Research on the generation and annotation method of thin section images of tight oil reservoir based on deep learning.

The cast thin sections of tight oil reservoirs contain important parameters such as rock mineral composition and content, porosity, permeability and stratigraphic characteristics, which are of great significance for reservoir evaluation. The use of deep learning technology for intelligent identification of thin section images is a development trend of mineral identification. However, the difficulty of making cast thin sections, the complexity of the making process and the high cost of thin section annotation have led to a lack of cast thin section images, which cannot meet the training requirements of deep learning image recognition models. In order to increase the sample size and improve the training effect of deep learning model, we proposed a generation and annotation method of thin section images of tight oil reservoir based on deep learning, by taking Fuyu reservoir in Sanzhao Sag as the target area. Firstly, the Augmentor strategy space was used to preliminarily augment the original images while preserving the original image features to meet the requirements of the model. Secondly, the category attention mechanism was added to the original StyleGAN network to avoid the influence of the uneven number of components in thin sections on the quality of the generated images. Then, the SALM annotation module was designed to achieve semi-automatic annotation of the generated images. Finally, experiments on image sharpness, distortion, standard accuracy and annotation efficiency were designed to verify the advantages of the method in image quality and annotation efficiency.

Retinoic acid tiers mitochondrial metabolism to Sertoli Cell-Mediated efferocytosis via a non-RAR-dependent mechanism.

Efferocytosis of massive non-viable germ cells by Sertoli cells (SCs), the specialized phagocytes, is essential for maintaining testis homeostasis. What elusive is the contribution of mitochondrial metabolism to this energy-consuming process, as SC has a preference of aerobic glycolysis. All-trans retinoic acid (ATRA, hereafter referred to as RA) is a well-known morphogen that primarily acts through the nuclear RA receptor (RAR). It sustains SC blood-testisbarrier integrity, and it's SC-derived RA sets the timing of meiotic commitment. In this study, we revisited RA in SC biology, from the perspective of SC-mediated efferocytosis. We provide evidence that RA induces transcriptional programming of multiple regulators involved in efferocytosis, which thereby represses SC-mediated efferocytosis, via a RAR-independent mechanism, as blocking pan-RAR activity fails to rescue RA-induced defective efferocytosis. RA-treated SCs exhibit alternations in mitochondrial dynamics and metabolism, and the hindered efferocytosis can be rescued by stimulating mitochondrial OXPHOS via pharmacological targeting of AMPK and PDK. We thus prefer to propose a signaling axis of RA-mitochondrial metabolism-efferocytosis. Our study uncovers a hitherto unappreciated role of RA in SC biology and tiers mitochondria metabolism to SC-mediated efferocytosis, contributing a deeper understanding of SC in male reproduction.

Proteolytic cleavage and inactivation of the TRMT1 tRNA modification enzyme by SARS-CoV-2 main protease.

Nonstructural protein 5 (Nsp5) is the main protease of SARS-CoV-2 that cleaves viral polyproteins into individual polypeptides necessary for viral replication. Here, we show that Nsp5 binds and cleaves human tRNA methyltransferase 1 (TRMT1), a host enzyme required for a prevalent post-transcriptional modification in tRNAs. Human cells infected with SARS-CoV-2 exhibit a decrease in TRMT1 protein levels and TRMT1-catalyzed tRNA modifications, consistent with TRMT1 cleavage and inactivation by Nsp5. Nsp5 cleaves TRMT1 at a specific position that matches the consensus sequence of SARS-CoV-2 polyprotein cleavage sites, and a single mutation within the sequence inhibits Nsp5-dependent proteolysis of TRMT1. The TRMT1 cleavage fragments exhibit altered RNA binding activity and are unable to rescue tRNA modification in TRMT1-deficient human cells. Compared to wild-type human cells, TRMT1-deficient human cells infected with SARS-CoV-2 exhibit reduced levels of intracellular viral RNA. These findings provide evidence that Nsp5-dependent cleavage of TRMT1 and perturbation of tRNA modification patterns contribute to the cellular pathogenesis of SARS-CoV-2 infection.

