Exome-wide association analysis identifies novel risk loci for alcohol-associated hepatitis.

BACKGROUND AND AIMS: Alcohol-associated hepatitis (AH) is a clinically severe, acute disease that afflicts only a fraction of patients with alcohol use disorder (AUD). Genomic studies of alcohol-associated cirrhosis (AC) have identified several genes of large effect, but the genetic and environmental factors that lead to AH and AC, and their degree of genetic overlap, remain largely unknown. This study aims to identify genes and genetic variation that contribute to the development of AH. APPROACH AND RESULTS: Exome-sequencing of patients with AH (N=784) and heavy drinking controls (N=951) identified exome-wide significant association for AH at PNPLA3, as previously observed for AC in GWAS, although with a much lower effect-size. SNPs of large effect-size at ICOSLG (Chr 21) and TOX4/RAB2B (Chr 14), were also exome-wide significant. ICOSLG encodes a co-stimulatory signal for T-cell proliferation and cytokine secretion and induces B-cell proliferation and differentiation. TOX4 was previously implicated in diabetes and immune system function. Other genes previously implicated in AC did not strongly contribute to AH, and the only prominently implicated (but not exome wide significant) gene overlapping with AUD was ADH1B. Polygenic signals for AH were observed in both common and rare variant analysis and identified genes with roles associated with inflammation. CONCLUSIONS: This study has identified two new genes of high effect size with a previously unknown contribution to ALD, and highlights both the overlap in etiology between liver diseases, and the unique origins of AH.

Sensory nerves drive migration of dental pulp stem cells via the CGRP-Ramp1 axis in pulp repair.

Dental pulp stem cells (DPSCs) are responsible for maintaining pulp structure and function after pulp injury. DPSCs migrate directionally to the injury site before differentiating into odontoblast-like cells, which is a prerequisite and a determinant in pulp repair. Increasing evidence suggests that sensory neuron-stem cell crosstalk is critical for maintaining normal physiological functions, and sensory nerves influence stem cells mainly by neuropeptides. However, the role of sensory nerves on DPSC behaviors after pulp injury is largely unexplored. Here, we find that sensory nerves released significant amounts of calcitonin gene-related peptide (CGRP) near the injury site, acting directly on DPSCs via receptor activity modifying protein 1 (RAMP1) to promote collective migration of DPSCs to the injury site, and ultimately promoting pulp repair. Specifically, sensory denervation leads to poor pulp repair and ectopic mineralization, in parallel with that DPSCs failed to be recruited to the injury site. Furthermore, in vitro evidence shows that sensory nerve-deficient microenvironment suppressed DPSC migration prominently among all related behaviors. Mechanistically, the CGRP-Ramp1 axis between sensory neurons and DPSCs was screened by single-cell RNA-seq analysis and immunohistochemical studies confirmed that the expression of CGRP rather than Ramp1 increases substantially near the damaged site. We further demonstrated that CGRP released by sensory nerves binds the receptor Ramp1 on DPSCs to facilitate cell collective migration by an indirect co-culture system using conditioned medium from trigeminal neurons, CGRP recombinant protein and antagonists BIBN4096. The treatment with exogenous CGRP promoted the recruitment of DPSCs, and ultimately enhanced the quality of pulp repair. Targeting the sensory nerve could therefore provide a new strategy for stem cell-based pulp repair and regeneration.

Bioactive atropisomers: Unraveling design strategies and synthetic routes for drug discovery.

Atropisomerism, an expression of axial chirality caused by limited bond rotation, is a prominent aspect within the field of medicinal chemistry. It has been shown that atropisomers of a wide range of compounds, including established FDA-approved drugs and experimental molecules, display markedly different biological activities. The time-dependent reversal of chirality in atropisomers poses complexity and obstacles in the process of drug discovery and development. Nonetheless, recent progress in understanding atropisomerism and enhanced characterization methods have greatly assisted medicinal chemists in the effective development of atropisomeric drug molecules. This article provides a comprehensive review of their special design thoughts, synthetic routes, and biological activities, serving as a reference for the synthesis and biological evaluation of bioactive atropisomers in the future.

