolled with the following distribution: 13 congenital, 13 inflammatory, 3 cirrhosis, and 11 other. Four dogs had GDU (10%; 95% confidence interval [CI], 3%‐24%) and 6 dogs had erosions (15%; 95% CI, 6%‐30%). No difference was found in total endoscopic score (P = .21) or in the proportion of dogs with ulcers, erosions or both versus those without (P = .25) among the groups. Conclusions and Clinical Importance Gastroduodenal ulceration was found in 10% of dogs with liver disease in this population. Additional studies are warranted to confirm these findings in larger numbers of dogs with specific disease etiologies.

To study the chemical evolution across cosmic epochs, we investigate Ne, S, Cl, and Ar abundance patterns in the Cosmic Origins Spectrograph Legacy Archive Spectroscopic SurveY (CLASSY). CLASSY comprises local star-forming galaxies (SFGs; 0.02 < z < 0.18) with enhanced star formation rates, making them strong analogues to high- z SFGs. With direct measurements of electron temperature, we derive accurate ionic abundances for all elements and assess ionization correction factors (ICFs) to account for unseen ions and derive total abundances. We find Ne/O, S/O, Cl/O, and Ar/O exhibit constant trends with gas-phase metallicity for 12+log(O/H) < 8.5 but significant correlation for Ne/O and Ar/O with metallicity for 12+log(O/H) > 8.5, likely due to ICFs. Thus, the applicability of the ICFs to integrated spectra of galaxies could bias results, underestimating true abundance ratios. Using CLASSY as a local reference, we assess the evolution of Ne/O, S/O, and Ar/O in galaxies at z > 3, finding no cosmic evolution of Ne/O, while the lack of direct abundance determinations for S/O and Ar/O can bias the interpretation of the evolution of these elements. We determine the fundamental metallicity relationship (FMR) for CLASSY and compare to the high-redshift FMR, finding no evolution. Finally, we perform the first mass–neon relationship analysis across cosmic epochs, finding a slight evolution to high Ne at later epochs. The robust abundance patterns of CLASSY galaxies and their broad range of physical properties provide essential benchmarks for interpreting the chemical enrichment of the early galaxies observed with the JWST.

We investigate the impact of adoption of electric vehicles and cleaner fuels on future surface levels of PM _2.5 and ozone over Delhi for two contrasting seasons, pre-monsoon and post-monsoon. We run the WRF-Chem atmospheric transport model at high resolution (4 km) with two transport emission scenarios for year 2030: (1) a scenario with electrification of two- and three-wheelers and light commercial vehicles, and (2) a scenario which also includes conversion of diesel vehicles to compressed natural gas (CNG). Compared to the baseline values in 2019, the scenario with both electrification and conversion of diesel vehicles to CNG has a greater reduction in PM _2.5 concentrations (up to 5%) than the electrification of two- and three-wheelers and light commercial vehicles alone (within 1%), mainly due to the the greater reduction in primary emissions of PM _2.5 and black carbon from diesel conversion to CNG. Vehicles electrification could result in an increase in the daily maximum 8-hours ozone concentrations, which are partially offset by additionally converting to CNG—by −1.9% and +2.4% during pre-monsoon and post-monsoon seasons. This reflects higher NO _x emissions from the CNG vehicle scenario compared to electrification-alone scenario, which limits the increase of surface ozone in the VOC-limited chemical environment over Delhi. Our findings highlight the importance of a coordinated strategy for PM _2.5 and ozone when considering traffic emission controls, and highlight that the transition to electric vehicles should be accompanied by the conversion of diesel vehicles to CNG to limit surface ozone increase and achieve greater reduction in PM _2.5 concentrations over Delhi. However, the small changes in PM _2.5 and in ozone compared to the baseline scenario highlight the importance of joint emissions reduction from other sectors to achieve substantial progress in PM _2.5 and ozone air quality in Delhi.

