Hypoxia-preconditioned bone marrow-derived mesenchymal stem cells protect neurons from cardiac arrest-induced pyroptosis.

JOURNAL/nrgr/04.03/01300535-202504000-00027/figure1/v/2024-07-06T104127Z/r/image-tiff Cardiac arrest can lead to severe neurological impairment as a result of inflammation, mitochondrial dysfunction, and post-cardiopulmonary resuscitation neurological damage. Hypoxic preconditioning has been shown to improve migration and survival of bone marrow-derived mesenchymal stem cells and reduce pyroptosis after cardiac arrest, but the specific mechanisms by which hypoxia-preconditioned bone marrow-derived mesenchymal stem cells protect against brain injury after cardiac arrest are unknown. To this end, we established an in vitro co-culture model of bone marrow-derived mesenchymal stem cells and oxygen-glucose deprived primary neurons and found that hypoxic preconditioning enhanced the protective effect of bone marrow stromal stem cells against neuronal pyroptosis, possibly through inhibition of the MAPK and nuclear factor κB pathways. Subsequently, we transplanted hypoxia-preconditioned bone marrow-derived mesenchymal stem cells into the lateral ventricle after the return of spontaneous circulation in an 8-minute cardiac arrest rat model induced by asphyxia. The results showed that hypoxia-preconditioned bone marrow-derived mesenchymal stem cells significantly reduced cardiac arrest-induced neuronal pyroptosis, oxidative stress, and mitochondrial damage, whereas knockdown of the liver isoform of phosphofructokinase in bone marrow-derived mesenchymal stem cells inhibited these effects. To conclude, hypoxia-preconditioned bone marrow-derived mesenchymal stem cells offer a promising therapeutic approach for neuronal injury following cardiac arrest, and their beneficial effects are potentially associated with increased expression of the liver isoform of phosphofructokinase following hypoxic preconditioning.

Construction of a prediction model for pulmonary infection and its risk factors in Intensive Care Unit patients.

Objective: To identify independent risk factors of pulmonary infection in intensive care unit (ICU) patients, and to construct a prediction model. Methods: Medical data of 398 patients treated in the ICU of Jiaxing Hospital of Traditional Chinese Medicine from January 2019 to January 2023 were analyzed. Univariate and multivariate logistic regression analyses were used to identify independent risk factors for pulmonary infection in ICU patients. R software was used to construct a nomogram prediction model, and the prediction model was internally validated using computer simulation bootstrap method. Predictive value of the model was analyzed using the receiver operating characteristic (ROC) curve. Results: A total of 97 ICU patients (24.37%) developed pulmonary infection. Age, ICU stay time, invasive operation, diabetes, duration of mechanical ventilation, and state of consciousness were all identified as risk factors for pulmonary infection. The calibration curve of the constructed nomogram prediction model showed a good consistency between the predicted value of the model and the actual observed value. ROC curve analysis showed that the area under the curve (AUC) of the model was 0.784 (95% CI: 0.731-0.837), indicating a certain predictive value. Conclusions: Age, length of stay in ICU, invasive operation, diabetes, duration of mechanical ventilation, and state of consciousness are risk factors for pulmonary infection in ICU patients. The nomogram prediction model constructed based on the above risk factors has shown a good predictive value.

A comparison of morning priming exercise using traditional-set and cluster-set configurations on afternoon explosive performance.