The virus responsible for COVID-19 infections is known as SARS-CoV-2. Like all viruses, SARS-CoV-2 carries instructions to make proteins and other molecules that play essential roles in enabling the virus to multiply and spread. Viruses are unable to make these molecules themselves, so they infect cells and trick them into making the molecules and assembling new virus particles on their behalf instead. When SARS-CoV2 infects cells, the host cells are reprogrammed to make chains containing several virus proteins that need to be severed from each other by a virus enzyme, known as Nsp5, to enable the proteins to work properly. Previous studies suggested that Nsp5 may also interact with a human protein known as TRMT1, which helps with the production of new proteins in cells. However, it was not clear how Nsp5 may bind to TRMT1 or how this interaction may affect the host cell. Zhang et al. used biochemical and molecular techniques in human cells to study how Nsp5 interacts with TRMT1. The experiments found that the virus enzyme cuts TRMT1 into fragments that are inactive and are subsequently destroyed by the cells. Moreover, Nsp5 cuts TRMT1 at exactly the same position corresponding to the cleavage sites of the viral proteins. Mutation of the sequence in TRMT1 renders Nsp5 ineffective at cutting the protein. SARS-CoV-2 infection caused TRMT1 levels to decrease inside the cells, in turn, leading to a drop in TRMT1 activity. The virus multiplied less in cells that were unable to produce TRMT1 compared to normal human cells, suggesting that the virus benefits from TRMT1 early during infection, before inactivating it at a later point. These findings suggest that one way SARS-CoV-2 causes disease is by decreasing the levels of a human protein that regulates protein production. In the future, the work of Zhang et al. may provide new markers for detecting infections of SARS-CoV-2 and other similar viruses and guide efforts to make more effective therapies against them.

Turbulent flow field in maglev centrifugal blood pumps of CH-VAD and HeartMate III: secondary flow and its effects on pump performance.

Secondary flow path is one of the crucial aspects during the design of centrifugal blood pumps. Small clearance size increases stress level and blood damage, while large clearance size can improve blood washout and reduce stress level. Nonetheless, large clearance also leads to strong secondary flows, causing further blood damage. Maglev blood pumps rely on magnetic force to achieve rotor suspension and allow more design freedom of clearance size. This study aims to characterize turbulent flow field and secondary flow as well as its effects on the primary flow and pump performance, in two representative commercial maglev blood pumps of CH-VAD and HeartMate III, which feature distinct designs of secondary flow path. The narrow and long secondary flow path of CH-VAD resulted in low secondary flow rates and low disturbance to the primary flow. The flow loss and blood damage potential of the CH-VAD mainly occurred at the secondary flow path, as well as the blade clearances. By contrast, the wide clearances in HeartMate III induced significant disturbance to the primary flow, resulting in large incidence angle, strong secondary flows and high flow loss. At higher flow rates, the incidence angle was even larger, causing larger separation, leading to a significant decrease of efficiency and steeper performance curve compared with CH-VAD. This study shows that maglev bearings do not guarantee good blood compatibility, and more attention should be paid to the influence of secondary flows on pump performance when designing centrifugal blood pumps.

Cerebral autoregulation: A reliable predictor of prognosis in patients receiving intravenous thrombolysis.

AIMS: To investigate the characteristics of dynamic cerebral autoregulation (dCA) after intravenous thrombolysis (IVT) and assess the relationship between dCA and prognosis. METHODS: Patients with unilateral acute ischemic stroke receiving IVT were prospectively enrolled; those who did not were selected as controls. All patients underwent dCA measurements, by quantifying the phase difference (PD) and gain, at 1-3 and 7-10 days after stroke onset. Simultaneously, two dCA-based nomogram models were established to verify the predictive value of dCA for patients with mild-to-moderate stroke. RESULTS: Finally, 202 patients who received IVT and 238 who did not were included. IVT was positively correlated with higher PD on days 1-3 and 7-10 after stroke onset. PD values in both sides at 1-3 days after stroke onset and in the affected side at 7-10 days after onset were independent predictors of unfavorable outcomes in patients who received IVT. Additionally, in patients with mild-to-moderate stroke who received IVT, the dCA-based nomogram models significantly improved the risk predictive ability for 3-month unfavorable outcomes. CONCLUSION: IVT has a positive effect on dCA in patients with acute stroke; furthermore, dCA may be useful to predict the prognosis of patients with IVT.

