The expression of co-inhibitory receptors, such as CTLA-4 and PD-1, on effector T cells is a key mechanism for ensuring immune homeostasis. Dysregulated expression of co-inhibitory receptors on CD4
T ...cells promotes autoimmunity, whereas sustained overexpression on CD8
T cells promotes T cell dysfunction or exhaustion, leading to impaired ability to clear chronic viral infections and diseases such as cancer
. Here, using RNA and protein expression profiling at single-cell resolution in mouse cells, we identify a module of co-inhibitory receptors that includes not only several known co-inhibitory receptors (PD-1, TIM-3, LAG-3 and TIGIT) but also many new surface receptors. We functionally validated two new co-inhibitory receptors, activated protein C receptor (PROCR) and podoplanin (PDPN). The module of co-inhibitory receptors is co-expressed in both CD4
and CD8
T cells and is part of a larger co-inhibitory gene program that is shared by non-responsive T cells in several physiological contexts and is driven by the immunoregulatory cytokine IL-27. Computational analysis identified the transcription factors PRDM1 and c-MAF as cooperative regulators of the co-inhibitory module, and this was validated experimentally. This molecular circuit underlies the co-expression of co-inhibitory receptors in T cells and identifies regulators of T cell function with the potential to control autoimmunity and tumour immunity.
The Atlantic meridional overturning circulation (AMOC) is an important component of the North Atlantic climate system. Here, simulations from 10 coupled climate models are used to calculate patterns ...of sea surface temperature (SST) and subsurface density change associated with decadal AMOC variability. The models are evaluated using observational constraints and it is shown that all 10 models suffer from North Atlantic Deep Water transports that are too shallow, although the biases are least severe in the Community Climate System Model, version 4 (CCSM4). In the models that best compare with observations, positive AMOC anomalies are associated with reduced Labrador Sea stratification and increased midocean (800–1800 m) densities in the subpolar gyre. Maximum correlations occur when AMOC anomalies lag Labrador Sea stratification and subsurface density anomalies by 2–6 yr and 0–3 yr, respectively. In all 10 models, North Atlantic warming follows positive AMOC anomalies, but the patterns and magnitudes of SST change are variable. A simple detection and attribution analysis is then used to evaluate the utility of Atlantic midocean density and Labrador Sea stratification indices for detecting changes to the AMOC in the presence of increasing CO₂ concentrations. It is shown that trends in midocean density are identifiable (although not attributable) significantly earlier than trends in the AMOC. For this reason, subsurface density observations could be a useful complement to transport observations made at specific latitudes and may help with the more rapid diagnosis of basin-scale changes in the AMOC. Using existing observations, it is not yet possible to detect a robust trend in the AMOC using either midocean densities or transport observations from 26.5°N.
What Is Strep Throat? Rayborn, Cari H; Jackson, Christopher D; Summers, Nathan A
JAMA : the journal of the American Medical Association,
05/2024, Letnik:
331, Številka:
20
Journal Article
Semaglutide and Cardiovascular Outcomes Campbell, Laura A; Jenkins, Alexa V; Jackson, Christopher D
The New England journal of medicine,
2024-Feb-22, Letnik:
390, Številka:
8
Journal Article
In the United States, falls are the leading cause of fatal and nonfatal injuries for geriatric patients. With a growing aging population, medical trainees must gain experience with geriatric ...assessments, including fall risk and prevention. To the authors' knowledge, no prior studies have explored who most often initiates fall discussions between Internal Medicine (IM) residents and geriatric (age 65 years and older) patients. Our objective was to determine who most often initiates fall discussions between IM residents and geriatric patients and the barriers to having these discussions.
This 2023 quantitative needs assessment used surveys distributed to ambulatory geriatric patients, IM residents, and attending physicians within an urban IM resident continuity clinic. We used the Stopping Elderly Accidents, Death & Injuries assessment from the Centers for Disease Control and Prevention to determine patient fall risk.
Response rates were 46%, 51%, and 67% for patients, residents, and attendings, respectively. Of the 39 patients who were assessed, 51% were at risk of falling. Eighty-seven percent of patients have had a fall discussion with their residents, and 59% reported these were resident initiated; however, 75% of 28 residents reported initiating fall conversations rarely, and all 4 attendings said that they started these discussions most of the time while staffing patients with residents. Modifiable resident-identified barriers to discussing falls included forgetfulness and lack of knowledge regarding completing a fall risk assessment.
Most patients have conversations about falling with their physicians, but discrepancies exist regarding who initiates them. Data from this study suggest that attendings may be instrumental in starting these conversations. Reminder systems and fall risk didactic curricula may increase resident-initiated fall discussions.
Current inflammatory bowel disease (IBD) therapies are ineffective in a high proportion of patients. Combining bulk and single-cell transcriptomics, quantitative histopathology and in situ ...localization across three cohorts of patients with IBD (total n = 376), we identify coexpressed gene modules within the heterogeneous tissular inflammatory response in IBD that map to distinct histopathological and cellular features (pathotypes). One of these pathotypes is defined by high neutrophil infiltration, activation of fibroblasts and vascular remodeling at sites of deep ulceration. Activated fibroblasts in the ulcer bed display neutrophil-chemoattractant properties that are IL-1R, but not TNF, dependent. Pathotype-associated neutrophil and fibroblast signatures are increased in nonresponders to several therapies across four independent cohorts (total n = 343). The identification of distinct, localized, tissular pathotypes will aid precision targeting of current therapeutics and provides a biological rationale for IL-1 signaling blockade in ulcerating disease.
To date, efforts to switch the cofactor specificity of oxidoreductases from nicotinamide adenine dinucleotide phosphate (NADPH) to nicotinamide adenine dinucleotide (NADH) have been made on a ...case-by-case basis with varying degrees of success. Here we present a straightforward recipe for altering the cofactor specificity of a class of NADPH-dependent oxidoreductases, the ketol-acid reductoisomerases (KARIs). Combining previous results for an engineered NADH-dependent variant of Escherichia coli KARI with available KARI crystal structures and a comprehensive KARI-sequence alignment, we identified key cofactor specificity determinants and used this information to construct five KARIs with reversed cofactor preference. Additional directed evolution generated two enzymes having NADH-dependent catalytic efficiencies that are greater than the wild-type enzymes with NADPH. High-resolution structures of a wild-type/variant pair reveal the molecular basis of the cofactor switch.
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