We present the design and first results of the inner circumgalactic medium (CGM) of QSO line-of-sight emitting galaxies at z ∼ 2–3, Keck Baryonic Structure Survey (KBSS)-InCLOSE. The survey will connect galaxy properties (e.g., stellar mass M _* , interstellar medium, hereafter ISM, metallicity) with the physical conditions of the inner CGM (e.g., kinematics, metallicity) to directly observe the galaxy-scale baryon cycle. We obtain deep Keck/KCWI optical IFU pointings of KBSS QSOs to discover new star-forming galaxies at small projected distances b ≲ 12″ (98 kpc, $\overline{z}=2.3$ ), then obtain follow-up Keck/MOSFIRE near-IR spectra to confirm their redshifts. We leverage KBSS images and Keck/High Resolution Echelle Spectrometer QSO spectra to model stellar populations and inner CGM absorption. In this paper, we analyze two QSO fields and discover more than 15 new galaxies with KCWI, then use MOSFIRE for two galaxies Q2343-G1 ( z = 2.43; G1) and Q2233-N1 ( z = 3.15; N1), which are both associated with damped Lyα absorbers. We find that G1 has typical M _* , UV/optical emission properties. N1 has lower M _* with very strong nebular emission. We jointly analyze neutral phase CGM and ionized ISM in N/O (for the first time at this z ), dust extinction, and high-ionization CGM finding that G1's CGM is metal poor and less evolved than its ISM, while N1's CGM and ISM abundances are comparable; their CGM shows ∼1 dex less dust extinction than the ISM; and G1's CGM has direct evidence of hot, metal-rich galactic outflow ejecta. These findings support that metals and dust are driven into the CGM from outflows, but may also be, e.g., stripped ISM gas or satellite enrichment. The full KBSS-InCLOSE sample will explore these scenarios.

Task-specific training has been shown to be an effective neuromotor rehabilitation intervention, however, this repetitive approach is not always very engaging. Virtual reality (VR) systems are becoming increasingly popular in therapy due to their ability to encourage movement through customizable and immersive environments. Additionally, VR can allow for a standardization of tasks that is often lacking in upper extremity research. Here, 16 healthy participants performed upper extremity movement tasks synced to music, using a commercially available VR game known as Beat Saber. VR tasks were customized to characterize participants’ joint angles with respect to each task’s specified cardinal direction (inward, outward, upward, or downward) and relative task location (medial, lateral, high, and/or low). Movement levels were designed using three common therapeutic approaches: (1) one arm moving only (unilateral), (2) two arms moving in mirrored directions about the participant’s midline (mirrored), or (3) two arms moving in opposing directions about the participant’s midline (opposing). Movement was quantified using an XSens System, a wearable inertial measurement unit (IMU) technology. Results reveal a highly engaging and effective approach to quantifying movement strategies. Inward and outward (horizontal) tasks resulted in decreased wrist extension. Upward and downward (vertical) tasks resulted in increased shoulder flexion, wrist radial deviation, wrist ulnar deviation, and elbow flexion. Lastly, compared to opposing, mirrored, and unilateral movement levels often exaggerated joint angles. Virtual reality games, like Beat Saber, offer a repeatable and customizable upper extremity intervention that has the potential to increase motivation in therapeutic applications.

Abstract Background Early identification of HCV is a critical health priority, especially now that treatment options are available to limit further transmission and provide cure before long-term sequelae develop. Emergency departments (EDs) are important clinical settings for HCV screening given that EDs serve many at-risk patients who do not access other forms of healthcare. In this article, we describe the rationale and design of The Determining Effective Testing in Emergency Departments and Care Coordination on Treatment Outcomes (DETECT) for Hepatitis C (Hep C) Screening Trial. Methods The DETECT Hep C Screening Trial is a multi-center prospective pragmatic randomized two-arm parallel-group superiority trial to test the comparative effectiveness of nontargeted and targeted HCV screening in the ED with a primary hypothesis that nontargeted screening is superior to targeted screening when identifying newly diagnosed HCV. This trial will be performed in the EDs at Denver Health Medical Center (Denver, CO), Johns Hopkins Hospital (Baltimore, MD), and the University of Mississippi Medical Center (Jackson, MS), sites representing approximately 225,000 annual adult visits, and designed using the PRECIS-2 framework for pragmatic trials. When complete, we will have enrolled a minimum of 125,000 randomized patient visits and have performed 13,965 HCV tests. In Denver, the Screening Trial will serve as a conduit for a distinct randomized comparative effectiveness trial to evaluate linkage-to-HCV care strategies. All sites will further contribute to embedded observational studies to assess cost effectiveness, disparities, and social determinants of health in screening, linkage-to-care, and treatment for HCV. Discussion When complete, The DETECT Hep C Screening Trial will represent the largest ED-based pragmatic clinical trial to date and all studies, in aggregate, will significantly inform how to best perform ED-based HCV screening. Trial registration ClinicalTrials.gov ID: NCT04003454 . Registered on 1 July 2019.