Thermochemical CO2 Reduction to Methanol over Metal-Based Single-Atom Catalysts (SACs): Outlook and Challenges for Developments.

The conversion of thermodynamically inert CO2 into methanol holds immense promise for addressing the pressing environmental and energy challenges of our time. This article offers a succinct overview of the development of single-atom catalysts (SACs) for thermochemical hydrogenation of CO2 to methanol, encompassing research advancements, advantages, potential hurdles, and other essential aspects related to these catalysts. Our aim of this work is to provide a deeper understanding of the intricacies of the catalytic structures of the single-atom sites and their unique structure-activity relationships in catalyzing the conversion of CO2 to methanol. We also present insights into the optimal design of SACs, drawing from our own research and those of fellow scientists. This research thrust is poised to contribute significantly to the development of next-generation SACs, which are crucial in advancing the sustainable production of methanol from CO2.

Deubiquitination of CDC6 by OTUD6A promotes tumour progression and chemoresistance.

BACKGROUND: CDC6 is an oncogenic protein whose expression level fluctuates during the cell cycle. Although several E3 ubiquitin ligases responsible for the ubiquitin-mediated proteolysis of CDC6 have been identified, the deubiquitination pathway for CDC6 has not been investigated. METHODS: The proteome-wide deubiquitinase (DUB) screening was used to identify the potential regulator of CDC6. Immunofluorescence, protein half-life and deubiquitination assays were performed to determine the protein stability of CDC6. Gain- and loss-of-function experiments were implemented to analyse the impacts of OUTD6A-CDC6 axis on tumour growth and chemosensitivity in vitro. N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced conditional Otud6a knockout (CKO) mouse model and tumour xenograft model were performed to analyse the role of OTUD6A-CDC6 axis in vivo. Tissue specimens were used to determine the association between OTUD6A and CDC6. RESULTS: OTUD6A interacts with, depolyubiquitinates and stabilizes CDC6 by removing K6-, K33-, and K48-linked polyubiquitination. Moreover, OTUD6A promotes cell proliferation and decreases sensitivity to chemotherapy by upregulating CDC6. CKO mice are less prone to BCa tumorigenesis induced by BBN, and knockdown of OTUD6A inhibits tumour progression in vivo. Furthermore, OTUD6A protein level has a positive correlation with CDC6 protein level, and high protein levels of OTUD6A and CDC6 are associated with poor prognosis in patients with bladder cancer. CONCLUSIONS: We reveal an important yet missing piece of novel DUB governing CDC6 stability. In addition, our findings propose a model for the OTUD6A-CDC6 axis that provides novel insights into cell cycle and chemosensitivity regulation, which may become a potential biomarker and promising drug target for cancer treatment.

n-Bu4NI/K2S2O8 Mediated Csp2-Csp2 Bond Cleavage - Transformylation from p-Anisaldehyde to Primary Amides.

n-Bu4NI/K2S2O8 mediated transformylation from p-anisaldehyde to primary amides is reported. The mechanistic studies suggest the reaction occurs via a single electron transfer pathway. Based on the DFT electronic structure calculations of various reaction pathways, the most plausible mechanism involves the formation of a phenyl radical cation and an arenium ion as the key intermediates. It represents the first example where p-anisaldehyde is employed as a formyl source via a non-metal mediated Csp2-Csp2 bond cleavage.

Butyrate protects the intestinal barrier by upregulating Fut2 expression via MEK4-JNK signaling pathway activation.