Promoter variations of ClERF1 gene determines flesh firmness in watermelon.

BACKGROUND: Flesh firmness is a critical factor that influences fruit storability, shelf-life and consumer's preference as well. However, less is known about the key genetic factors that are associated with flesh firmness in fresh fruits like watermelon. RESULTS: In this study, through bulk segregant analysis (BSA-seq), we identified a quantitative trait locus (QTL) that influenced variations in flesh firmness among recombinant inbred lines (RIL) developed from cross between the Citrullus mucosospermus accession ZJU152 with hard-flesh and Citrullus lanatus accession ZJU163 with soft-flesh. Fine mapping and sequence variations analyses revealed that ethylene-responsive factor 1 (ClERF1) was the most likely candidate gene for watermelon flesh firmness. Furthermore, several variations existed in the promoter region between ClERF1 of two parents, and significantly higher expressions of ClERF1 were found in hard-flesh ZJU152 compared with soft-flesh ZJU163 at key developmental stages. DUAL-LUC and GUS assays suggested much stronger promoter activity in ZJU152 over ZJU163. In addition, the kompetitive allele-specific PCR (KASP) genotyping datasets of RIL populations and germplasm accessions further supported ClERF1 as a possible candidate gene for fruit flesh firmness variability and the hard-flesh genotype might only exist in wild species C. mucosospermus. Through yeast one-hybrid (Y1H) and dual luciferase assay, we found that ClERF1 could directly bind to the promoters of auxin-responsive protein (ClAux/IAA) and exostosin family protein (ClEXT) and positively regulated their expressions influencing fruit ripening and cell wall biosynthesis. CONCLUSIONS: Our results indicate that ClERF1 encoding an ethylene-responsive factor 1 is associated with flesh firmness in watermelon and provide mechanistic insight into the regulation of flesh firmness, and the ClERF1 gene is potentially applicable to the molecular improvement of fruit-flesh firmness by design breeding.

Future in the past: paternal reprogramming of offspring phenotype and the epigenetic mechanisms.

That certain preconceptual paternal exposures reprogram the developmental phenotypic plasticity in future generation(s) has conceptualized the "paternal programming of offspring health" hypothesis. This transgenerational effect is transmitted primarily through sperm epigenetic mechanisms-DNA methylation, non-coding RNAs (ncRNAs) and associated RNA modifications, and histone modifications-and potentially through non-sperm-specific mechanisms-seminal plasma and circulating factors-that create 'imprinted' memory of ancestral information. The epigenetic landscape in sperm is highly responsive to environmental cues, due to, in part, the soma-to-germline communication mediated by epididymosomes. While human epidemiological studies and experimental animal studies have provided solid evidences in support of transgenerational epigenetic inheritance, how ancestral information is memorized as epigenetic codes for germline transmission is poorly understood. Particular elusive is what the downstream effector pathways that decode those epigenetic codes into persistent phenotypes. In this review, we discuss the paternal reprogramming of offspring phenotype and the possible underlying epigenetic mechanisms. Cracking these epigenetic mechanisms will lead to a better appreciation of "Paternal Origins of Health and Disease" and guide innovation of intervention algorithms to achieve 'healthier' outcomes in future generations. All this will revolutionize our understanding of human disease etiology.

Bioinformatics-based identification of key candidate genes and signaling pathways in patients with Parkinson's disease and obstructive sleep apnea.