The impact of two priming exercise protocols using traditional (TS) or cluster-set (CS) arrangements on explosive performance 6 hours later were examined. Sixteen male collegiate athletes performed three testing sessions (one baseline without any prior exercise in the morning and two experimental sessions) separated by 72 hours. Participants completed two morning (9-11 am) priming protocols in a randomized order, either using a TS (no rest between repetitions) or CS (30 seconds of rest between repetitions) configuration. The protocols consisted of 3 sets × 3 repetitions of barbell back squat at 85% of 1 repetition maximum, with 4 minutes of rest between sets. In the afternoon (3-5 pm) of each trial, after a 6-hour rest period, a physical test battery was conducted that replicated baseline testing, including countermovement jump, 20-meter straight-line sprint, and T-test abilities. Across both conditions, participants exhibited increased countermovement jump height, 20-meter sprint time and T-test time compared to baseline (P < 0.05). Improvements in countermovement jump height (+4.4 ± 5.4%; P = 0.008) and 20-meter sprint time (+1.3 ± 1.7%; P = 0.022), but not T-test time (+1.1 ± 3.3%; P = 0.585), were significantly greater for CS than TS. In conclusion, compared to a traditional set arrangement, a morning-based priming protocol using a cluster-set configuration led to superior explosive performance benefits in the afternoon.

Progress of SGLT2 inhibitors in the treatment of common immune-related nephropathies.

The immune system can lead to a variety of renal diseases through direct or indirect mechanisms. In immune-mediated nephropathy, though standardized treatment, there are still a small number of patients with further decline in renal function, which may even progress to renal failure; sodium-glucose cotransporter protein 2 (SLC5A2,SGLT2) inhibitors not only can significantly reduce blood glucose, but also have an additional protective effect on the kidneys and the heart; this review concludes the potential mechanism of the renal protective effect of SGLT2i and the new advances in the recent years in common immune-mediated nephropathies, which can provide new theoretical references to optimize the therapeutic strategy of common immune-mediated nephropathies.

Elucidating the role of angiogenesis-related genes in colorectal cancer: a multi-omics analysis.

Background: Angiogenesis plays a pivotal role in colorectal cancer (CRC), yet its underlying mechanisms demand further exploration. This study aimed to elucidate the significance of angiogenesis-related genes (ARGs) in CRC through comprehensive multi-omics analysis. Methods: CRC patients were categorized according to ARGs expression to form angiogenesis-related clusters (ARCs). We investigated the correlation between ARCs and patient survival, clinical features, consensus molecular subtypes (CMS), cancer stem cell (CSC) index, tumor microenvironment (TME), gene mutations, and response to immunotherapy. Utilizing three machine learning algorithms (LASSO, Xgboost, and Decision Tree), we screen key ARGs associated with ARCs, further validated in independent cohorts. A prognostic signature based on key ARGs was developed and analyzed at the scRNA-seq level. Validation of gene expression in external cohorts, clinical tissues, and blood samples was conducted via RT-PCR assay. Results: Two distinct ARC subtypes were identified and were significantly associated with patient survival, clinical features, CMS, CSC index, and TME, but not with gene mutations. Four genes (S100A4, COL3A1, TIMP1, and APP) were identified as key ARCs, capable of distinguishing ARC subtypes. The prognostic signature based on these genes effectively stratified patients into high- or low-risk categories. scRNA-seq analysis showed that these genes were predominantly expressed in immune cells rather than in cancer cells. Validation in two external cohorts and through clinical samples confirmed significant expression differences between CRC and controls. Conclusion: This study identified two ARG subtypes in CRC and highlighted four key genes associated with these subtypes, offering new insights into personalized CRC treatment strategies.

Ursolic acid improves necroptosis via STAT3 signaling in intestinal ischemia/reperfusion injury.

Intestinal ischemia/reperfusion injury (IRI) poses a serious threat to human survival and quality of life with high mortality and morbidity rates. The current absence of effective treatments for intestinal IRI highlights the urgent need to identify new therapeutic targets. Ursolic acid (UA), a pentacyclic triterpene natural compound, has been shown to possess various pharmacological properties including intestinal protection. However, its potential protective efficacy on intestinal IRI remains elusive. This study aimed to investigate the effect of UA on intestinal IRI and explore the underlying mechanisms. To achieve this, we utilized network pharmacology to analyze the mechanism of UA in intestinal IRI and assessed UA's effects on intestinal IRI using a mouse model of superior mesenteric artery occlusion/reperfusion and an in vitro model of oxygen-glucose deprivation and reperfusion-induced IEC-6 cells. Our results demonstrated that UA improved necroptosis through the RIP1/RIP3/MLKL pathway, reduced necroinflammation via the HMGB1/TLR4/NF-κB pathway, attenuated morphological damage, and enhanced intestinal barrier function. Furthermore, UA pretreatment downregulated the phosphorylation level of signal transducer and activator of transcription 3 (STAT3). The effects of UA were attenuated by the STAT3 agonist Colivelin. In conclusion, our study suggests that UA can improve intestinal IRI by inhibiting necroptosis in enterocytes via the suppression of STAT3 activation. These results provide a theoretical basis for UA treatment of intestinal IRI and related clinical diseases.

