Inflammation-mediated neurodegeneration occurs in the acute and the chronic phases of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Classically ...activated (M1) microglia are key players mediating this process. Here, we identified Galectin-1 (Gal1), an endogenous glycan-binding protein, as a pivotal regulator of M1 microglial activation that targets the activation of p38MAPK-, CREB-, and NF-κB-dependent signaling pathways and hierarchically suppresses downstream proinflammatory mediators, such as iNOS, TNF, and CCL2. Gal1 bound to core 2 O-glycans on CD45, favoring retention of this glycoprotein on the microglial cell surface and augmenting its phosphatase activity and inhibitory function. Gal1 was highly expressed in the acute phase of EAE, and its targeted deletion resulted in pronounced inflammation-induced neurodegeneration. Adoptive transfer of Gal1-secreting astrocytes or administration of recombinant Gal1 suppressed EAE through mechanisms involving microglial deactivation. Thus, Gal1-glycan interactions are essential in tempering microglial activation, brain inflammation, and neurodegeneration, with critical therapeutic implications for MS.
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► Gal1 deactivates classically activated M1 microglia ► Gal1-glycan interactions promote retention of CD45 on the surface of microglial cells ► Lack of Gal1 favors classical microglial activation, inflammation, and neurodegeneration ► Astrocytes control microglial activation and neuroinflammation via Gal1
The pulmonary artery catheter (PAC) has been used in a wide range of critically ill patients. It is not indicated for routine care of heart failure (HF), but its role in cardiogenic shock (CS) has ...not been clarified.
We conducted a retrospective cohort study with the use of the National Inpatient Sample and identified a total of 9,431,944 adult patients admitted from 2004 to 2014 with the primary diagnosis of HF (n = 8,516,528) or who developed CS (n = 915,416) during the index hospitalization. Overall, patients with PAC had increased hospital costs, length of stay, and mechanical circulatory support use. In patients with HF, PAC use was associated with higher mortality (9.9% vs 3.3%, OR 3.96; P < .001) but the excess of mortality declined over time. In those with CS, PAC was associated with lower mortality (35.1% vs 39.2%, OR 0.91; P < .001) and in-hospital cardiac arrest (14.9% vs 18.3%, OR 0.77; P < .001); this paradox persisted after propensity score matching.
The use of PAC in CS has decreased from 2004 to 2014, although its use is now associated with improved outcomes, which may reflect better selection of patients or better use of the information to guide therapies. Our data provide reassurance that PAC use in this population is an appropriate strategy.
Human personality is 30-60% heritable according to twin and adoption studies. Hundreds of genetic variants are expected to influence its complex development, but few have been identified. We used a ...machine learning method for genome-wide association studies (GWAS) to uncover complex genotypic-phenotypic networks and environmental interactions. The Temperament and Character Inventory (TCI) measured the self-regulatory components of personality critical for health (i.e., the character traits of self-directedness, cooperativeness, and self-transcendence). In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified five clusters of people with distinct profiles of character traits regardless of genotype. Third, we found 42 SNP sets that identified 727 gene loci and were significantly associated with one or more of the character profiles. Each character profile was related to different SNP sets with distinct molecular processes and neuronal functions. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of 95% of the 42 SNP sets in healthy Korean and German samples, as well as their associations with character. The identified SNPs explained nearly all the heritability expected for character in each sample (50 to 58%). We conclude that self-regulatory personality traits are strongly influenced by organized interactions among more than 700 genes despite variable cultures and environments. These gene sets modulate specific molecular processes in brain for intentional goal-setting, self-reflection, empathy, and episodic learning and memory.
Cancer therapy-related cardiac dysfunction (CTRCD) is one of the most feared and undesirable side effects of chemotherapy, occurring in approximately 10% of the patients. It can be classified as ...direct (dose-dependent vs dose-independent) or indirect, either case being potentially permanent or reversible. Risk assessment, recognition, and prevention of CTRCD are crucial.
Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces cardiovascular death and worsening heart failure in patients with chronic heart failure and reduced ejection fraction. Early ...initiation during an acute heart failure (AHF) hospitalization may facilitate decongestion, improve natriuresis, and facilitate safe transition to a beneficial outpatient therapy for both diabetes and heart failure.
