The rockefeller university

Leptin is an adipose tissue hormone that maintains homeostatic control of adipose tissue mass by regulating the activity of specific neural populations controlling appetite and metabolism1. Leptin regulates food intake by inhibiting orexigenic agouti-related protein (AGRP) neurons and activating anorexigenic pro-opiomelanocortin (POMC) neurons2. However, whereas AGRP neurons regulate food intake on a rapid time scale, acute activation of POMC neurons has only a minimal effect3-5. This has raised the possibility that there is a heretofore unidentified leptin-regulated neural population that rapidly suppresses appetite. Here we report the discovery of a new population of leptin-target neurons expressing basonuclin 2 (Bnc2) in the arcuate nucleus that acutely suppress appetite by directly inhibiting AGRP neurons. Opposite to the effect of AGRP activation, BNC2 neuronal activation elicited a place preference indicative of positive valence in hungry but not fed mice. The activity of BNC2 neurons is modulated by leptin, sensory food cues and nutritional status. Finally, deleting leptin receptors in BNC2 neurons caused marked hyperphagia and obesity, similar to that observed in a leptin receptor knockout in AGRP neurons. These data indicate that BNC2-expressing neurons are a key component of the neural circuit that maintains energy balance, thus filling an important gap in our understanding of the regulation of food intake and leptin action. We find that leptin-target neurons expressing basonuclin 2 in the arcuate nucleus that acutely suppress appetite by directly inhibiting agouti-related protein neurons are a key component of the neural circuit that maintains energy balance.

Background: One-third of people living with dementia (PLWD) have highly fragmented care (i.e., care spread across many ambulatory providers without a dominant provider). It is unclear whether PLWD with fragmented care and their caregivers perceive gaps in communication among the providers involved and whether any such gaps are perceived as benign inconveniences or as clinically meaningful, leading to adverse events. We sought to determine the frequency of perceived gaps in communication (coordination) among providers and the frequency of self-reported adverse events attributed to poor coordination. Methods: We conducted a cross-sectional study in the context of a Medicare accountable care organization (ACO) in New York in 2022-2023. We included PLWD who were attributed to the ACO, had fragmented care in the past year by claims (reversed Bice-Boxerman Index >= 0.86), and were in a pragmatic clinical trial on care management. We used an existing survey instrument to determine perceptions of care coordination and perceptions of four adverse events (repeat tests, drug-drug interactions, emergency department visits, and hospital admissions). ACO care managers collected data by telephone, using clinical judgment to determine whether each survey respondent was the patient or a caregiver. We used descriptive statistics to summarize results. Results: Of 167 eligible PLWD, surveys were completed for 97 (58.1%). Of those, 88 (90.7%) reported having >1 ambulatory visit and >1 ambulatory provider and were thus at risk for gaps in care coordination and included in the analysis. Of those, 23 respondents were patients (26.1%) and 64 were caregivers (72.7%), with one respondent's role missing. Overall, 57% of respondents reported a problem (or "gap") in the coordination of care and, separately, 18% reported an adverse event that they attributed to poor care coordination. Conclusion: Gaps in coordination of care for PLWD are reported to be very common and often perceived as hazardous.

Methyl-CpG-binding protein 2 (MeCP2) is a master regulator of neuronal gene expression, and its genetic mutations cause the neurodevelopmental disorder Rett syndrome. Single-molecule experiments have enabled the direct visualization of the dynamics of MeCP2 on DNA, shedding light on how the specific chromatin context tunes MeCP2 function.

The complex carbohydrate structures decorating human proteins and lipids, also called glycans, are abundantly present at cell surfaces and in the secretome. Glycosylation is vital for biological processes including cell-cell recognition, immune responses, and signaling pathways. Therefore, the structural and functional characterization of the human glycome is gaining more and more interest in basic biochemistry research and in the context of developing new therapies, diagnostic tools, and biotechnology applications. For glycomics to reach its full potential in these fields, it is critical to appreciate the specific factors defining the function of the human glycome. Here, we review the glycosyltransferases (the writers) that form the glycome and the glycan-binding proteins (the readers) with an essential role in decoding glycan functions. While abundantly present throughout different cells and tissues, the function of specific glycosylation features is highly dependent on their context. In this review, we highlight the relevance of studying the glycome in the context of specific carrier proteins, cell types, and subcellular locations. With this, we hope to contribute to a richer understanding of the glycome and a more systematic approach to identifying the roles of glycosylation in human physiology.

Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained1,2. Here, we report on two unrelated people who had HSE as children and are homozygous for rare deleterious variants of TMEFF1, which encodes a cell membrane protein that is preferentially expressed by brain cortical neurons. TMEFF1 interacts with the cell-surface HSV-1 receptor NECTIN-1, impairing HSV-1 glycoprotein D- and NECTIN-1-mediated fusion of the virus and the cell membrane, blocking viral entry. Genetic TMEFF1 deficiency allows HSV-1 to rapidly enter cortical neurons that are either patient specific or derived from CRISPR-Cas9-engineered human pluripotent stem cells, thereby enhancing HSV-1 translocation to the nucleus and subsequent replication. This cellular phenotype can be rescued by pretreatment with type I interferon (IFN) or the expression of exogenous wild-type TMEFF1. Moreover, ectopic expression of full-length TMEFF1 or its amino-terminal extracellular domain, but not its carboxy-terminal intracellular domain, impairs HSV-1 entry into NECTIN-1-expressing cells other than neurons, increasing their resistance to HSV-1 infection. Human TMEFF1 is therefore a host restriction factor for HSV-1 entry into cortical neurons. Its constitutively high abundance in cortical neurons protects these cells from HSV-1 infection, whereas inherited TMEFF1 deficiency renders them susceptible to this virus and can therefore underlie HSE. A study of two childhood cases of herpes simplex encephalitis shows that TMEFF1 interacts with the HSV-1 cell-surface receptor NECTIN-1, preventing HSV-1 from fusing with the cell membrane and entering cortical neurons.