Differences in the risk of immune-related pneumonitis between PD-1 and PD-L1 inhibitors: a meta-analysis according to the new mirror-principle and PRISMA guidelines.

PURPOSE: To compare the risk of immune-associated pneumonitis between PD-1 and PD-L1 inhibitors, the meta-analysis was designed. METHOD: The difference in risk of immune-associated pneumonitis between PD-1 and PD-L1 inhibitors was assessed by two different meta-analysis methods, the Mirror-pairing and the PRISMA guidelines. RESULTS: A total of eighty-eight reports were used for meta-analysis, while thirty-two studies were used for the Mirror-pairing. Both PD-1 and PD-L1 inhibitors (used alone or combined with chemotherapy) increased the risk of developing immune-related pneumonitis (P < 0.00001; P < 0.00001). Based on indirect analyses results (subgroup analyses), the risk of PD-L1-induced pneumonitis was weaker than that of PD-1 inhibitors when the control group was chemotherapy (OR = 3.33 vs. 5.43) or placebo (OR = 2.53 vs. 3.19), while no obvious significant differences were found (P = 0.17; P = 0.53). For the Mirror-pairing-based meta-analysis, the risk of PD-1-induced pneumonitis was significantly higher than that of PD-L1 inhibitors (OR = 1.46, 95%CI [1.08, 1.98], I2 = 0%, Z = 2.47 (P = 0.01)). However, this difference was not significant, when they were combined with chemotherapy (OR = 1.05, 95%CI [0.68, 1.60], I2 = 38%, Z = 0.21 (P = 0.84)). CONCLUSION: Both PD-1 and PD-L1 inhibitors increased the risk of immune-related pneumonitis, while the risk of PD-1-induced pneumonitis was significantly higher than that of PD-L1 inhibitors.

Intraindividual comparison of CT and MRI for predicting vessels encapsulating tumor clusters in hepatocellular carcinoma.

OBJECTIVES: To establish and validate scoring models for predicting vessels encapsulating tumor clusters (VETC) in hepatocellular carcinoma (HCC) using computed tomography (CT) and magnetic resonance imaging (MRI), and to intra-individually compare the predictive performance between the two modalities. METHODS: We retrospectively included 324 patients with surgically confirmed HCC who underwent preoperative dynamic CT and MRI with extracellular contrast agent between June 2019 and August 2020. These patients were then divided into a discovery cohort (n = 227) and a validation cohort (n = 97). Imaging features and Liver Imaging Reporting and Data System (LI-RADS) categories of VETC-positive HCCs were evaluated. Logistic regression analyses were conducted on the discovery cohort to identify clinical and imaging predictors associated with VETC-positive cases. Subsequently, separate CT-based and MRI-based scoring models were developed, and their diagnostic performance was compared using generalized estimating equations. RESULTS: On both CT and MRI, VETC-positive HCCs exhibited a higher frequency of size > 5.0 cm, necrosis or severe ischemia, non-smooth tumor margin, targetoid appearance, intratumor artery, and heterogeneous enhancement with septations or irregular ring-like structure compared to VETC-negative HCCs (all p < 0.05). Regarding LI-RADS categories, VETC-positive HCCs were more frequently categorized as LR-M than VETC-negative cases (all p < 0.05). In the validation cohort, the CT-based model showed similar sensitivity (76.7% vs. 86.7%, p = 0.375), specificity (83.6% vs. 74.6%, p = 0.180), and area under the curve value (0.80 vs. 0.81, p = 0.910) to the MRI-based model in predicting VETC-positive HCCs. CONCLUSION: Preoperative CT and MRI demonstrated comparable performance in the identification of VETC-positive HCCs, thus displaying promising predictive capabilities. CLINICAL RELEVANCE STATEMENT: Both computed tomography and magnetic resonance imaging demonstrated promise in preoperatively identifying the vessel-encapsulating tumor cluster pattern in hepatocellular carcinoma, with no statistically significant difference between the two modalities, potentially adding additional prognostic value. KEY POINTS: Computed tomography (CT) and magnetic resonance imaging (MRI) show promise in the preoperative identification of vessels encapsulating tumor clusters-positive hepatocellular carcinoma (HCC). HCC with vessels encapsulating tumor cluster patterns were more frequently LR-M compared to those without. These CT and MRI models showed comparable ability in identifying vessels encapsulating tumor clusters-positive HCC.

