The rockefeller university

The brain is highly sensitive to damage caused by infection and inflammation1,2. Herpes simplex virus 1 (HSV-1) is a neurotropic virus and the cause of herpes simplex encephalitis3. It is unknown whether neuron-specific antiviral factors control virus replication to prevent infection and excessive inflammatory responses, hence protecting the brain. Here we identify TMEFF1 as an HSV-1 restriction factor using genome-wide CRISPR screening. TMEFF1 is expressed specifically in neurons of the central nervous system and is not regulated by type I interferon, the best-known innate antiviral system controlling virus infections. Depletion of TMEFF1 in stem-cell-derived human neurons led to elevated viral replication and neuronal death following HSV-1 infection. TMEFF1 blocked the HSV-1 replication cycle at the level of viral entry through interactions with nectin-1 and non-muscle myosin heavy chains IIA and IIB, which are core proteins in virus-cell binding and virus-cell fusion, respectively4-6. Notably, Tmeff1-/- mice exhibited increased susceptibility to HSV-1 infection in the brain but not in the periphery. Within the brain, elevated viral load was observed specifically in neurons. Our study identifies TMEFF1 as a neuron-specific restriction factor essential for prevention of HSV-1 replication in the central nervous system. A study identifies TMEFF1 as a neuron-specific restriction factor essential for prevention of replication of herpes simplex virus type 1 in the central nervous system.

Background Mechanical thrombectomy (MT) is the treatment standard in eligible patients with acute ischemic stroke (AIS) secondary to large vessel occlusions (LVO). Studies have shown that good collateral status is a strong predictor of MT efficacy, thus making collateral status important to quickly assess. The Los Angeles Motor Scale is a clinically validated tool for identifying LVO in the field. The aim of this study is to investigate whether admission LAMS score is also associated with the American Society of Interventional and Therapeutic Neuroradiology (ASITN) collateral score on digital subtraction angiography (DSA). Methods We conducted a retrospective multicenter cohort study of consecutive patients presenting with AIS caused by LVO from 9/1/2017 to 10/1/2023 with diagnostically adequate DSA imaging. Demographic, clinical, and imaging data was collected through manual chart review. Both univariate and multivariate analysis were applied to assess associations. A p-value <0.05 was considered significant. Results A total of 308 patients (median age: 68, IQR: 57.5-77) were included in the study. On multivariate logistic regression analysis, we found that lower admission LAMS score (adjusted OR: 0.82, 95% CI: 0.68-0.98, p < 0.05) and higher ASPECTS score (adjusted OR: 1.21, 95% CI: 1.02-1.42, p < 0.05) were independently associated with good DSA ASITN collateral score of 3-4. Conclusions Admission LAMS and ASPECTS score are both independently associated with DSA ASITN collateral score. This demonstrates the capability of LAMS to act as a surrogate marker of CS in the field.

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.

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.

A search for direct production of low-mass dimuon resonances is performed using root s = 13TeV proton-proton collision data collected by the CMS experiment during the 2017-2018 operation of the CERN LHC with an integrated luminosity of 96.6 fb(-1). The search exploits a dedicated high-rate trigger stream that records events with two muons with transverse momenta as low as 3 GeV but does not include the full event information. The search is performed by looking for narrow peaks in the dimuon mass spectrum in the ranges of 1.1-2.6 GeV and 4.2-7.9 GeV. No significant excess of events above the expectation from the standard model background is observed. Model-independent limits on production rates of dimuon resonances within the experimental fiducial acceptance are set. Competitive or world's best limits are set at 90% confidence level for a minimal dark photon model and for a scenario with two Higgs doublets and an extra complex scalar singlet (2HDM+S). Values of the squared kinetic mixing coefficient epsilon(2) in the dark photon model above 10(-6) are excluded over most of the mass range of the search. In the 2HDM+S, values of the mixing angle sin(theta(H)) above 0.08 are excluded over most of the mass range of the search with a fixed ratio of the Higgs doublets vacuum expectation tan beta = 0.5.

A new measurement of inclusive-jet cross sections in the Breit frame in neutral current deep inelastic scattering using the ZEUS detector at the HERA collider is presented. The data were taken in the years 2004-2007 at a centre-of-mass energy of 318 GeV and correspond to an integrated luminosity of 347 pb(-1). The jets were reconstructed using the k(t)-algorithm in the Breit reference frame. They have been measured as a function of the squared momentum transfer, Q(2), and the transverse momentum of the jets in the Breit frame, p(perpendicular to,Breit). The measured jet cross sections are compared to previous measurements and to perturbative QCD predictions. The measurement has been used in a next-to-next-to-leading-order QCD analysis to perform a simultaneous determination of parton distribution functions of the proton and the strong coupling, resulting in a value of alpha(s) (M-Z(2)) = 0.1142 +/- 0.0017 (experimental/fit)(-0.0007)(+0.0006) (model/parameterisation)(-0.0004)(+0.0006) (scale), whose accuracy is improved compared to similarmeasurements. In addition, the running of the strong coupling is demonstrated using data obtained at different scales.