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Prognostic implications of multiple chamber longitudinal strains and myocardial work in restrictive cardiomyopathy
Per and polyfluoroalkyl substances affect thyroid hormones for people with a history of exposure from drinking water
Abstract Per- and polyfluoroalkyl substances (PFAS) may disrupt thyroid hormones although the literature shows mixed evidence of this effect and exposure to mixtures of PFAS remains poorly understood. We used the Michigan PFAS Exposure and Health Study cohort to examine linear and nonlinear associations between serum PFAS concentrations, both alone and as a mixture, and serum thyroid hormone concentrations. Study participants included 728 adolescents and adults living in an area with past PFAS contamination of drinking water. We quantified 39 individual PFAS and four thyroid hormones in serum from participants between the years 2020 and 2021. Linear regression, weighted quantile sum (WQS) regression, supervised Principal Component Analysis (PCA), and Bayesian Kernel Machine Regression (BKMR) were used. When analyzed individually, a 1% increase in PFUnA serum concentrations was associated with a 0.023% decrease in TT3 concentration (95% CI: -0.04%, -0.01%, p < 0.05). All three mixture analyses consistently indicated an inverse relationship between PFAS mixtures and TT3 concentrations: (1) a one standard deviation increase in the WQS of the PFAS mixture was associated with a 2.0% decrease in TT3 concentration (95% CI= -4%, 0%, p < 0.05) adjusting for covariates, (2) using PCA, one standard deviation increase in a PFAS mixture was associated with a 1.2% decrease in TT3 (95% CI: -2.1%, -0.4%), and (3) BKMR similarly suggested a negative association between the PFAS mixture and TT3. We observed cross-sectional associations between a mixture of serum PFAS concentrations and thyroid hormone dysregulation, largely manifesting as decreased TT3 serum concentrations.
Assessment the impact of palygorskite modified by chlorides on speciation and environmental risk of heavy metals in soil contaminated
Mechanism of dracorhodin in accelerating diabetic foot ulcer healing via the Nrf2 pathway, a network pharmacology, molecular docking and experimental validation
Assessing safety in horizontal curves using surrogate safety measures and machine learning
Protein-enriched intermittent meal replacement combined with moderate-intensity training for weight loss and body composition in overweight women
Abstract The global rise in overweight and obesity has been exacerbated by sedentary lifestyles and suboptimal dietary habits. Traditional weight loss methods often struggle with adherence due to restrictive diets and metabolic adaptations. Intermittent meal replacement (IMR), incorporating formulated protein-enriched nutritional shakes, has emerged as a potential strategy for weight management. However, its combined effects with moderate-intensity continuous training (MICT) remain underexplored. This study aimed to evaluate the impact of a weight loss method incorporating formulated protein-enriched nutritional shake IMR in conjunction with MICT workout for overweight female adults. This 8-week parallel randomized controlled trial investigated the impact of protein-enriched IMR combined with MICT on weight loss and body composition in overweight female adults. Participants were randomly assigned to either the MICT group or MICT + IMR group. Body composition, hematological, and urinary biomarkers were assessed pre- and post-intervention. The MICT + IMR Group achieved a greater reduction in body weight (-3.70 kg vs. -1.17 kg, p < 0.001) and body fat mass (-2.25 kg vs. -1.19 kg, p < 0.001) compared to the MICT group. Additionally, fasting blood glucose and insulin levels significantly improved in the MICT + IMR Group, suggesting enhanced metabolic regulation. IMR, when combined with MICT, is a viable strategy for short-term weight loss in overweight women, offering improved fat reduction and metabolic benefits compared to exercise alone. Trial registration: Chinese Clinical Trail Registry, ChiCTR2300076750. Registered 17 October 2023, https://www.chictr.org.cn/bin/project/edit?pid=197611.
Increasing load factor in logistics and evaluating shipment performance with machine learning methods: A case from the automotive industry
Structural basis for the prolonged photocycle of sensory rhodopsin II revealed by serial synchrotron crystallography
Abstract Microbial rhodopsins form a diverse family of light-sensitive seven-transmembrane helix retinal proteins that function as active proton or ion pumps, passive light-gated ion channels, and photosensors. To understand how light-sensing in archaea is initiated by sensory rhodopsins, we perform serial synchrotron X-ray crystallography (SSX) studies of light induced conformational changes in sensory rhodopsin II (NpSRII) from the archaea Natronomonas pharaonis, both collecting time-resolved SSX data and collecting SSX data during continuous illumination. Comparing light-induced electron density changes in NpSRII with those reported for bacteriorhodopsin (bR) reveals several common light-induced structural perturbations. Unlike bR, however, helix G of NpSRII does not unwind near the conserved lysine residue to which retinal is covalently bound and therefore transient water molecule binding sites do not arise immediately to the cytoplasmic side of retinal. These structural differences prolong the duration of the NpSRII photocycle relative to bR, allowing time for the light-initiated sensory signal to be amplified.