BACKGROUND: Necrotizing enterocolitis (NEC) is a severe gastrointestinal inflammatory disease in neonates. Fucosyltransferase 2 (Fut2) regulates intestinal epithelial cell fucosylation. In this study, we aimed to investigate butyrate-mediated upregulation of Fut2 expression and the underlying mechanisms. METHODS: In vivo and in vitro models were established. SP600125 was used to inhibit the MEK4-JNK pathway, and anisomycin was used to activate the MEK4-JNK pathway. Fut2, occludin, and ZO-1 expressions were assessed. Furthermore, intestinal permeability was analyzed by FITC-Dextran. The expression of proteins in the MEK-4-JNK pathway was examined by western blotting. RESULTS: In vivo, the addition of exogenous butyrate notably upregulated Fut2, occludin, and ZO-1 expressions and reduced intestinal permeability in mice with NEC. Butyrate may increase the phosphorylation of MEK4, JNK, and c-jun, which are key components of the MEK4-JNK pathway. Additionally, SP600125 inhibited their phosphorylation, which was reversed by anisomycin treatment. In vitro, butyrate substantially increased occludin and ZO-1 expressions. Butyrate considerably increased Fut2 expression and markedly upregulated p-MEK4, p-JNK, and p-c-jun expressions. SP600125 administration decreased their expressions, while anisomycin administration increased their expressions. CONCLUSION: Butyrate upregulated Fut2 expression via activation of the MEK4-JNK pathway, improved intestinal barrier integrity, and protected neonatal mice from NEC. IMPACT: We found that exogenous butyrate could improve intestinal barrier integrity and protect against NEC in neonatal mice. Our data showed that exogenous butyrate supplementation upregulated Fut2 expression by activating the MEK4-JNK pathway. Our study provides novel insights into the pathogenesis of NEC, thereby laying an experimental foundation for future clinical research on the use of butyrate in NEC treatment.

Serum macroelements and microelements levels in periparturient dairy cows in relation to fatty liver diseases.

BACKGROUND: Fatty liver in dairy cows is a common metabolic disease defined by triglyceride (TG) buildup in the hepatocyte. Clinical diagnosis of fatty liver is usually done by liver biopsy, causing considerable economic losses in the dairy industry owing to the lack of more effective diagnostic methods. Therefore, this study aimed to investigate the potential utility of blood biomarkers for the diagnosis and early warning of fatty liver in dairy cows. RESULTS: A total of twenty-four lactating cows within 28 days after parturition were randomly selected as experimental animals and divided into healthy cows (liver biopsy tested, n = 12) and cows with fatty liver (liver biopsy tested, n = 12). Inductively coupled plasma mass spectrometry (ICP-MS) was used to determine the macroelements and microelements in the serum of two groups of cows. Compared to healthy cows (C), concentrations of calcium (Ca), potassium (K), magnesium (Mg), strontium (Sr), selenium (Se), manganese (Mn), boron (B) and molybdenum (Mo) were lower and copper (Cu) was higher in fatty liver cows (F). Meanwhile, the observed differences in macroelements and microelements were related to delivery time, with the greatest major disparity between C and F occurring 7 days after delivery. Multivariable analysis was used to test the correlation between nine serum macroelements, microelements and fatty liver. Based on variable importance projection and receiver operating characteristic (ROC) curve analysis, minerals Ca, Se, K, B and Mo were screened as the best diagnostic indicators of fatty liver in postpartum cows. CONCLUSIONS: Our data suggested that serum levels of Ca, K, Mg, Se, B, Mo, Mn, and Sr were lower in F than in C. The most suitable period for an early-warning identification of fatty liver in cows was 7 days after delivery, and Ca, Se, K, B and Mo were the best diagnostic indicators of fatty liver in postpartum cows.

n-Bu4NI/K2S2O8-MEDIATED C-N COUPLING BETWEEN ALDEHYDES AND AMIDES.

n-Bu4NI/K2S2O8 mediated C-N coupling between aldehydes and amides is reported. A strong electronic effect is observed on the aromatic aldehyde substrates. The transformylation from aldehyde to amide takes place exclusively when an aromatic aldehyde bears electron-donating groups at either the ortho or para position of the formyl group, while the cross-dehydrogenative coupling dominates in the absence of these groups. Both the density functional theory (DFT) thermochemistry calculations and experimental data support the proposed single electron transfer mechanism with the formation of an acyl radical intermediate in the cross-dehydrogenative coupling. The n-Bu4NI/K2S2O8 mediated oxidative cyclization between 2-aminobenzamide and aldehydes is also reported, with four quinazolin-4(3H)-ones prepared in 65-99% yields.

The Role of Sensory Nerves in Dental Pulp Homeostasis: Histological Changes and Cellular Consequences after Sensory Denervation.

