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Abstract Background Base excess (BE) is associated with mortality from many diseases. However, the relationship between BE and mortality in patients with ischemic stroke remains uncertain. Our aim is to investigate the relationship between BE values upon admission to the ICU and mortality rates in critically ill stroke patients. Methods The current study enrolled 1,572 patients with ischemic stroke (863 males and 709 females). The associations of BE with intensive care unit (ICU), hospital, 28-day, and 1-year mortalities were assessed using multivariable logistic regression or Cox proportional hazards model. The potential impact of the Sequential Organ Failure Assessment (SOFA) score (

Mulberry has a long history of use as an edible fruit and medicine. Studies have shown that mulberry possesses several functional characteristics including antioxidation, anti-inflammation and anticancer. In recent years, mulberry wine has gained much attention from consumers due to its abundant bioactive components and distinctive sensory attributes. Based on the latest research, this review summarizes the health effects of mulberry wine from the perspective of bioactive components, clarifies the aroma composition of mulberry wine, discusses the main factors affecting the aroma quality of mulberry wine and prospected the future research trends. It is expected to provide new ideas for theoretical study and product development of mulberry wine, which will be helpful to promote the quality standardization of mulberry wine and enhance the economic value of mulberry wine industry.

Computer-aided diagnosis (CAD) plays a crucial role in the clinical application of Alzheimer’s disease (AD). In particular, convolutional neural network (CNN)-based methods are highly sensitive to subtle changes caused by brain atrophy in medical images (e.g., magnetic resonance imaging, MRI). Due to computational resource constraints, most CAD methods focus on quantitative features in specific regions, neglecting the holistic nature of the images, which poses a challenge for a comprehensive understanding of pathological changes in AD. To address this issue, we propose a lightweight dual multi-level hybrid pyramid convolutional neural network (DMA-HPCNet) to aid clinical diagnosis of AD. Specifically, we introduced ResNet as the backbone network and modularly extended the hybrid pyramid convolution (HPC) block and the dual multi-level attention (DMA) module. Among them, the HPC block is designed to enhance the acquisition of information at different scales, and the DMA module is proposed to sequentially extract different local and global representations from the channel and spatial domains. Our proposed DMA-HPCNet method was evaluated on baseline MRI slices of 443 subjects from the ADNI dataset. Experimental results show that our proposed DMA-HPCNet model performs efficiently in AD-related classification tasks with low computational cost.

Abstract Background Lung cancer is a highly prevalent malignancy and has the highest mortality rate among all tumors due to lymph node metastasis. Bone marrow and umbilical cord-derived mesenchymal stem cells (MSCs) have demonstrated tumor-suppressive effects on lung cancer. This study investigated the effects of DPSC lysate on proliferation, apoptosis, migration and invasion of cancer cells were studied in vivo and in vitro. Methods The proliferation, apoptosis, and migration/metastasis were evaluated by cell counting kit-8 assay, Annexin-V and propidium iodide staining, and the transwell assay, respectively. The expression levels of apoptosis-, cell cycle-, migration-, and adhesion-related mRNA and proteins were measured by qRT-PCR and western blot. The level and mRNA expression of tumor markers carcino embryonic antigen (CEA), neuron-specific enolase (NSE), and squamous cell carcinoma (SCC) were measured by Enzyme-linked immunosorbent assay (ELISA) and qRT-PCR. Finally, a tumor-bearing mouse model was constructed to observe the tumor-suppressive effect of DPSC lysate after intraperitoneal injection. Results DPSC lysate decreased the viability of A549 cells and induced apoptosis in lung cancer cells. Western blot confirmed that levels of Caspase-3, Bax, and Bad were increased, and Bcl-2 protein levels were decreased in A549 cells treated with DPSC lysate. In addition, DPSC lysate inhibited the migration and invasion of A549 cells; downregulated key genes of the cell cycle, migration, and adhesion; and significantly suppressed tumor markers. Xenograft results showed that DPSC lysate inhibited tumor growth and reduced tumor weight. Conclusions DPSC lysate inhibited proliferation, invasion, and metastasis; promoted apoptosis in lung cancer cells; and suppressed tumor growth- potentially providing a cell-based alternative therapy for lung cancer treatment. Graphical Abstract