Identification of ribosomal protein S21 as a potential prognostic and immunotherapy biomarker for hepatocellular carcinoma.

BACKGROUND: Recent studies show that ribosomal protein S21 (RPS21) plays a role in the development and progression of various malignancies. However, the biological value of RPS21 in hepatocellular carcinoma (HCC) and its association with immunotherapy remain unknown. METHODS: Here, we examined the differential expression of RPS21 between HCC and normal liver tissues, using the TCGA, ICGC and GEO databases, followed by verification by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) in LO2, SMMC7721, HepG2, and MHCC-97H cell lines. Kaplan-Meier and Cox regression analyses were applied to investigate how RPS21 expression influenced overall survival, and a nomogram was established to predict prognosis among HCC patients. We further analyzed how RPS21 expression was related to tumor immune microenvironment, immunotherapy efficiency, and genomic alterations, and investigated potential underlying mechanisms. RESULTS: RPS21 upregulation was observed in HCC tissues and cell lines, compared to normal controls. Survival analysis revealed that RPS21 overexpression was significantly associated with poor clinical outcomes (all p < 0.05). Functional enrichment analyses indicated that differentially expressed genes relative to RPS21 expression were mainly involved in tumor response, proliferation, and metabolism. Additionally, RPS21 expression was positively correlated with the infiltration of activated CD4+ T cells and tumor mutational burden (all p < 0.05). Moreover, RPS21 was co-expressed with immune-related genes and immune checkpoint genes. Analyses of drug sensitivity predict that HCC patients with low RPS21 expression were more sensitive to targeted immunotherapy. CONCLUSIONS: The present results suggested that RPS21 might be a promising prognostic marker and a potential immunotherapy target for patients with HCC.

Actn2 defects accelerates H9c2 hypertrophy via ERK phosphorylation under chronic stress.

BACKGROUND: In humans, ACTN2 mutations are identified as highly relevant to a range of cardiomyopathies such as DCM and HCM, while their association with sudden cardiac death has been observed in forensic cases. Although ACTN2 has been shown to regulate sarcomere Z-disc organization, a causal relationship between ACTN2 dysregulation and cardiomyopathies under chronic stress has not yet been investigated. OBJECTIVE: In this work, we explored the relationship between Actn2 dysregulation and cardiomyopathies under dexamethasone treatment. METHODS: Previous cases of ACTN2 mutations were collected and the conservative analysis was carried out by MEGA 11, the possible impact on the stability and function of ACTN2 affected by these mutations was predicted by Polyphen-2. ACTN2 was suppressed by siRNA in H9c2 cells under dexamethasone treatment to mimic the chronic stress in vitro. Then the cardiac hypertrophic molecular biomarkers were elevated, and the potential pathways were explored by transcriptome analysis. RESULTS: Actn2 suppression impaired calcium uptake and increased hypertrophy in H9c2 cells under dexamethasone treatment. Concomitantly, hypertrophic molecular biomarkers were also elevated in Actn2-suppressed cells. Further transcriptome analysis and Western blotting data suggested that Actn2 suppression led to the excessive activation of the MAPK pathway and ERK cascade. In vitro pharmaceutical intervention with ERK inhibitors could partially reverse the morphological changes and inhibit the excessive cardiac hypertrophic molecular biomarkers in H9c2 cells. CONCLUSION: Our study revealed a functional role of ACTN2 under chronic stress, loss of ACTN2 function accelerated H9c2 hypertrophy through ERK signaling. A commercial drug, Ibudilast, was identified to reverse cell hypertrophy in vitro.