In this review, we explore the social behavior of the fruit fly Drosophila melanogaster, integrating mechanistic, ecological and evolutionary perspectives. Despite its status as a major laboratory model organism, D. melanogaster's social life remains generally underappreciated by biologists. Adult flies attract others to food sources through pheromone deposition, leading to group formation. Within these groups, males engage in competitive reproductive behaviors while females adopt complex mating patterns and lay eggs communally. Both sexes adapt their reproductive behaviors to early as well as current social experience. Communal egg-laying by females promotes larval group formation, with larvae cooperating to dig tunnels for protection and breathing while feeding. Aggregation is also visible at the pupal stage, suggesting a social dimension to the entire life cycle of this species. We examine the competitive and cooperative behaviors of D. melanogaster, considering the ecological context (resource distribution, predation, parasitism pressures, and reproductive strategies) that influences these social interactions. We also discuss how individual behavior and physiology varies with group size and diversity, potentially as an adaptation to the costs and benefits of being in a group. This review underscores the potential of fruit flies in advancing research on social interactions and dynamics, demonstrating their usefulness for the fields of sociality, evolution and social neurosciences.

Background. Development of a screening assay for the clinical use of broadly neutralizing antibodies (bnAbs) is a priority for HIV therapy and cure initiatives. Methods. We assessed the PhenoSense Monoclonal Antibody Assay (Labcorp-Monogram Biosciences), which is Clinical Laboratory Improvement Amendments (CLIA) validated and has been used prospectively and retrospectively in multiple recent bnAb clinical trials. Results. When performed on plasma and longitudinal peripheral blood mononuclear cell samples (before and during antiretroviral therapy, respectively), as sourced from a recent clinical trial, the PhenoSense assay produced robust reproducibility, concordance across sample types, and expected ranges in the susceptibility measures of bnAbs in clinical development. When applied retrospectively to baseline samples from 3 recent studies, the PhenoSense assay correlated with published laboratory-based study evaluations, but baseline bnAb susceptibility was not consistently predictive of durable virus suppression. Assessment of assay feasibility in 4 recent clinical studies provides estimates of assay success rate and processing time. Conclusions. The PhenoSense Monoclonal Antibody Assay provides reproducible bnAb susceptibility measurements across relevant sample types yet is not consistently predictive of virus suppression. Logistical and operational assay requirements can affect timely clinical trial conduct. These results inform bnAb studies in development.

Patients with severe West Nile virus and SARS-CoV-2 infections deserve accurate diagnosis of underlying diseases, determining possible anti-interferon autoantibody production, since they must receive antiviral and immunological therapies to enhance antiviral response.The current study aimed to investigate determinants of severity in a previously healthy patient who experienced 2 life-threatening infections, from West Nile Virus (WNV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). During coronavirus disease 2019 (COVID-19) hospitalization he was diagnosed with a thymoma, retrospectively identified as already present at the time of WNV infection. Heterozygosity for p.Pro554Ser in the TLR3 gene, which increases susceptibility to severe COVID-19, and homozygosity for CCR5 c.554_585del, associated with severe WNV infection, were found. Neutralizing anti-interferon (IFN)-alpha and anti-IFN-omega autoantibodies were detected, likely induced by the underlying thymoma and increasing susceptibility to both severe COVID-19 pneumonia and West Nile encephalitis.

Myriad DNA-binding proteins undergo dynamic assembly, translocation, and conformational changes while on DNA or alter the physical configuration of the DNA substrate to control its metabolism. It is now possible to directly observe these activities-often central to the protein function-thanks to the advent of single-molecule fluorescence- and force-based techniques. In particular, the integration of fluorescence detection and force manipulation has unlocked multidimensional measurements of protein-DNA interactions and yielded unprecedented mechanistic insights into the biomolecular processes that orchestrate cellular life. In this review, we first introduce the different experimental geometries developed for single-molecule correlative force and fluorescence microscopy, with a focus on optical tweezers as the manipulation technique. We then describe the utility of these integrative platforms for imaging protein dynamics on DNA and chromatin, as well as their unique capabilities in generating complex DNA configurations and uncovering force-dependent protein behaviors. Finally, we give a perspective on the future directions of this emerging research field.

Immune responses need to be regulated to prevent autoimmunity. CRISPR-Cas systems provide adaptive immunity in prokaryotes through the acquisition of short DNA sequences from invading viruses (bacteriophages), known as spacers. Spacers are inserted into the CRISPR locus and serve as templates for the transcription of guides used by RNA-guided nucleases to recognize complementary nucleic acids of the invaders and start the CRISPR immune response. In type II-A CRISPR systems, Cas9 uses the guide RNA to cleave target DNA sequences in the genome of infecting phages, and the tracrRNA to bind the promoter of cas genes and repress their transcription. We previously isolated a Cas9 mutant carrying the I473F substitution that increased the frequency of spacer acquisition by 2-3 orders of magnitude, leading to a fitness cost due to higher levels of autoimmunity. Here, we investigated the molecular basis underlying these findings. We found that the I473F mutation decreases the association of Cas9 to tracrRNA, limiting its repressor function, leading to high levels of expression of cas genes, which in turn increase the strength of the type II-A CRISPR-Cas immune response. We obtained similar results for a related type II-A system, and therefore our findings highlight the importance of the interaction between Cas9 and its tracrRNA cofactor in tuning the immune response to balanced levels that enable phage defense but avoid autoimmunity. Graphical Abstract