OBJECTIVES: Existing evidence exhibits that obstructive sleep apnea (OSA) is a potential consequence of Parkinson's disease (PD) or a contributor to PD progression. This investigation aimed to detect potential critical genes and molecular mechanisms underlying interactions between PD and OSA through bioinformatics analyses. METHODS: The Gene Expression Omnibus (GEO) database was employed to obtain the expression profiles GSE20163 and GSE135917. The identification of common genes connected to PD and OSA was performed utilizing weighted gene co-expression network analysis and the R 4.0.4 program. The Cytoscape program was utilized to generate a network of protein-protein interactions (PPI), and the CytoHubba plugin was utilized to detect hub genes. Subsequently, functional enrichment analyses of the hub genes were conducted. Markers with increased diagnostic values for PD and OSA were confirmed using the GEO datasets GSE8397 and GSE38792. RESULTS: Typically, 57 genes that are common were identified in PD and OSA. Among these common genes, the top 10 hub genes in the PPI network were chosen. The verified datasets confirmed the presence of three important genes: CADPS, CHGA, and SCG3. Functional enrichment analysis revealed that these hub genes mostly participate in GABAergic synapses. CONCLUSION: Our findings suggest that CADPS, CHGA, and SCG3 are key genes involved in molecular mechanisms underlying interactions between OSA and PD. Functional enrichment of hub genes indicated a link between GABAergic synapses and the shared pathogenesis of PD and OSA. These candidate genes and corresponding pathways offer novel insights regarding biological targets that underlie the transcriptional connection between OSA and PD.

A hemodynamic analysis of energy loss in abdominal aortic aneurysm using three-dimension idealized model.

Objective: The aim of this study is to perform specific hemodynamic simulations of idealized abdominal aortic aneurysm (AAA) models with different diameters, curvatures and eccentricities and evaluate the risk of thrombosis and aneurysm rupture. Methods: Nine idealized AAA models with different diameters (3 cm or 5 cm), curvatures (0° or 30°) and eccentricities (centered on or tangent to the aorta), as well as a normal model, were constructed using commercial software (Solidworks; Dassault Systemes S.A, Suresnes, France). Hemodynamic simulations were conducted with the same time-varying volumetric flow rate extracted from the literature and 3-element Windkessel model (3 EWM) boundary conditions were applied at the aortic outlet. Several hemodynamic parameters such as time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), relative residence time (RRT), endothelial cell activation potential (ECAP) and energy loss (EL) were obtained to evaluate the risk of thrombosis and aneurysm rupture under different conditions. Results: Simulation results showed that the proportion of low TAWSS region and high OSI region increases with the rising of aneurysm diameter, whereas decreases in the curvature and eccentric models of the corresponding diameters, with the 5 cm normal model having the largest low TAWSS region (68.5%) and high OSI region (40%). Similar to the results of TAWSS and OSI, the high ECAP and high RRT areas were largest in the 5 cm normal model, with the highest wall-averaged value (RRT: 5.18 s, ECAP: 4.36 Pa-1). Differently, the increase of aneurysm diameter, curvature, and eccentricity all lead to the increase of mean flow EL and turbulent EL, such that the highest mean flow EL (0.82 W · 10-3) and turbulent EL (1.72 W · 10-3) were observed in the eccentric 5 cm model with the bending angle of 30°. Conclusion: Collectively, increases in aneurysm diameter, curvature, and eccentricity all raise mean flow EL and turbulent flow EL, which may aggravate the damage and disturbance of flow in aneurysm. In addition, it can be inferred by conventional parameters (TAWSS, OSI, RRT and ECAP) that the increase of aneurysm diameter may raise the risk of thrombosis, whereas the curvature and eccentricity appeared to have a protective effect against thrombosis.