Abstract Background First Nations (FN) people of Canada experience health, social, and systemic inequities due to colonization. Consequently, COVID-19 has placed further mental health stress on people related to personal finances, employment security and worry over infection, resulting in exacerbated effects of unresolved past medical and physical traumas. This study aims to understand the experiences related to mental health in an Alberta FN community during the early stages of the pandemic. Methods In partnership with FN leadership, the study implemented an online cross-sectional survey. Adults from a large FN community in Alberta, Canada, were asked to complete a survey, including two mental health-related screening questionnaires: (1) Generalized Anxiety Disorder-2 item; and (2) Patient Health Questionnaire-2 item. In addition, respondents could provide responses to open-ended questions about their experiences. Results Among 106 respondents, 95 (89.6%) finished the survey; 18% of adults screened positive for depressive symptoms (score of 3 or greater) and reported difficulty following public health advice for using hand sanitizer, maintaining social distancing, or self-isolating. 21% of adults screened positive for symptoms of anxiety (score of 3 or greater) and reported difficulty maintaining social distance, self-isolating, obtaining food and clothing, or meeting other basic living requirements. Conclusions FN communities may be disproportionately affected by COVID-19, and may experience exacerbated symptoms of anxiety, depression and overall poor mental health and well-being. Additional supports and services, including for mental health, should be considered for FN in the context of COVID-19 public health measures. Highlights The COVID-19 pandemic has brought upon increased stress and accompanying symptoms of anxiety and depression for a First Nations community in Alberta. Studies, such as this one, that characterize the influence of the COVID-19 pandemic on mental health among First Nations people, are urgently needed because of increasing demands on healthcare systems due to the pandemic and potential delays in the care of patients living with pre-existing mental health conditions. There is an opportunity to capitalize on First Nations people’s experiences of post-traumatic growth proactively supporting/maintaining their well-being and possibly the development of community-based mental health interventions and supports.

Abstract Background Previous studies evaluating the accuracy of computed tomography (CT) in detecting caudal vena cava (CVC) invasion by adrenal tumors (AT) used a binary system and did not evaluate for other vessels. Objective Test a 7‐point scale CT grading system for accuracy in predicting vascular invasion and for repeatability among radiologists. Build a decision tree based on CT criteria to predict tumor type. Methods Retrospective observational cross‐sectional case study. Abdominal CT studies were analyzed by 3 radiologists using a 7‐point CT grading scale for vascular invasion and by 1 radiologist for CT features of AT. Animals Dogs with AT that underwent adrenalectomy and had pre‐ and postcontrast CT. Results Ninety‐one dogs; 45 adrenocortical carcinomas (50%), 36 pheochromocytomas (40%), 9 adrenocortical adenomas (10%) and 1 unknown tumor. Carcinoma and pheochromocytoma differed in pre‐ and postcontrast attenuation, contralateral adrenal size, tumor thrombus short‐ and long‐axis, and tumor and thrombus mineralization. A decision tree was built based on these differences. Adenoma and malignant tumors differed in contour irregularity. Probability of vascular invasion was dependent on CT grading scale, and a large equivocal zone existed between 3 and 6 scores, lowering CT accuracy to detect vascular invasion. Radiologists' agreement for detecting abnormalities (evaluated by chance‐corrected weighted kappa statistics) was excellent for CVC and good to moderate for other vessels. The quality of postcontrast CT study had a negative impact on radiologists' performance and agreement. Conclusions and Clinical Importance Features of CT may help radiologists predict AT type and provide probabilistic information on vascular invasion.