Transcription factor NFYA inhibits ferroptosis in lung adenocarcinoma cells by regulating PEBP1.

BACKGROUND: Ferroptosis is an iron-dependent programmed cell death mediated by lipid peroxidation. The purpose was to explore the molecular mechanism by which phosphatidylethanolamine-binding protein 1 (PEBP1) regulates ferroptosis in lung adenocarcinoma (LUAD), hoping to identify novel therapeutic targets for LUAD. METHODS: The expression, enrichment pathways and upstream transcription factors of PEBP1 were analyzed using bioinformatics tools. Dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) experiments were conducted to validate the interaction and binding relationship between PEBP1 and the upstream transcription factor nuclear transcription factor Y subunit α (NFYA). Quantitative reverse transcription PCR (qRT-PCR) was conducted to measure the expression levels of PEBP1 and NFYA mRNA in LUAD cells. Cell viability was detected by cell counting kit-8 assay. In addition, levels of malondialdehyde (MDA), Fe2+, and lipid reactive oxygen species (ROS) were assessed to evaluate ferroptosis levels in LUAD cells. RESULTS: PEBP1 was downregulated and significantly enriched in the ferroptosis signaling pathway in LUAD. Overexpression of PEBP1 suppressed cell viability remarkably, while levels of MDA, Fe2+, and lipid ROS were increased. Conversely, knockdown of PEBP1 produced the opposite effects. The upstream transcription factor NFYA, predicted to be involved in the regulation of PEBP1, was also upregulated in LUAD. Dual-luciferase reporter assay, ChIP, and molecular experiments revealed that NFYA transcriptionally suppressed the expression of PEBP1, and overexpression of NFYA could reverse the effects caused by PEBP1 overexpression. CONCLUSION: PEBP1 regulated ferroptosis in LUAD, and the transcription factor NFYA inhibited ferroptosis in LUAD cells by transcriptionally downregulating PEBP1 expression.

Clonal expansion of Tn1546-like transposon-carrying vancomycin-resistant Enterococcus faecium, a nationwide study in Taiwan, 2004-2018.

OBJECTIVES: The prevalence of vancomycin-resistant Enterococcus faecium (VREfm) has increased significantly in Taiwan. We investigated the molecular epidemiology of clinical VREfm isolates to increase our understanding on their spread and changes in population structure over a 14-year span. METHODS: A total of 1113 E. faecium isolates were collected biennially from 2004 to 2018 in Taiwan. MICs were determined by broth microdilution. Whole-genome sequencing (WGS) was performed on 229 VREfm isolates to characterize their genetic environment of vancomycin resistance and wgMLST was used to investigate their clonal relationship. RESULTS: Among the 229 isolates, ST17 and ST78 predominated, especially during the later years, and their prevalences increased from 14.6% (7/48) and 25.0% (12/48) in 2004-2010 to 47.5% (87/181) and 29.8% (54/181) in 2012-2018, respectively. Four types of vanA-carrying Tn1546 variants were detected, with type 1 and type 2 predominated. Type 1 Tn1546 contained an addition of IS1251, while type 2 resembled type 1 but had an addition of IS1678. wgMLST revealed several distinct clusters of ST17 and ST78 isolates, with type 1 Tn1546-harbouring ST17-Cluster 16 being the largest and most widespread clones throughout the study years. Type 2 Tn1546-carrying ST78 became a predominant clone (Cluster 21) after 2012. Isolates within these clusters are highly similar despite being from different hospitals, regions, and study year. CONCLUSION: The increase of VREfm in Taiwan was attributed to horizontal transfer of vanA-carrying Tn1546 variants between different STs and spread of persistent clones. This study highlights the importance of integrating WGS into surveillance to combat antimicrobial resistance.