Homeostatic maintenance is essential for pulp function. Disrupting pulp homeostasis may lead to pulp degeneration, such as fibrosis and calcifications. Sensory nerves constitute a crucial component of the dental pulp. However, the precise involvement of sensory nerves in pulp homeostasis remains uncertain. In this study, we observed the short-term and long-term histological changes in the dental pulp after inferior alveolar nerve transection. Additionally, we cultured primary dental pulp cells (DPCs) from the innervated and denervated groups and compared indicators of cellular senescence and cellular function. The results revealed that pulp fibrosis occurred at 2 w after the operation. Furthermore, the pulp area, as well as the height and width of the pulp cavity, showed accelerated reductions after sensory denervation. Notably, the pulp area at 16 w after the operation was comparable to that of 56 w old rats. Sensory denervation induced excessive extracellular matrix (ECM) deposition and increased predisposition to mineralization. Furthermore, sensory denervation promoted the senescence of DPCs. Denervated DPCs exhibited decelerated cell proliferation, arrest in the G2/M phase of the cell cycle, imbalance in the synthesis and degradation of ECM, and enhanced mineralization. These findings indicate that sensory nerves play an essential role in pulp homeostasis maintenance and dental pulp cell fate decisions, which may provide novel insights into the prevention of pulp degeneration.

Characteristics and fractionations of sediment oxygen demand in a complex tidal river network area.

Tidal river networks are affected by the tide and influenced by complex factors related to sediment oxygen demand (SOD). In this study, we used chemical inhibition to measure the oxygen consumption of different types of SOD to explore the specific oxygen consumption mechanism of sediments. Then, we evaluated the diffusion fluxes of the sediment-water interface and factors affecting SOD using diffusive gradients in thin films. Total SOD in the tidal river network area of the Pearl River basin was ∼0.5928 g/m2/day, which was 8.47% higher than that in the non-tidal river network area but lower than that in black and odorous water reported previously. In the tidal river network area, biological SOD was 15.6% higher in summer than in winter, and the difference in total SOD was greatly influenced by human activity. We observed a significant effect of sediment on SOD in winter, whereas there were no significant correlations between sediment and SOD in summer. Different particle-size distributions lead to different organic matter contents, resulting in different biological SOD ratios between seasons. Our study found that seasonal tidal changes can affect ion exchange at the sediment water interface, leading to changes in SOD.These findings will be of great significance for the study of phenomena associated with low dissolved oxygen in tidal river networks and provide directions for future sediment pollution control.

A Highly-Fluorinated Lithium Borate Main Salt Empowering Stable Lithium Metal Batteries.

Traditional lithium salts are difficult to meet practical application demand of lithium metal batteries (LMBs) under high voltages and temperatures. LiPF6, as the most commonly used lithium salt, still suffers from notorious moisture sensitivity and inferior thermal stability under those conditions. Here, we synthesize a lithium salt of lithium perfluoropinacolatoborate (LiFPB) comprising highly-fluorinated and borate functional groups to address the above issues. It is demonstrated that the LiFPB shows superior thermal and electrochemical stability without any HF generation under high temperatures and voltages. In addition, the LiFPB can form a protective outer-organic and inner-inorganic rich cathode electrolyte interphase on LiCoO2 (LCO) surface. Simultaneously, the FPB- anions tend to integrate into lithium ion solvation structure to form a favorable fast-ion conductive LiBxOy based solid electrolyte interphase on lithium (Li) anode. All these fantastic features of LiFPB endow LCO (1.9 mAh cm-2)/Li metal cells excellent cycling under both high voltages and temperatures (e.g., 80 % capacity retention after 260 cycles at 60 °C and 4.45 V), and even at an extremely elevated temperature of 100 °C. This work emphasizes the important role of salt anions in determining the electrochemical performance of LMBs at both high temperature and voltage conditions.

APOL1 risk variants affect podocyte lipid homeostasis and energy production in focal segmental glomerulosclerosis.