Early tirofiban administration after intravenous thrombolysis in acute ischemic stroke (ADVENT): Study protocol of a multicenter, randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Nearly half of patients with acute ischemic stroke who undergo intravenous thrombolysis (IVT) fail to achieve excellent functional outcomes. Early administration of tirofiban after IVT may improve patient outcomes. OBJECTIVE: To evaluate the efficacy and safety of early tirofiban administration after intravenous tenecteplase in patients with acute ischemic stroke. METHODS AND DESIGN: The ADVENT trial is a multicenter, randomized, parallel-controlled, double-blind clinical trial. A total of 1084 patients undergoing IVT without subsequent endovascular treatment will be recruited from multiple hospitals in China. Subjects will be randomized in a 1:1 ratio to receive tirofiban or placebo, which will be infused within 6 h after IVT until 24 h after IVT, at 0.4 µg/kg/min for 30 min and then at 0.1 µg/kg/min. The primary efficacy outcome is the proportion of patients with excellent functional outcomes (modified Rankin Scale (mRS) ⩽ 1) at 90 days. Secondary outcomes include the proportion of patients with favorable functional outcomes (mRS ⩽ 2) at 90 days and neurological functional assessments evaluated during hospitalization. Symptomatic intracranial hemorrhage will be the primary safety outcome. Mortality and other adverse events will be recorded. DISCUSSION: This pivotal trial will provide important data on the early administration of antiplatelet therapy after IVT and may promote progress in treatment standards. TRIAL REGISTRY: ClinicalTrials.gov (NCT06045156).

A comprehensive review on signaling attributes of serine and serine metabolism in health and disease.

Serine is a metabolite with ever-expanding metabolic and non-metabolic signaling attributes. By providing one­carbon units for macromolecule biosynthesis and functional modifications, serine and serine metabolism largely impinge on cellular survival and function. Cancer cells frequently have a preference for serine metabolic reprogramming to create a conducive metabolic state for survival and aggressiveness, making intervention of cancer-associated rewiring of serine metabolism a promising therapeutic strategy for cancer treatment. Beyond providing methyl donors for methylation in modulation of innate immunity, serine metabolism generates formyl donors for mitochondrial tRNA formylation which is required for mitochondrial function. Interestingly, fully developed neurons lack the machinery for serine biosynthesis and rely heavily on astrocytic l-serine for production of d-serine to shape synaptic plasticity. Here, we recapitulate recent discoveries that address the medical significance of serine and serine metabolism in malignancies, mitochondrial-associated disorders, and neurodegenerative pathologies. Metabolic control and epigenetic- and posttranslational regulation of serine metabolism are also discussed. Given the metabolic similarities between cancer cells, neurons and germ cells, we further propose the relevance of serine metabolism in testicular homeostasis. Our work provides valuable hints for future investigations that will lead to a deeper understanding of serine and serine metabolism in cellular physiology and pathology.

Retinoic acid signaling in development and differentiation commitment and its regulatory topology.

Retinoic acid (RA), the derivative of vitamin A/retinol, is a signaling molecule with important implications in health and disease. It is a well-known developmental morphogen that functions mainly through the transcriptional activity of nuclear RA receptors (RARs) and, uncommonly, through other nuclear receptors, including peroxisome proliferator-activated receptors. Intracellular RA is under spatiotemporally fine-tuned regulation by synthesis and degradation processes catalyzed by retinaldehyde dehydrogenases and P450 family enzymes, respectively. In addition to dictating the transcription architecture, RA also impinges on cell functioning through non-genomic mechanisms independent of RAR transcriptional activity. Although RA-based differentiation therapy has achieved impressive success in the treatment of hematologic malignancies, RA also has pro-tumor activity. Here, we highlight the relevance of RA signaling in cell-fate determination, neurogenesis, visual function, inflammatory responses and gametogenesis commitment. Genetic and post-translational modifications of RAR are also discussed. A better understanding of RA signaling will foster the development of precision medicine to improve the defects caused by deregulated RA signaling.

Proteolytic cleavage and inactivation of the TRMT1 tRNA modification enzyme by SARS-CoV-2 main protease.