Global scientific trends on exosomes therapy for osteoporosis from 2004 to 2023: A bibliometric and visualized analysis.

BACKGROUND: Exosomes have emerged as pivotal mediators in modulating physiological and pathological processes implicated in osteoporosis (OP) through their distinctive mode of intracellular communication. The use of exosomes has evoked considerable interest, catalyzing a surge in research endeavors on a global scale. This study endeavors to scrutinize contemporary landscapes and burgeoning trends in this realm. METHODS: The Web of Science Core Collection was used to retrieve publications on exosomes therapy for OP within the time frame of January 1, 2004 to December 31, 2023. The bibliometric methodology was applied to study and index the collected data. VOSviewer and citespace software were used to conduct visualization, co-authorship, co-occurrence, and publication trend analyses of exosome therapy in OP. RESULTS: A total of 610 publications (443 articles and 167 reviews) from 51 countries and 911 institutions were included in this study. Shanghai Jiao Tong University, Central South University, Sichuan University, and Zhejiang University are leading research institutions in this field. Stem Cell Research Therapy published the highest number of articles and has emerged as the most cited journal. Of the 4077 scholars who participated in the study, Xie, Hui, Zhang, Yan, Tan, and Yi-Juan had the largest number of articles. Furthermore, according to the cluster analysis of external keywords, future research hotspots can be categorized into 3 directions: research status of exosomes for the treatment of OP, treatment of OP through exosome-regulated signaling pathways, and exosomes as targeted drug delivery systems. CONCLUSION: This study suggests that the number of future publications on exosome therapy for OP will increase, with a focus on fundamental investigations into drug-loading capacities and molecular mechanisms. In summary, this study presents the first systematic bibliometric analysis of exosome therapy publications in OP, providing an objective and comprehensive overview of the field and a valuable reference for researchers in this domain.

Genome-Wide Association Study Reveals the Genetic Basis of Crude Fiber Components in Brassica napus L. Shoots at Stem Elongation Stage.

Brassica napus is currently the principal field crop for producing materials for primary, secondary and tertiary industries. B. napus shoots at stem elongation stage are rich in anthocyanins, vitamin C and mineral elements such as selenium, calcium and zinc, and represent a new type of green vegetable. However, the high crude fiber (CF) content of B. napus shoots affects their taste, and few studies have focused on the quality traits of these vegetables. In this study, we investigated five traits related to the CF components, including neutral detergent fiber (NDF), acid detergent fiber (ADF), acid detergent lignin (ADL), hemicellulose (Hem) and cellulose (Cel), of B. napus shoots. Whole-genome resequencing at a depth of ∼20× was utilized to genotype an association panel of 202 diverse accessions, which resulted in the identification of 6,093,649 single nucleotide polymorphisms (SNPs) and 996,252 indels, respectively. A genome-wide association study (GWAS) was performed for the five CF-related traits based on the phenotypic data observed in four environments. A total of 1,285 significant SNPs were detected at the threshold of -log10 (p) = 5.16, and 97 significant association regions were obtained. In addition, seven candidate genes located on chromosomes A2 (one gene), A8 (three genes), A9 (two genes) and C9 (one gene) related to CF traits were identified, and ten lines containing low CF contents were selected as excellent germplasm resources for breeding. Our results contributed new insights into the genetic basis of CF traits and suggested germplasm resources for the quality improvement of B. napus shoots.

Analysis of size effect and its influencing factors of brittle red sandstone with different heights.