Lipotoxicity was recently reported in several forms of kidney disease, including focal segmental glomerulosclerosis (FSGS). Susceptibility to FSGS in African Americans is associated with the presence of genetic variants of the Apolipoprotein L1 gene (APOL1) named G1 and G2. If and how endogenous APOL1 may alter mitochondrial function by the modifying cellular lipid metabolism is unknown. Using transgenic mice expressing the APOL1 variants (G0, G1 or G2) under endogenous promoter, we show that APOL1 risk variant expression in transgenic mice does not impair kidney function at baseline. However, APOL1 G1 expression worsens proteinuria and kidney function in mice characterized by the podocyte inducible expression of nuclear factor of activated T-cells (NFAT), which we have found to cause FSGS. APOL1 G1 expression in this FSGS-model also results in increased triglyceride and cholesterol ester contents in kidney cortices, where lipid accumulation correlated with loss of renal function. In vitro, we show that the expression of endogenous APOL1 G1/G2 in human urinary podocytes is associated with increased cellular triglyceride content and is accompanied by mitochondrial dysfunction in the presence of compensatory oxidative phosphorylation (OXPHOS) complexes elevation. Our findings indicate that APOL1 risk variant expression increases the susceptibility to lipid-dependent podocyte injury, ultimately leading to mitochondrial dysfunction.

Genetically predicted selenium concentrations and thyroid function: A two-sample Mendelian randomization study.

OBJECTIVE: The impact of selenium (Se) on human thyroid function remains unclear, with inconsistent results from recent epidemiological studies. Moreover, the observed associations are prone to bias due to potential confounding and reverse causation. Mendelian randomization (MR) analysis facilitates the large minimization of biases produced by environmental and lifestyle influences, providing unconfounded estimates of causal effects using instrumental variables. We aim to examine the association between Se concentrations and human thyroid function using a two-sample MR analysis. DESIGN AND METHODS: Genetic instruments for Se concentrations, including toenail and blood (TAB) and blood Se concentrations, were identified from a genome-wide association study (GWAS) of blood Se (n = 5477) and toenail Se levels (n = 4162). GWAS summary statistics on thyroid phenotypes were downloaded from the ThyroidOmics consortium, including thyroid-stimulating hormone (TSH) (n = 54,288), free thyroxin (FT4) (n = 49,269), hypo (n = 53,423), and hyperthyroidism (n = 51,823). The MR study was conducted using the inverse-variance weighted (IVW) method, supplemented with the weighted median and the mode-based method. RESULTS: Genetically determined TAB Se was negatively associated with FT4 (ß = -.067; 95% confidence interval [CI] = -0.106, -0.028; p = 0.001) using the IVW analyses, as well in the additional analyses using the weighted median and weighted-mode methods. No evidence in heterogeneity, pleiotropy or outlier single-nucleotide polymorphisms was detected (all p > 0.05). Suggestive casual association between increased genetically determined TAB Se concentrations and decreased hypothyroidism risk was found by the IVW method (odds ratio [OR] = 0.847; 95% CI = 0.728, 0.985; p = 0.031). The causal effect of TAB Se on FT4 was observed in women (ß = -.076; 95% CI = -0.129, -0.024; p = 0.004). However, the influence of genetically determined higher Se concentrations on TSH levels and hyperthyroidism revealed insignificance in the primary and sensitivity analyses. CONCLUSIONS: The present MR study indicated that high Se concentration enable the decreasing of FT4 levels, and the effects of Se concentrations on FT4 remain sex-specific.

A region-specific modulation of sleep slow waves on interictal epilepsy markers in focal epilepsy.

OBJECTIVE: Sleep strongly activates interictal epileptic activity through an unclear mechanism. We investigated how scalp sleep slow waves (SSWs), whose positive and negative half-waves reflect the fluctuation of neuronal excitability between the up and down states, respectively, modulate interictal epileptic events in focal epilepsy. METHODS: Simultaneous polysomnography was performed in 45 patients with drug-resistant focal epilepsy during intracranial electroencephalographic recording. Scalp SSWs and intracranial spikes and ripples (80-250 Hz) were detected; ripples were classified as type I (co-occurring with spikes) or type II (occurring alone). The Hilbert transform was used to analyze the distributions of spikes and ripples in the phases of SSWs. RESULTS: Thirty patients with discrete seizure-onset zone (SOZ) and discernable sleep architecture were included. Intracranial spikes and ripples accumulated around the negative peaks of SSWs and increased with SSW amplitude. Phase analysis revealed that spikes and both ripple subtypes in SOZ were similarly facilitated by SSWs exclusively during down state. In exclusively irritative zones outside SOZ (EIZ), SSWs facilitated spikes and type I ripples across a wider range of phases and to a greater extent than those in SOZ. The type II and type I ripples in EIZ were modulated by SSWs in different patterns. Ripples in normal zones decreased specifically during the up-to-down transition and then increased after the negative peak of SSW, with a characteristically high post-/pre-negative peak ratio. SIGNIFICANCE: SSWs modulate interictal events in an amplitude-dependent and region-specific pattern. Pathological ripples and spikes were facilitated predominantly during the cortical down state. Coupling analysis of SSWs could improve the discrimination of pathological and physiological ripples and facilitate seizure localization.