Nonstructural protein 5 (Nsp5) is the main protease of SARS-CoV-2 that cleaves viral polyproteins into individual polypeptides necessary for viral replication. Here, we show that Nsp5 binds and cleaves human tRNA methyltransferase 1 (TRMT1), a host enzyme required for a prevalent post-transcriptional modification in tRNAs. Human cells infected with SARS-CoV-2 exhibit a decrease in TRMT1 protein levels and TRMT1-catalyzed tRNA modifications, consistent with TRMT1 cleavage and inactivation by Nsp5. Nsp5 cleaves TRMT1 at a specific position that matches the consensus sequence of SARS-CoV-2 polyprotein cleavage sites, and a single mutation within the sequence inhibits Nsp5-dependent proteolysis of TRMT1. The TRMT1 cleavage fragments exhibit altered RNA binding activity and are unable to rescue tRNA modification in TRMT1-deficient human cells. Compared to wildtype human cells, TRMT1-deficient human cells infected with SARS-CoV-2 exhibit reduced levels of intracellular viral RNA. These findings provide evidence that Nsp5-dependent cleavage of TRMT1 and perturbation of tRNA modification patterns contribute to the cellular pathogenesis of SARS-CoV-2 infection.

A Predictive Model to Evaluate Pathologic Complete Response in Rectal Adenocarcinoma.

Introduction: Neoadjuvant chemo-radiotherapy (nCRT) before surgery was a standard treatment strategy for locally advanced rectal cancer (LARC). The aim of this study was to assess the relationship between the predictive factors and pathological complete response (pCR) in rectal cancer patients, especially in ultra-low ones. Method: A total of 402 patients were involved in this retrospective study. The logistic regression analyses were used to compare the different subgroups in univariate analysis. Multivariate analysis was performed to determine the independent predictive factors of pCR by using a logistic regression model. Results: A total of 402 patients received preoperative CRT. In all patients, multivariate analysis revealed that circumferential tumor extent rate (CER) (≤ 2/3cycle vs >2/3 cycle, P < .001, OR = 4.834, 95% CI: 2.309-10.121), carcinoembryonic antigen (CEA) level (both ≤ 5 vs pre > 5 and post ≤ 5 vs both > 5, P = .033, OR = 1.537, 95% CI: 1.035-2.281), and interval time between the end of CRT and surgery (P = .031, OR = 2.412, 95% CI: 1.086-5.358) were predictive factors for pCR. The area under the curve (AUC) of the predictive model was 0.709 (95% CI: 0.649-0.769), which was significantly higher than the CER (0.646, 95% CI: 0.584-0.709), interval time (0.563, 95% CI: 0.495-0.631) and CEA level (0.586, 95% CI: 0.518-0.655). In ultra-low rectal patients, multivariate logistic regression analysis revealed that CER (≤ 2/3 cycle vs > 2/3 cycle, P = .003, OR = 7.203, 95% CI: 1.934-26.823) and mismatch repair (MMR) status (pMMR vs dMMR, P = .016, OR = 0.173, 95% CI: 0.041-0.720) were predictive factors for pCR. The AUC of the predictive model was 0.653 (95% CI: 0.474-0.832). Conclusion: New predictive models were varied by the histologic types and MMR statuses to evaluate the trend of tumor response to nCRT in all RC cases and ultra-low RC patients, which may be used to individualize stratify for selected LARC patients.

Exploring the ignored role of escaped algae in a pilot-scale DWDS: Disinfectant consumption, DBP yield and risk formation.

