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Orthogonal or non‐cross‐reacting transcription factors are used in synthetic biology as components of genetic circuits. Brödel et al. (2016) engineered 12 such cIλ transcription factor variants using a directed evolution ‘PACEmid’ system. The variants operate as dual activator/repressors and expand gene circuit construction possibilities. However, the high‐copy phagemid vectors carrying the cIλ variants imposed high metabolic burden upon cells. Here, the authors ‘remaster’ the phagemid backbones to relieve their burden substantially, exhibited by a recovery in Escherichia coli growth. The remastered phagemids' ability to function within the PACEmid evolver system is maintained, as is the cIλ transcription factors' activity within these vectors. The low‐burden phagemid versions are more suitable for use in PACEmid experiments and synthetic gene circuits; the authors have, therefore, replaced the original high‐burden phagemids on the Addgene repository. The authors’ work emphasises the importance of understanding metabolic burden and incorporating it into design steps in future synthetic biology ventures.

Latino men who have sex with men (LMSM) account for a disproportionate and growing number of HIV diagnoses in the United States. Intersectional stigma remains a key driver of HIV inequities; however, most quantitative intersectional stigma measures are limited and do not consider the larger social context. NEXUS is a longitudinal cohort study that will use social network methods and theory to rigorously measure intersectional stigma among LMSM and quantify the longitudinal association between intersectional stigma and HIV prevention outcomes. We will prospectively enroll 500 HIV-negative LMSM in San Diego, California, and follow participants over 1 year. At baseline and every 6 months thereafter (Month 0, Month 6, and Month 12), participants will complete an interviewer-administered social network inventory and a self-administered survey to collect information on their social networks (alter types, size, and characteristics) and HIV prevention engagement (HIV testing and pre-exposure prophylaxis use), respectively. Information on HIV prevention engagement will also be abstracted from medical records. Intersectional stigma will be operationalized as a multilevel latent variable comprised of observed measures of anticipated and enacted stigma experienced by a participant from an alter toward the participant's Latino, masculine, and sexual identities. Multilevel structural equation modeling will be used to estimate the longitudinal association between intersectional stigma, HIV testing, and pre-exposure prophylaxis use, considering potential mediators and moderators. NEXUS recruitment began in June 2021, and as of March 11, 2025, a total of 482 participants had been enrolled. Enrollment is planned to end by May 2025, with baseline results expected late 2025 and through the following year. Data collection for our prospective study aims is expected to be complete in June 2026, with data analysis and expected results published later that year. NEXUS will advance quantitative intersectional stigma measurement using a novel social network approach. This study will identify intervention targets to reduce HIV inequities among LMSM and mitigate the harms of intersectional stigma in this population.

Sustainable bioprocesses for energy and materials production and waste resource recovery are needed to support circular economic development. Enzyme surface display on cells or functionalized materials has emerged as a promising paradigm for sustainable bioprocess innovation. Surface (S)-layers are geometric, monomolecular, highly stable crystalline protein lattices encasing the outside of many bacteria and archaea. Several S-layer genes have been shown to tolerate heterologous insertions, thereby enabling high-density display of peptides of interest on cell surfaces without additional costly immobilisation or conjugation steps. Here, we employ an S-layer display platform in Caulobacter vibrioides CB2A JS4038 to express functional cellulases up to 445 amino acids in length. We explore critical design considerations needed for successful catalytic display and demonstrate synergistic activities between differentially expressed cellulases relevant to combinatorial lignocellulosic biomass conversion. Functionalised S-layers capable of transforming lignocellulosic biomass could have useful applications in engineering whole-cell biocatalysts and synthetic microbial consortia tuned for different bioprocess applications.

This groundbreaking film introduces viewers to men and women who have never experienced sexual attraction. In 2000, David Jay came out as asexual to his parents, a quality he accepts about himself. And David is not alone; studies show that as much as one percent of the population may be asexual. Living in a society obsessed with sex, how does one deal with life as an outsider? In (A)Sexual, people describe firsthand the challenges of acknowledging to themselves--and others--their asexuality.

Chronic kidney disease (CKD) affects ~10% of the population and cardiovascular disease is its commonest complication. Despite treatment, patient outcomes remain poor and newer therapies are urgently needed. Here, we investigated the systemic and renal effects of apelin in CKD. In a randomized, double-blind, placebo-controlled, crossover study, 24 subjects (12 patients with CKD and 12 matched healthy subjects) received pyroglutamated apelin-13 ([Pyr 1 ]apelin-13, 1 nmol/min and 30 nmol/min) or matched placebo on two separate visits. Systemic and renal hemodynamics were monitored throughout. The co-primary endpoints were change in systemic vascular resistance index and renal blood flow. Secondary endpoints were change in blood pressure, cardiac output, pulse wave velocity, glomerular filtration rate, natriuresis, free water clearance and urinary protein excretion. In both health and CKD, 30 nmol/min [Pyr 1 ]apelin-13 reduced mean arterial pressure by ~4%, systemic vascular resistance by ~12%, and increased cardiac index by ~10%, compared to placebo (p < 0.05 for all). Both doses of [Pyr 1 ]apelin-13 increased renal blood flow by ~15%, natriuresis by ~20% and free water clearance by ~10%, compared to placebo (p < 0.05 for all). In patients with chronic kidney disease only, glomerular filtration rate fell by ~10%, effective filtration fraction by ~5% and proteinuria by ~25% (p < 0.01 for all). Apelin has short-term cardiovascular and renal benefits in CKD. If maintained longer-term, these should improve patient outcomes. Clinical trials of long-acting oral apelin agonists are justified in CKD and other conditions with impaired salt and water balance. Registration number at www.clinicalTrials.gov : NCT03956576. Funded by Kidney Research UK.  Despite treatment, patients with chronic kidney disease remain at high risk of kidney failure and cardiovascular disease. Here, the authors show that apelin offers potential cardiorenal protection for this high-risk patient group.