The objective is to assess the efficacy and safety of initiating dapagliflozin within the first 24 hours of hospitalization in patients with AHF compared to usual care.
DICTATE-AHF is a prospective, multicenter, open-label, randomized trial enrolling a planned 240 patients in the United States. Patients with type 2 diabetes hospitalized with hypervolemic AHF and an estimated glomerular filtration rate of at least 30 mL/min/1.73m2 are eligible for participation. Patients are randomly assigned 1:1 to dapagliflozin 10 mg once daily or structured usual care until day 5 or hospital discharge. Both treatment arms receive protocolized diuretic and insulin therapies. The primary endpoint is diuretic response expressed as the cumulative change in weight per cumulative loop diuretic dose in 40 mg intravenous furosemide equivalents. Secondary and exploratory endpoints include inpatient worsening AHF, 30-day hospital readmission for AHF or diabetic reasons, change in NT-proBNP, and measures of natriuresis. Safety endpoints include the incidence of hyper/hypoglycemia, ketoacidosis, worsening kidney function, hypovolemic hypotension, and inpatient mortality.
The DICTATE-AHF trial will establish the efficacy and safety of early initiation of dapagliflozin during AHF across both AHF and diabetic outcomes in patients with diabetes.
Carcass weight (HCW) and marbling (MARB) are critical for meat quality and market value in beef cattle. In composite breeds like Brangus, which meld the genetics of Angus and Brahman, SNP-based ...analyses have illuminated some genetic influences on these traits, but they fall short in fully capturing the nuanced effects of breed of origin alleles (BOA) on these traits. Focus on the impacts of BOA on phenotypic features within Brangus populations can result in a more profound understanding of the specific influences of Angus and Brahman genetics. Moreover, the consideration of BOA becomes particularly significant when evaluating dominance effects contributing to heterosis in crossbred populations. BOA provides a more comprehensive measure of heterosis due to its ability to differentiate the distinct genetic contributions originating from each parent breed. This detailed understanding of genetic effects is essential for making informed breeding decisions to optimize the benefits of heterosis in composite breeds like Brangus. This study aims to identify quantitative trait loci (QTL) influencing HCW and MARB by utilizing SNP and BOA information, incorporating additive, dominance, and overdominance effects within a multi-generational Brangus commercial herd. We analyzed phenotypic data from 1,066 genotyped Brangus steers. BOA inference was performed using LAMP-LD software using Angus and Brahman reference sets. SNP-based and BOA-based GWAS were then conducted considering additive, dominance, and overdominance models. The study identified numerous QTLs for HCW and MARB. A notable QTL for HCW was associated to the SGCB gene, pivotal for muscle growth, and was identified solely in the BOA GWAS. Several BOA GWAS QTLs exhibited a dominance effect underscoring their importance in estimating heterosis. Our findings demonstrate that SNP-based methods may not detect all genetic variation affecting economically important traits in composite breeds. BOA inclusion in genomic evaluations is crucial for identifying genetic regions contributing to trait variation and for understanding the dominance value underpinning heterosis. By considering BOA, we gain a deeper understanding of genetic interactions and heterosis, which is integral to advancing breeding programs. The incorporation of BOA is recommended for comprehensive genomic evaluations to optimize trait improvements in crossbred cattle populations.
The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and ...contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.
Regulated glycosylation controls T cell processes, including activation, differentiation and homing by creating or masking ligands for endogenous lectins. Here we show that stimuli promoting T helper ...type 1 (TH1), TH2 or interleukin 17-producing T helper (TH-17) differentiation can differentially regulate the glycosylation pattern of T helper cells and modulate their susceptibility to galectin-1, a glycan-binding protein with anti-inflammatory activity. Although TH1- and TH-17-differentiated cells expressed the repertoire of cell surface glycans critical for galectin-1-induced cell death, TH2 cells were protected from galectin-1 through differential sialylation of cell surface glycoproteins. Consistent with those findings, galectin-1-deficient mice developed greater TH1 and TH-17 responses and enhanced susceptibility to autoimmune neuroinflammation. Our findings identify a molecular link among differential glycosylation of T helper cells, susceptibility to cell death and termination of the inflammatory response.
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