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The hypothalamus in the central nervous system (CNS) has important functions in controlling systemic metabolism. A calorie-rich diet triggers CNS immune activation, impairing metabolic control and promoting obesity and Type 2 Diabetes (T2D), but the mechanisms driving hypothalamic immune activation remain unclear. Here we identify regulatory T cells (Tregs) as key modulators of hypothalamic immune responses. In mice, calorie-rich environments activate hypothalamic CD4 + T cells, infiltrating macrophages and microglia while reducing hypothalamic Tregs. mRNA profiling of hypothalamic CD4 + T cells reveals a Th1-like activation state, with increased Tbx21 , Cxcr3 and Cd226 but decreased Ccr7 and S1pr1 . Importantly, results from Treg loss-of function and gain-of-function experiments show that Tregs limit hypothalamic immune activation and reverse metabolic impairments induced by hyper-caloric feeding. Our findings thus help refine the current model of Treg-centered immune-metabolic crosstalk in the brain and may contribute to the development of precision immune modulation for obesity and diabetes. Hypothalamus participates in systemic metabolic processes, while high calorie intake increases immune activation in the central nervous system. Here the authors show that reduced regulatory T cells in the hypothalamus contribute to elevated immune activation in a high calorie environment, thereby prompting a potential therapy target for metabolic diseases.

To successfully colonize the intestine, bacteria must survive passage through the stomach. The permeability of the outer membrane renders the periplasm of Gram-negative bacteria vulnerable to stomach acid, which inactivates proteins. Here we report that the semipermeable nature of the outer membrane allows the development of a strong Donnan equilibrium across this barrier at low pH. As a result, when bacteria are exposed to conditions that mimic gastric juice, periplasmic chloride concentrations rise to levels that exceed 0.6 M. At these chloride concentrations, proteins readily aggregate in vitro. The acid sensitivity of strains lacking acid-protective chaperones is enhanced by chloride, suggesting that these chaperones protect periplasmic proteins both from acidification and from the accompanying accumulation of chloride. These results illustrate how organisms have evolved chaperones to respond to the substantial chemical threat imposed by otherwise innocuous chloride concentrations that are amplified to proteotoxic levels by low-pH-induced Donnan equilibrium effects.

On Iowa State's first offensive play of the game, sophomore defensive back Tevin Madison intercepted a pass from Iowa State quarterback Sam Richardson.

Tosha Foster, unit manager for Hospitality Services, said she met with a Blue Bell representative Tuesday who told her the next phases include shipping to the Dallas area and then the Lubbock area.

Three days of nonstop and extremely loud music, huge crowds and blistering heat may sound like hell to some people, but this is exactly what I knew I would be in for when I purchased a pass to weekend one of Austin City Limits Music Festival.

Considering its roster had seven new players, including five freshmen, and a key player injured during the 2014-2015 season, the Texas Tech men's basketball team didn't have as dismal of a season as some may think.

Graffiti supporting the movement covered walls around the city, they even put the phrase on the famous Arc de Triomphe and in the garden at the Palace of Versailles.

Plasma cell differentiation is a tightly regulated process that requires appropriate T cell helps to reach the induction threshold. To further understand mechanisms by which T cell inputs regulate B cell fate decision, we investigate the minimal IL-2 stimulation for triggering human plasma cell differentiation in vitro. Here we show that the timed repression of BACH2 through IL-2-mediated ERK/ELK1 signalling pathway directs plasma cell lineage commitment. Enforced BACH2 repression in activated B cells unlocks the plasma cell transcriptional program and induces their differentiation into immunoglobulin M-secreting cells. RNA-seq and ChIP-seq results further identify BACH2 target genes involved in this process. An active regulatory region within the BACH2 super-enhancer, under ELK1 control and differentially regulated upon B-cell activation and cellular divisions, helps integrate IL-2 signal. Our study thus provides insights into the temporal regulation of BACH2 and its targets for controlling the differentiation of human naive B cells. T cells help B cells to differentiate into antibody-producing plasma cells. Here the authors show that T cells produce interleukin-2 to activate ERK/ELK1 and suppress BACH2 expression by modulating the BACH2 super-enhancer, thereby altering BACH2 downstream transcription programs for plasma cell differentiation.

Historically, HER2 status in invasive breast cancer has been categorized as HER2-positive (IHC 3+, IHC 2+/ISH+) or HER2-negative (IHC 0, IHC 1+, IHC 2+/ISH-). Patients meeting IHC 0 with membrane staining (HER2-ultralow) criteria may benefit from HER2-targeted therapies such as trastuzumab deruxtecan. This cohort study assessed the prevalence of HER2-ultralow expression by re-scoring HER2 IHC slides using Mayo Clinic electronic health record data. Three hundred patients with advanced breast cancer (Stages III-IV) and documented HER2 IHC 0 status (January 2017-March 2023) were identified. One slide per patient was digitized and independently re-scored by two Mayo Clinic pathologists following the 2023 ASCO-CAP guidelines, including tumor staining percentage to denote HER2-ultralow status. A sensitivity analysis was performed by a third independent pathologist. The re-scored patients had a mean age of 57.7 years (SD = 13.6). Most samples (95%, n = 285) remained scored IHC 0 by at least one pathologist; 60% of these met HER2-ultralow criteria per at least one pathologist. HER2-ultralow prevalence ranged from 43% to 45% per pathologist, with 57% overall interpathologist concordance. Samples with no observable staining comprised most of the concordant cases. Treatment patterns were similar between HER2-ultralow and no-staining groups; however, time to treatment failure (TTF) varied between groups across lines of therapy (LOT). In HR- positive cohorts, median TTF for LOT1 was 7.73 months in patients with HER2-ultralow versus 9.43 months with no observable IHC staining. In HR- negative cohorts, median TTF was 5.00 months for HER2-ultralow versus 3.17 months with no observable IHC staining. Similar TTF trends were observed in LOT2-LOT3. Approximately three in five samples originally classified as IHC 0 met HER2-ultralow criteria, suggesting many patients may benefit from HER2-directed therapy if reclassified. These findings highlight potential challenges of identifying HER2-ultralow expression and suggest the need for enhanced pathologist training, adherence to best practices, and integration of digital pathology and artificial intelligence solutions. Trial Registration: ClinicalTrials.gov_identifier: NCT03734029.