Fractional flow reserve versus intravascular imaging to guide decision-making for percutaneous coronary intervention in intermediate lesions: A meta-analysis.

BACKGROUND: Both fractional flow reserve (FFR) and intravascular imaging (IVI) have been used to guide the decision-making for percutaneous coronary intervention (PCI) in intermediate coronary stenosis. Nevertheless, studies that directly compared the prognostic significance of these two strategies are scarce. AIMS: The aim of this meta-analyses was to evaluate the impact of FFR versus IVI to guide the decision-making in PCI for intermediate stenosis on clinical outcomes. METHODS: We systematically searched PubMed, Embase, Cochrane, and relevant database from inception date to September 2022 for observational studies and randomized clinical trials (RCTs) which compared FFR and IVI-based decision-making in PCI for intermediate stenosis. The primary outcome was a composite of major adverse cardiac event (MACE). Pooled risk ratios (RR) were calculated using random effects models and heterogeneity were evaluated with the I2 statistic. RESULTS: We identified 5 studies (3 RCTs and 2 observational studies) with 3208 patients. The follow-up duration ranged from 12 to 24 months. Among five studies, four compared FFR with intravascular ultrasound while one compared FFR with optical coherence tomography. There was no statistically difference between FFR and IVI in the incidence of MACE (RR: 1.19; 95% confidence interval: 0.85-1.68; p = 0.31) and its individual components. These results were consistent regardless of various cut-off value of PCI across the studies. Compared with IVI, FFR was associated with a lower PCI rate (37.0% vs. 60.3%; p < 0.001). CONCLUSIONS: The decision to perform PCI for intermediate stenosis guided by FFR or IVI showed a similar clinical outcome. The use of FFR significantly reduced the need for PCI.

Immobilization of Laccase by Alkali-Etched Bimetallic CoCu-MOF To Enhance Enzyme Loading and Congo Red Degradation.

In this work, the strategy of immobilizing enzymes in bimetallic-organic frameworks was adopted to overcome the disadvantages of free laccases. The surface amino-silanizing of bimetallic CoCu-MOF-H hydrothermally synthesized was performed by (3-Aminopropyl)triethoxysilane (APTES). Then, glutaraldehyde was used as the cross-linking agent, laccase was covalently grafted onto CoCu-MOF-H-APTES to prepare Lac-CoCu-MOF-H-APTE. In addition, CoCu-MOF-OH also was synthesized by alkali etching of CoCu-MOF-H, and Lac-CoCu-MOF-OH-APTES composites were obtained by a similar strategy. The result showed that the relative enzyme activity of Lac-CoCu-MOF-OH-APTES exhibited 264.02% (1.8 times than that of Lac-CoCu-MOF-H-APTES) after six cycles of stability tests, while the free enzyme was almost inactivated. Moreover, the Congo red (CR) removal rate of Lac-CoCu-MOF-OH-APTES exceeded 95% within 1 h and exceeded 89.18% after six cycles at pH 3.5 and 50 °C. This work has the potential to provide a broader application prospect for CR degradation by laccase in the future.

Comprehensive analysis of transcriptomics and metabolomics to understand chronic ethanol induced murine cardiotoxicity.