Atmospheric conditions affect the release of anemophilous pollen. Zhang et al. use a pollen emission model together with future climate data to simulate changes in pollen emission. The study shows that climate change driven pollen increase and seasonal changes may increase seasonal allergies

Abstract Canine diabetes has been considered a potential model of human type 1 diabetes (T1D), however the detection of autoantibodies common in humans with T1D in affected dogs is inconsistent. The aim of this study was to compare autoantibody responses in diabetic and healthy control dogs using a novel nucleic acid programmable protein array (NAPPA) platform. We performed a cross-sectional study of autoantibody profiles of 30 diabetic and 30 healthy control dogs of various breeds. Seventeen hundred human proteins related to the pancreas or diabetes were displayed on NAPPA arrays and interrogated with canine sera. The median normalized intensity (MNI) for each protein was calculated, and results were compared between groups to identify candidate autoantibodies. At a specificity of 90%, six autoantibodies had sensitivity greater than 10% (range 13–20%) for distinguishing diabetic and control groups. A combination of three antibodies (anti-KANK2, anti-GLI1, anti-SUMO2) resulted in a sensitivity of 37% (95% confidence interval (CI) 0.17–0.67%) at 90% specificity and an area under the receiver operating characteristics curve of 0.66 (95% CI 0.52–0.80). While this study does not provide conclusive support for autoimmunity as an underlying cause of diabetes in dogs, future studies should consider the use of canine specific proteins in larger numbers of dogs of breeds at high risk for diabetes.

β- and γ-herpesviruses transcribe their late genes in a manner distinct from host transcription. This process is directed by a complex of viral transcriptional activator proteins that hijack cellular RNA polymerase II and an unknown set of additional factors. We employed proximity labeling coupled with mass spectrometry, followed by CRISPR and siRNA screening to identify proteins functionally associated with the Kaposi's sarcoma-associated herpesvirus (KSHV) late gene transcriptional complex. These data revealed that the catalytic subunit of the viral DNA packaging motor, ORF29, is both dynamically associated with the viral transcriptional activator complex and potentiates gene expression late in infection. Through genetic mutation and deletion of ORF29, we establish that its catalytic activity potentiates viral transcription and is required for robust accumulation of essential late proteins during infection. Thus, we propose an expanded role for ORF29 that encompasses its established function in viral packaging and its newly discovered contributions to viral transcription and late gene expression in KSHV.

Summary: The cystic fibrosis (CF) respiratory tract harbors pathogenic bacteria that cause life-threatening chronic infections. Of these, Pseudomonas aeruginosa becomes increasingly dominant with age and is associated with worsening lung function and declining microbial diversity. We aimed to understand why P. aeruginosa dominates over other pathogens to cause worsening disease. Here, we show that P. aeruginosa responds to dynamic changes in iron concentration, often associated with viral infection and pulmonary exacerbations, to become more competitive via expression of the TseT toxic effector. However, this behavior can be therapeutically targeted using the iron chelator deferiprone to block TseT expression and competition. Overall, we find that iron concentration and TseT expression significantly correlate with microbial diversity in the respiratory tract of people with CF. These findings improve our understanding of how P. aeruginosa becomes increasingly dominant with age in people with CF and provide a therapeutically targetable pathway to help prevent this shift.

Abstract Background Regional body compositions are differentially associated with cardiometabolic risk factors. Simultaneous inclusion of both upper and lower body composition predictors in models is not often done, and studies which do include both measures (1) tend to exclude some tissue(s) of potential metabolic relevance, and (2) have used study populations with underrepresentation of individuals with African ancestries. Further, most body composition analyses do not employ compositional data analytic approaches, which may result in spurious associations. Objective The objective of this analysis was to assess associations of abdominal and thigh adipose (AT) and muscle tissues with hypertension and type 2 diabetes using compositional data analytic methods. Research Design and Methods This cross‐sectional analysis included 610 African Caribbean men (median age: 62 years; mean BMI: 27.8 kg/m2). Abdominal (three components: subcutaneous [ASAT] and visceral [VAT] AT, ‘other’ abdominal tissue) and mid‐thigh (four components: subcutaneous and intermuscular AT, muscle, bone) compositions were measured by computed tomography; additive log ratio transformations were applied to each composition. Regression models were used to simultaneously assess associations of abdominal and thigh component ratios with continuous risk factors (blood pressures, fasting glucose and insulin, HOMA‐IR) and disease categories. Results A two‐fold increase in ASAT:‘Other’ ratio was associated with higher continuous risk factors and with odds of being in a higher hypertension (OR: 1.77, 95%CI: 1.10–2.84) or diabetes (OR: 1.81, 95%CI: 1.06–3.10) category. A two‐fold increased VAT ratio was only associated with higher log‐insulin and log‐HOMA‐IR (β = 0.10, p