Insufficient treatments during bloom-forming seasons allow algae to enter the subsequent drinking water distribution system (DWDS). Yet, scarce information is available regarding the role escaped algae to play in the DWDS, and how they interact with the system. Thus, three scenarios were conducted: a pilot DWDS with algae (a), pipe water (b), and pipe water with algae (c). Experimental results showed that, compared to biofilm and bulk water, escaped algae required fewer disinfectants. Competition for disinfectants varied with algal strains (Microcystis aeruginosa, MA; Pseudanabaena sp., PS) and disinfectant types (chlorine, Cl2; chloriamine, NH2Cl). Algae in the MA-Cl2 group showed the highest demand (6.25%-36.02%). However, the low-concentration disinfectants distributed to algae could trigger distinct algal status alternations. Cl2 diffused into intact MA cells and reacted with intracellular compositions. Damaged PS cells reached 100% within 2 h. Typical disinfection byproducts (DBPs), including trihalomethanes (THMs), haloacetic acids and halogenated acetonitriles were examined. Disinfectant types and algal strains affected DBP yield and distribution. Although disinfectants consumed by algae might not promote dissolved DBP formation, especially for THMs. DBP formation of the other components was affected by escaped algae via changing disinfectant assignment (reduced by 45.45% for MA-Cl2) and transformation efficiency (by 34.52%). The cytotoxicity risks were estimated. Dissolved DBP-induced risks were not added when escaped algae occurred, whereas disruption and release of intracellular substances increased risks; the maximum cytotoxicity did not occur at 12 h rather than at the end (24 h). Overall, this study provided an innovative perspective on algal-related water quality issues in water systems.

The emerging era of lactate: A rising star in cellular signaling and its regulatory mechanisms.

Cellular metabolites are ancient molecules with pleiotropic implications in health and disease. Beyond their cognate roles, they have signaling functions as the ligands for specific receptors and the precursors for epigenetic or posttranslational modifications. Lactate has long been recognized as a metabolic waste and fatigue product mainly produced from glycolytic metabolism. Recent evidence however suggests lactate is an unique molecule with diverse signaling attributes in orchestration of numerous biological processes, including tumor immunity and neuronal survival. The copious metabolic and non-metabolic functions of lactate mediated by its bidirectional shuttle between cells or intracellular organelles lead to a phenotype called "lactormone." Importantly, the mechanisms of lactate signaling, via acting as a molecular sensor and a regulator of NAD+ metabolism and AMP-activated protein kinase signaling, and via the newly identified lactate-driven lactylation, have been discovered. Further, we include a brief discussion about the autocrine regulation of efferocytosis by lactate in Sertoli cells which favoraerobic glycolysis. By emphasizing a repertoire of the most recent discovered mechanisms of lactate signaling, this review will open tantalizing avenues for future investigations cracking the regulatory topology of lactate signaling covered in the veil of mystery.

Allelic variations of ClACO gene improve nitrogen uptake via ethylene-mediated root architecture in watermelon.

KEY MESSAGE: The ClACO gene encoding 1-aminocyclopropane-1-carboxylate oxidase enabled highly efficient 15N uptake in watermelon. Nitrogen is one of the most essential nutrient elements that play a pivotal role in regulating plant growth and development for crop productivity. Elucidating the genetic basis of high nitrogen uptake is the key to improve nitrogen use efficiency for sustainable agricultural productivity. Whereas previous researches on nitrogen absorption process are mainly focused on a few model plants or crops. To date, the causal genes that determine the efficient nitrogen uptake of watermelon have not been mapped and remains largely unknown. Here, we fine-mapped the 1-aminocyclopropane-1-carboxylate oxidase (ClACO) gene associated with nitrogen uptake efficiency in watermelon via bulked segregant analysis (BSA). The variations in the ClACO gene led to the changes of gene expression levels between two watermelon accessions with different nitrogen uptake efficiencies. Intriguingly, in terms of the transcript abundance of ClACO, it was concomitant with significant differences in ethylene evolutions in roots and root architectures between the two accessions and among the different genotypic offsprings of the recombinant BC2F1(ZJU132)-18. These findings suggest that ethylene as a negative regulator altered nitrogen uptake efficiency in watermelon by controlling root development. In conclusion, our current study will provide valuable target gene for precise breeding of 'green' watermelon varieties with high-nitrogen uptake efficiencies.

Hyperoside mediates protection from diabetes kidney disease by regulating ROS-ERK signaling pathway and pyroptosis.