Alcohol abuse has attracted public attention and long-term alcohol exposure can lead to alcohol-featured non-ischemic dilated cardiomyopathy. However, the precise underlying mechanisms of alcoholic cardiomyopathy remain to be elucidated. This study aimed to comprehensively characterize alcohol abuse-mediated effects on downstream metabolites and genes transcription using a multi-omics strategy. We established chronic ethanol intoxication model in adult male C57BL/6 mice through 8 weeks of 95% alcohol vapor administration and performed metabolomics analysis, mRNA-seq and microRNA-seq analysis with myocardial tissues. Firstly, ethanol markedly induced ejection fraction reductions, cardiomyocyte hypertrophy, and myocardial fibrosis in mice with myocardial oxidative injury. In addition, the omics analysis identified a total of 166 differentially expressed metabolites (DEMs), 241 differentially expressed genes (DEGs) and 19 differentially expressed microRNAs (DEmiRNAs), respectively. The results highlighted that alcohol abuse mainly interfered with endogenous lipids, amino acids and nucleotides production and the relevant genes transcription in mice hearts. Based on KEGG database, the affected signaling pathways are primarily mapped to the antigen processing and presentation, regulation of actin cytoskeleton, AMPK signaling pathway, tyrosine metabolism and PPAR signaling pathway, etc. Furthermore, 9 hub genes related to oxidative stress from DEGs were selected based on function annotation, and potential alcoholic cardiotoxic oxidative stress biomarkers were determined through establishing PPI network and DEmiRNAs-DEGs cross-talk. Altogether, our data strongly supported the conclusion that ethanol abuse characteristically affected amino acid and energy metabolism, nucleotide metabolism and especially lipids metabolism in mice hearts, and underlined the values of lipids signaling and oxidative stress in the treatment strategies.

Controllable adhesion behavior in underwater environments.

Microstructure adhesive pads can effectively manipulate objects in underwater environments. Current adhesive pads can achieve adhesion and separation with rigid substrates underwater; however, challenges remain in the control of adhesion and detachment of flexible materials. Additionally, underwater object manipulation necessitates considerable pre-pressure and is sensitive to water temperature fluctuations, potentially causing object damage and complicating adhesion and detachment processes. Thus, we present a novel, controllable adhesive pad inspired by the functional attributes of microwedge adhesive pads, combined with a mussel-inspired copolymer (MAPMC). In the context of underwater applications for flexible materials, the use of a microstructure adhesion pad with microwedge characteristics (MAPMCs) is a proficient approach to adhesion and detachment operations. This innovative method relies on the precise manipulation of the microwedge structure's collapse and recovery during its operation, which serves as the foundation for its efficacy in such environments. MAPMCs exhibit self-recovering elasticity, water flow interaction, and tunable underwater adhesion and detachment. Numerical simulations elucidate the synergistic effects of MAPMCs, highlighting the advantages of the microwedge structure for controllable, non-damaging adhesion and separation processes. The integration of MAPMCs into a gripping mechanism allows for the handling of diverse objects in underwater environments. Furthermore, by merging MAPMCs and a gripper within a linked system, our approach enables automatic, non-damaging adhesion, manipulation, and release of a soft jellyfish model. The experimental results indicate the potential applicability of MACMPs in underwater operations.

Surface-Water Nitrate Exposure to World Populations Has Expanded and Intensified during 1970-2010.

Excessive nitrate in surface waters deteriorates the water quality and threatens human health. Human activities have caused increased nitrate concentrations in global surface waters over the past 50 years. An assessment of the long-term trajectory of surface-water nitrate exposure to world populations and the associated potential health risks is imperative but lacking. Here, we used global spatially explicit data on surface-water nitrate concentrations and population density, in combination with thresholds for health risks from epidemiological studies, to quantify the long-term changes in surface-water nitrate exposure to world populations at multiple spatial scales. During 1970-2010, global populations potentially affected by acute health risks associated with surface-water nitrate exposure increased from 6 to 60 million persons per year, while populations at potential chronic health risks increased from 169 to 1361 million persons per year. Potential acute risks have increasingly affected Asian countries. Populations potentially affected by chronic risks shifted from dominance by high-income countries (in Europe and North America) to middle-income countries (in Asia and Africa). To mitigate adverse health effects associated with surface-water nitrate exposure, anthropogenic nitrogen inputs to natural environments should be drastically reduced. International and national standards of maximum nitrate contamination may need to be lowered.