Abstract Background Phalaris species (Poaceae) occupy diverse environments throughout all continents except Antarctica. Phalaris arundinacea is an important forage, ornamental, wetland restoration and biofuel crop grown globally as well as being a wetland invasive. The nuclear ribosomal internal transcribed spacer (ITS) region has been used for Phalaris barcoding as a DNA region with high nucleotide diversity for Phalaris species identification. Recent findings that P. arundinacea populations in Minnesota USA are most likely native and not European prompted this analysis to determine whether Eurasian vs. native North American P. arundinacea differed in ITS regions. Our objectives were to amplify and compare ITS regions (ITS1 and ITS2) of historic herbaria (1882–2001) and extant (fresh) Phalaris specimens; analyze ITS regions for species-specific polymorphisms (diagnostic SNPs) and compare ITS regions of historic Phalaris specimens with known, extant Phalaris species. Results We obtained complete ITS1 and ITS2 sequences from 31 Phalaris historic (herbaria samples, 1908 to 2001) and five extant (fresh) specimens. Herbaria Phalaris specimens did not produce new SNPs (single nucleotide polymorphisms) not present in extant specimens. Diagnostic SNPs were identified in 8/12 (66.6%) Phalaris species. This study demonstrates the use of herbaria tissue for barcoding as a means for improved species identification of Phalaris herbaria specimens. No significant correlation between specimen age and genomic DNA concentration was found. Phalaris arundinacea showed high SNP variation within its clade, with the North American being distinctly different than other USA and most Eurasian types, potentially allowing for future identification of specific SNPs to geographic origin. Conclusions While not as efficient as extant specimens to obtain DNA, Phalaris herbaria specimens can produce high quality ITS sequences to evaluate historic genetic resources and facilitate identification of new species-specific barcodes. No correlation between DNA concentration and age of historic samples (119 year range) occurred. Considerable polymorphism was exhibited in the P. arundinacea clade with several N. American accessions being distinct from Eurasian types. Further development of within species- and genus-specific barcodes could contribute to designing PCR primers for efficient and accurate identification of N. American P. arundinacea. Our finding of misidentified Phalaris species indicates the need to exercise stringent quality control measures on newly generated sequence data and to approach public sequence databases in a critical way.

Abstract Conservation of carnivores involves finding solutions to minimize habitat loss and human-wildlife conflict. Understanding the nature of land-use economics can allow us to mitigate both threats. In the Pantanal, the two main economic activities are cattle ranching and ecotourism, each of which directly and indirectly affect the persistence of jaguars (Panthera onca). To understand how the geography of these economic activities is related to jaguar populations, we developed a jaguar distribution model (JDM), livestock density model, and ecotourism lodge density model for the Pantanal. Due to the recent wildfires within the Pantanal, we also assess the impact of burnt areas that are suitable for jaguars, cattle ranching, and tourism. Our JDM indicate that 64% of the Pantanal holds suitable habitat for jaguars. However, jaguar habitat suitability was positively correlated with ecotourism, but negatively correlated with areas most suitable for intensive cattle-ranching. This demonstrates a biome-wide scenario compatible with jaguar conservation. Of particular concern, recent wildfires overlap most suitable areas for jaguars. If wildfires become increasingly frequent, this would represent a serious threat to jaguars and many other wildlife populations. We emphasize the global importance of the Pantanal wetland ecoregion as a key stronghold for long-term jaguar conservation.

The reef-fish fauna of the Tropical Eastern Pacific (TEP) includes 12 species of surgeonfishes (Acanthuridae), five of them in the genus Acanthurus. Recent recreational scuba diving at Isla Darwin in the Galapagos archipelago produced photographs of adults of an additional species of Acanthurus, A. mata (Cuvier, 1829), for which there are no previous records in the TEP. This species may have escaped previous notice due to its semi-pelagic habitat preference and its resemblance to Acanthurus xanthopterus Valenciennes, 1835, which occurs throughout much of the Galapagos.