We carried out uniaxial compression tests on brittle red sandstone with different heights. The test results show that the uniaxial compressive strength of rock sample increases first and then tends to be stable with the increase of the size, which is approximately stable between 75 and 81 MPa. Both elastic energy and dissipated energy increase with the increase of rock sample size. In order to further analyze the mechanism behind these phenomena, we combined advanced numerical simulation and theoretical analysis to explain these phenomena, and systematically analyzed the end face effect as one of the key factors affecting the uniaxial compression characteristics of brittle red sandstone for the first time. Small sized rock samples are very sensitive to end effect. The middle of the large sized rock samples is in a uniform compression state, and the effect of end effect is weakend. When there are rigid pads at both ends of the rock sample, there is an obvious elastic vertebral body during the loading process of the rock sample. The bearing capacity of rock samples with rigid pads is greater than that of rock samples without rigid pads, and the energy released during instantaneous failure of rock samples without rigid pads is greater than that of rock samples with rigid pads. The findings of this paper make a valuable contribution to establishing optimal study sample sizes and advancing the utilization of laboratory test mechanics parameters in engineering applications.

Past, present and future changes in the annual streamflow of the Lancang-Mekong River and their driving mechanisms.

The rapid development of the Greater Mekong Subregion (GMS) makes it essential to understand the major mechanisms controlling the streamflow, especially for the Lancang-Mekong River (abbr. Mekong River). We used instrumental annual streamflow data (1960-2007) from Chiang Saen hydrological station and several gridded hydroclimatic datasets to explore the hydroclimatic evolution of the Mekong River, together with its driving mechanisms. We found that changes in the Mekong streamflow are consistent with precipitation changes, and the Mekong is thus a precipitation-dominated river that is susceptible to the effects of ongoing climate change. The instrumental record of Mekong annual streamflow is closely related to hydroclimatic changes, especially those related to moisture, within the area from the Hengduan Mountains to the Chiang Saen Station. Based on these gridded records, we extended the Mekong annual streamflow record to cover 1891-2021 using nested multiple linear regression fitting. The fitted streamflow explained up to 57.6 % of the instrumental changes and it indicates that the major 2019 drought was not unique over the past century. Despite extremely low precipitation and high temperatures, it is likely that the effects of drought can be mitigated via hydraulic engineering regulation. Climatological analyses showed that the Mekong annual streamflow is driven by the El Niño-Southern Oscillation (ENSO) and the Indian Ocean Dipole (IOD), which is consistent with observed quasi-interannual cycles of 3-4 years. A multi-model ensemble of CMIP6 revealed that the Mekong annual streamflow will experience an upward trend in the future, accompanied by the more extreme impacts of ENSO and the IOD.

Crystal structure and characterization of monascin from the extracts of Monascus purpureus-fermented rice.

We present a novel solid form of monascin, an azaphilonoid derivative extracted from Monascus purpureus-fermented rice. The crystal structure, C21H26O5, was characterized by single-crystal X-ray diffraction and belongs to the orthorhombic space group P212121. To gain insight into the electronic properties of the short contacts in the crystalline state of monascin, we utilized the Experimental Library of Multipolar Atom Model 2 (ELMAM2) database to transfer the electron density of monascin in its crystalline state. Hirshfeld surface analysis, fingerprint analysis, electronic properties and energetic characterization reveal that intermolecular C-H...O hydrogen bonds play a crucial role in the noncovalent bonding interactions by connecting molecules into two- and three-dimensional networks. The molecular electrostatic potential (MEP) map of the monascin molecule demonstrates that negatively charged regions located at four O atoms are favoured binding sites for more positively charged amino acid residues during molecular recognition. In addition, powder X-ray diffraction confirms that no transformation occurs during the crystallization of monascin.

PEX3 promotes regenerative repair after myocardial injury in mice through facilitating plasma membrane localization of ITGB3.