The sonic hedgehog signaling inhibitor cyclopamine improves pulmonary arterial hypertension via regulating the bone morphogenetic protein receptor 2 pathway
Brain-wide microstrokes affect the stability of memory circuits in the hippocampus
Abstract Cognitive deficits affect over 70% of stroke survivors, yet the mechanisms by which multiple small ischemic events contribute to cognitive decline remain poorly understood. In this study, we employed chronic two-photon calcium imaging to longitudinally track the fate of individual neurons in the hippocampus of mice navigating a virtual reality environment, both before and after inducing brain-wide microstrokes. Our findings reveal that, under normal conditions, hippocampal neurons exhibit varying degrees of stability in their spatial memory coding. However, microstrokes disrupted this functional network architecture, leading to cognitive impairments. Notably, the preservation of stable coding place cells, along with the stability, precision, and persistence of the hippocampal network, was strongly predictive of cognitive outcomes. Mice with more synchronously active place cells near important locations demonstrated recovery from cognitive impairment. This study uncovers critical cellular responses and network alterations following brain injury, providing a foundation for novel therapeutic strategies preventing cognitive decline.
Covariation of scleral remodeling and PI3K/Akt signaling pathway in experimental myopia
Abstract The present study aimed to investigate the role of the PI3K/Akt signaling pathway in scleral remodeling in the development of negative lens-induced myopia (LIM). The change of scleral morphology in experimental myopic guinea pigs was observed by transmission electron microscopy, Masson staining, and TUNEL assay, respectively. Meanwhile, the levels of the PI3K/AKT signaling pathway- and scleral remodeling-related molecules in scleral tissues were determined by real-time quantitative PCR (qPCR), enzyme-linked immunosorbent assay (ELISA), immunofluorescence, immunohistochemical staining, and western blot, respectively. We found that 2-week myopic induction can elevate PIK3R3 and AKT2 levels and activate the PI3K/Akt signaling pathway, enhance the expression of E-cadherin and matrix metallopeptidase 2 (MMP2), and decrease the level of transforming growth factor-beta 1 (TGF-β1), tissue inhibitor of matrix metalloproteinase-2 (TIMP2), and collagen (COLI) in the scleral tissue of myopic guinea pigs, thereby leading to scleral remolding. However, 4-week myopic induction could inhibit the PI3K/AKT signaling pathway and induce apoptosis, accompanied by increased MMP2, E-cadherin, and decreased TGF-β1, TIMP2, and COLI. Results reveal that the disturbed PI3K/AKT signaling plays a role in scleral remodeling in the experimental myopia through orchestrating apoptosis.
Balance between bile acid conjugation and hydrolysis activity can alter outcomes of gut inflammation
TLR4 identified as a major depressive disorder gene signature mediating effects through multiple immune cells
Author Correction: Exome-wide analysis identifies three low-frequency missense variants associated with pancreatic cancer risk in Chinese populations
A significant correlation exists between CREBBP and CEBPA gene expression in de Novo adult acute myeloid leukemia
Abstract CREBBP, CEBPA, and DNMT3A are tumor suppressor genes whose dysfunction has been reported in hematologic malignancies. Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. We aim to assess the expression level of CREBBP, CEBPA, and DNMT3A genes in an Egyptian cohort with AML. We investigated the correlation between the selected genes’ mRNA levels and their association with clinical characteristics and survival. Herein, 53 adult participants diagnosed with AML were enrolled in the study. Quantitative RT-PCR was used, and computational analysis was added to analyze the relationship between the three genes. CREBBP expression influenced TLC negatively (r = -0.328, p = 0.017). DNMT3A gene expression was found to be significantly associated with CD117 positive (p = 0.028). There was no significant difference between males and females in the relative CREBBP, CEBPA, and DNMT3A expression. Remarkably, AML-M3 cases were devoid of CREBBP expression. The correlation matrix of the three genes detected a significant correlation only between CREBBP and CEBPA expression (r = 0.518, p < 0.0001), though the computational correlation analysis of these two genes was not significant. Our finding may suggest a complementary role of CREBBP and CEBPA in AML pathogenesis; however, further investigation on larger samples is still warranted to study the relationship of these genes with AML survival. We are also reporting here an adult AML case with an additional chromosome 19 as the sole cytogenetic abnormality.
Structural basis of cytokinin transport by the Arabidopsis AZG2
Timely angiography and embolization is effective emergency treatment for severe post-traumatic pelvic fractures
Structural Insights into Bortezomib-Induced Activation of the Caseinolytic Chaperone-Protease System in Mycobacterium tuberculosis
Abstract The caseinolytic protease (Clp) system has recently emerged as a promising anti-tuberculosis target. The anti-cancer drug bortezomib exhibits potent anti-mycobacterial activity and binds to Mycobacterium tuberculosis (Mtb) Clp protease complexes. We determine cryo-EM structures of Mtb ClpP1P2, ClpC1P1P2 and ClpXP1P2 complexes bound to bortezomib in different conformations. Structural and biochemical data indicate that sub-stoichiometric binding by bortezomib to the protease active sites orthosterically activates the MtbClpP1P2 complex. Bortezomib activation of MtbClpP1P2 induces structural changes promoting the recruitment of the chaperone-unfoldases, MtbClpC1 or MtbClpX, facilitating holoenzyme formation. The structures of the MtbClpC1P1P2 holoenzyme indicate that MtbClpC1 motion, induced by ATP rebinding at the MtbClpC1 spiral seam, translocates the substrate. In the MtbClpXP1P2 holoenzyme structure, we identify a specialized substrate channel gating mechanism involving the MtbClpX pore-2 loop and MtbClpP2 N-terminal domains. Our results provide insights into the intricate regulation of the Mtb Clp system and suggest that bortezomib can disrupt this regulation by sub-stoichiometric binding at the Mtb Clp protease sites.