Lymph node (LN) lymphatic endothelial cells (LEC) actively acquire and archive foreign antigens. Here, we address questions of how LECs achieve durable antigen archiving and whether LECs with high levels of antigen express unique transcriptional programs. We use single cell sequencing in dissociated LN tissue and spatial transcriptomics to quantify antigen levels in LEC subsets and dendritic cell populations at multiple time points after immunization and determine that ceiling and floor LECs archive antigen for the longest duration. We identify, using spatial transcriptomics, antigen positive LEC-dendritic cell interactions. Using a prime-boost strategy we find increased antigen levels within LECs after a second immunization demonstrating that LEC antigen acquisition and archiving capacity can be improved over multiple exposures. Using machine learning we define a unique transcriptional program within archiving LECs that predicts LEC archiving capacity in independent mouse and human data sets. We test this modeling, showing we can predict lower levels of LEC antigen archiving in chikungunya virus-infected mice and demonstrate in vivo the accuracy of our prediction. Collectively, our findings establish unique properties of LECs and a defining transcriptional program for antigen archiving that can predict antigen archiving capacity in different disease states and organisms. Dendritic cells are supplied antigens by other cells such as lymphatic endothelial cells (LEC) at late time points after immunization. Here the authors show antigen archiving is defined by a transcriptional program that can predict antigen archiving depending on the priming pathogen, and that boosting of immune responses increases the archiving.

Infection with chikungunya virus (CHIKV) causes disruption of draining lymph node (dLN) organization, including paracortical relocalization of B cells, loss of the B cell-T cell border, and lymphocyte depletion that is associated with infiltration of the LN with inflammatory myeloid cells. Here, we found that, during the first 24 hours of infection, CHIKV RNA accumulated in MARCO-expressing lymphatic endothelial cells (LECs) in both the floor and medullary LN sinuses. The accumulation of viral RNA in the LN was associated with a switch to an antiviral and inflammatory gene expression program across LN stromal cells, and this inflammatory response - including recruitment of myeloid cells to the LN - was accelerated by CHIKV-MARCO interactions. As CHIKV infection progressed, both floor and medullary LECs diminished in number, suggesting further functional impairment of the LN by infection. Consistent with this idea, antigen acquisition by LECs, a key function of LN LECs during infection and immunization, was reduced during pathogenic CHIKV infection.

Background Many health care practitioners use a variety of hands-on treatments to improve symptoms and disablement in patients with musculoskeletal pathology. Research to date indirectly suggests a potentially broad effect of manual therapy on the neuromotor processing of functional behavior within the supraspinal central nervous system (CNS) in a manner that may be independent of modification at the level of local spinal circuits. However, the effect of treatment speed, as well as the specific mechanism and locus of CNS changes, remain unclear. Methods/Design We developed a placebo-controlled, randomized study to test the hypothesis that manual therapy procedures directed to the talocrural joint in individuals with post-acute ankle sprain induce a change in corticospinal excitability that is relevant to improve the performance of lower extremity functional behavior. Discussion This study is designed to identify potential neuromotor changes associated with manual therapy procedures directed to the appendicular skeleton, compare the relative effect of treatment speed on potential neuromotor effects of manual therapy procedures, and determine the behavioral relevance of potential neuromotor effects of manual therapy procedures. Trial Registration http://www.clinicaltrials.gov identifier NCT00847769.

Data from the Harvard School of Public Health College Alcohol Study (1993) were used to describe weekly alcohol consumption and its associated problems among a representative national sample of college students. The median number of drinks consumed/week by all students, regardless of drinking status, was 1.5. When students were divided by drinking pattern, the median number of drinks/week was 0.7 for those who did not binge drink and 3.7 for those who did so infrequently. For frequent binge drinkers, the median was considerably higher: 14.5 drinks/week. Nationally, 1 in 5 five college students is a frequent binge drinker. Binge drinkers consumed 68% of all the alcohol that students reported drinking, and they accounted for the majority of alcohol-related problems. The data indicate that behavioral norms for alcohol consumption vary widely among students and across colleges. Therefore, it may not be possible to design an effective \"one size fits all\" approach to address college alcohol use.

Objectives. We described the process of engaging key stakeholders in a systematic review of requirements for a master of public health (MPH) degree within the Department of Health Behavior and Health Education, University of North Carolina Gillings School of Global Public Health, and summarized resulting changes. Methods. A benchmarking study of 11 peer institutions was completed. Key stakeholders (i.e., current students, alumni, faculty, staff, employers, and practicum preceptors) received online or print surveys. A faculty retreat was convened to process results and reach consensus on program revisions. Results. MPH program changes included (1) improved advising and mentoring program, (2) elimination of research and practice track options, (3) increased elective and decreased required credit hours, (4) replacement of master's paper requirement with “deliverables” (written products such as reports, documents, and forms) produced as part of the required “Capstone” course, (5) extended community field experience to 2 semesters and moved it to year 2 of the program, and (6) allowed practica of either 200, 300, or 400 hours. Conclusions. Engaging key stakeholders in the program review process yielded important changes to the MPH degree program requirements. Others may consider this approach when undertaking curriculum reviews.