The peroxisome is a versatile organelle that performs diverse metabolic functions. PEX3, a critical regulator of the peroxisome, participates in various biological processes associated with the peroxisome. Whether PEX3 is involved in peroxisome-related redox homeostasis and myocardial regenerative repair remains elusive. We investigate that cardiomyocyte-specific PEX3 knockout (Pex3-KO) results in an imbalance of redox homeostasis and disrupts the endogenous proliferation/development at different times and spatial locations. Using Pex3-KO mice and myocardium-targeted intervention approaches, the effects of PEX3 on myocardial regenerative repair during both physiological and pathological stages are explored. Mechanistically, lipid metabolomics reveals that PEX3 promotes myocardial regenerative repair by affecting plasmalogen metabolism. Further, we find that PEX3-regulated plasmalogen activates the AKT/GSK3ß signaling pathway via the plasma membrane localization of ITGB3. Our study indicates that PEX3 may represent a novel therapeutic target for myocardial regenerative repair following injury.

Natural Affinity Driven Modification by Silicene to Construct a "Thermal Switch" for Tumorous Bone Loss.

Tumorous bone defects present significant challenges for surgical bio-reconstruction due to the dual pathological conditions of residual tumor presence and extensive bone loss following excision surgery. To address this challenge, a "thermal switch" smart bone scaffold based on the silicene nanosheet-modified decalcified bone matrix (SNS@DBM) is developed by leveraging the natural affinity between collagen and silicene, which is elucidated by molecular dynamics simulations. Benefitting from its exceptional photothermal ability, biodegradability, and bioactivity, the SNS@DBM "thermal switch" provides an integrated postoperative sequential thermotherapy for tumorous bone loss by exerting three levels of photothermal stimulation (i.e., strong, moderate, and nonstimulation). During the different phases of postoperative bioconstruction, the SNS@DBM scaffold realizes simultaneous residual tumor ablation, tumor recurrence prevention, and bone tissue regeneration. These biological effects are verified in the tumor-bearing nude mice of patient-derived tissue xenografts and critical cranium defect rats. Mechanism research prompts moderate heat stimulus generated by and coordinating with SNSs can upregulate osteogenic genes, promote macrophages M2 polarization, and intensify angiogenesis of H-type vessels. This study introduces a versatile approach to the management of tumorous bone defects.

Quantitative transport mapping of multi-delay arterial spin labeling MRI detects early blood perfusion alterations in Alzheimer's disease.

BACKGROUND: Quantitative transport mapping (QTM) of blood velocity, based on the transport equation has been demonstrated higher accuracy and sensitivity of perfusion quantification than the traditional Kety's method-based cerebral blood flow (CBF). This study aimed to investigate the associations between QTM velocity and cognitive function in Alzheimer's disease (AD) using multiple post-labeling delay arterial spin labeling (ASL) MRI. METHODS: A total of 128 subjects (21 normal controls (NC), 80 patients with mild cognitive impairment (MCI), and 27 AD) were recruited prospectively. All participants underwent MRI examination and neuropsychological evaluation. QTM velocity and traditional CBF maps were computed from multiple delay ASL. Regional quantitative perfusion measurements were performed and compared to study group differences. We tested the hypothesis that cognition declines with reduced cerebral blood perfusion with consideration of age and gender effects. RESULTS: In cortical gray matter (GM) and the hippocampus, QTM velocity and CBF showed decreased values in the AD group compared to NC and MCI groups; QTM velocity, but not CBF, showed a significant difference between MCI and NC groups. QTM velocity and CBF showed values decreasing with age; QTM velocity, but not CBF, showed a significant gender difference between male and female. QTM velocity and CBF in the hippocampus were positively correlated with cognition, including global cognition, memory, executive function, and language function. CONCLUSION: This study demonstrated an increased sensitivity of QTM velocity as compared with the traditional Kety's method-based CBF. Specifically, we observed only in QTM velocity, reduced perfusion velocity in GM and the hippocampus in MCI compared with NC. Both QTM velocity and CBF demonstrated a reduction in AD vs. controls. Decreased QTM velocity and CBF in the hippocampus were correlated with poor cognitive measures. These findings suggest QTM velocity as potential biomarker for early AD blood perfusion alterations and it could provide an avenue for early intervention of AD.