Renal tubular injury is a key factor in the progression of diabetic kidney disease to end-stage renal disease. Hyperoside, a natural flavonol glycoside in various plants, is a potentially effective drug for the clinical treatment of diabetic kidney disease. However, the specific mechanisms remain unknown. Therefore, this study will explore the effect and mechanism of hyperoside on renal tubulointerstitium in diabetic kidney disease. db/db mouse (C57BL/KsJ) is a model of type 2 diabetes resulting from Leptin receptor point mutations, with the appearance of diabetic kidney disease. Therefore, db/db mice were used for in vivo experimental studies. In vitro, human renal tubular epithelial cells were incubated with bovine serum albumin to simulate the injury of renal tubular epithelial cells caused by excessive albumin in primary urine. The experimental results showed that hyperoside could improve kidney function and reduce kidney tissue damage in mice, and could inhibit oxidative stress, extracellularly regulated protein kinases 1/2 signaling activation, and pyroptosis in human renal tubular epithelial cells. Therefore, hyperoside inhibited oxidative stress by regulating the activation of the extracellularly regulated protein kinases 1/2/mitogen-activated protein kinase signaling pathway, thereby alleviating proteinuria-induced pyroptosis in renal tubular epithelial cells. This study provides novel evidence that could facilitate the clinical application of hyperoside in diabetic kidney disease treatment.

Pan-genome analysis sheds light on structural variation-based dissection of agronomic traits in melon crops.

Sweetness and appearance of fresh fruits are key palatable and preference attributes for consumers and are often controlled by multiple genes. However, fine-mapping the key loci or genes of interest by single genome-based genetic analysis is challenging. Herein, we present the chromosome-level genome assembly of 1 landrace melon accession (Cucumis melo ssp. agrestis) with wild morphologic features and thus construct a melon pan-genome atlas via integrating sequenced melon genome datasets. Our comparative genomic analysis reveals a total of 3.4 million genetic variations, of which the presence/absence variations (PAVs) are mainly involved in regulating the function of genes for sucrose metabolism during melon domestication and improvement. We further resolved several loci that are accountable for sucrose contents, flesh color, rind stripe, and suture using a structural variation (SV)-based genome-wide association study. Furthermore, via bulked segregation analysis (BSA)-seq and map-based cloning, we uncovered that a single gene, (CmPIRL6), determines the edible or inedible characteristics of melon fruit exocarp. These findings provide important melon pan-genome information and provide a powerful toolkit for future pan-genome-informed cultivar breeding of melon.

Heart Rate Variability Parameter Changes in Patients With Acute Ischemic Stroke Undergoing Intravenous Thrombolysis.

Background Autonomic dysfunction has been revealed in patients with acute ischemic stroke and is associated with poor prognosis. However, autonomic nervous system function assessed by heart rate variability (HRV) and its relationship with clinical outcomes in patients undergoing intravenous thrombolysis (IVT) remain unknown. Methods and Results Patients who did and did not undergo IVT between September 2016 and August 2021 were prospectively and consecutively recruited. HRV values were measured at 1 to 3 and 7 to 10 days after stroke to assess autonomic nervous system function. A modified Rankin scale score ≥2 at 90 days was defined as an unfavorable outcome. Finally, the analysis included 466 patients; 224 underwent IVT (48.1%), and 242 did not (51.9%). Linear regression showed a positive correlation of IVT with parasympathetic activation-related HRV parameters at 1 to 3 days (high frequency: ß=0.213, P=0.002) and with both sympathetic (low frequency: ß=0.152, P=0.015) and parasympathetic activation-related HRV parameters (high frequency: ß=0.153, P=0.036) at 7 to 10 days after stroke. Logistic regression showed HRV values and autonomic function within 1 to 3 and 7 to 10 days after stroke were independently associated with 3-month unfavorable outcomes after adjusting for confounders in patients who underwent IVT (all P<0.05). Furthermore, addition of HRV parameters to conventional risk factors significantly improved risk-predictive ability of 3-month outcome (the area under the receiver operating characteristic curve significantly improved from 0.784 [0.723-0.846] to 0.855 [0.805-0.906], P=0.002). Conclusions IVT positively affected HRV and autonomic nervous system activity, and autonomic function assessed by HRV in acute stroke phase was independently associated with unfavorable outcomes in patients undergoing IVT.