Abstract Spinal cord injury (SCI) is accompanied by loss of Zn2+, which is an important cause of glutamate excitotoxicity and death of local neurons as well as transplanted stem cells. Dental pulp stem cells (DPSCs) have the potential for neural differentiation and play an immunomodulatory role in the microenvironment, making them an ideal cell source for the repair of central nerve injury, including SCI. The zeolitic imidazolate framework 8 (ZIF-8) is usually used as a drug and gene delivery carrier, which can release Zn2+ sustainedly in acidic environment. However, the roles of ZIF-8 on neural differentiation of DPSCs and the effect of combined treatment on SCI have not been explored. ZIF-8-introduced DPSCs were loaded into gelatin methacryloyl (GelMA) hydrogel and in situ injected into the injured site of SCI rats. Under the effect of ZIF-8, axon number and axon length of DPSCs-differentiated neuro-like cells were significantly increased. In addition, ZIF-8 protected transplanted DPSCs from apoptosis in the damaged microenvironment. ZIF-8 promotes neural differentiation and angiogenesis of DPSCs by activating the Mitogen-activated protein kinase (MAPK) signaling pathway, which is a promising transport nanomaterial for nerve repair.

Alzheimer’s disease (AD) is the most prevalent form of dementia, characterized by a progressive cognitive decline. Sporadic AD, accounting for more than 95% of cases, may arise due to the influence of environmental factors. It was reported that periodontitis, a common oral ailment, shares several risk factors with AD, including advanced age, smoking, diabetes, and hypertension, among others. Periodontitis is an inflammatory disease triggered by dysbiosis of oral microorganisms, whereas Alzheimer’s disease is characterized by neuroinflammation. Many studies have indicated that chronic inflammation can instigate brain AD-related pathologies, including amyloid-β plaques, Tau protein hyperphosphorylation, neuroinflammation, and neurodegeneration. The potential involvement of periodontal pathogens and/or their virulence factors in the onset and progression of AD by the oral-brain axis has garnered significant attention among researchers with ongoing investigations. This review has updated the periodontal pathogens potentially associated with AD, elucidating their impact on the central nervous system, immune response, and related pathological processes in the brain to provide valuable insights for future research on the oral-brain axis.

Background. Observational researches reported the underlying correlation of plasma myeloperoxidase (MPO) concentration with respiratory tract infections (RTIs), but their causality remained unclear. Here, we examined the cause–effect relation between plasma MPO levels and RTIs. Materials and Methods. Datasets of plasma MPO levels were from the Folkersen et al. study (n = 21,758) and INTERVAL study (n = 3,301). Summarized data for upper respiratory tract infection (URTI) (2,795 cases and 483,689 controls) and lower respiratory tract infection (LRTI) in the intensive care unit (ICU) (585 cases and 430,780 controls) were from the UK Biobank database. The primary method for Mendelian randomization (MR) analysis was the inverse variance weighted approach, with MR-Egger and weighted median methods as supplements. Cochrane’s Q test, MR-Egger intercept test, MR pleiotropy residual sum and outliers global test, funnel plots, and leave-one-out analysis were used for sensitivity analysis. Results. We found that plasma MPO levels were positively associated with URTI (odds ratio (OR) = 1.135; 95% confidence interval (CI) = 1.011–1.274; P=0.032) and LRTI (ICU) (OR = 1.323; 95% CI = 1.006–1.739; P=0.045). The consistent impact direction is shown when additional plasma MPO level genome-wide association study datasets are used (URTI: OR = 1.158; 95% CI = 1.072–1.251; P0.050). The sensitivity analysis revealed no violations of MR presumptions. Conclusions. Plasma MPO levels may causally affect the risks of URTI and LRTI (ICU). In contrast, the causal role of URTI and LRTI (ICU) on plasma MPO concentration was not supported in our MR analysis. Further studies are needed to identify the relationship between RTIs and plasma MPO levels.

Platelets play important roles in thrombosis, hemostasis, inflammation, and infection. We aimed to evaluate the association between platelet count and its variation trend and prognosis of patient with infectious diseases in intensive care units (ICUs). This retrospective cohort study extracted 4,251 critically ill adult patients with infectious diseases from the eICU Collaborative Research Database, whose platelet counts were measured daily during the first 7 days after admission. In the survivors, platelet counts decreased in the first days after admission, reached a nadir on day 3, and then returned and continued to rise above the admission value. In non-survivors, the platelet counts decreased after admission, without a subsequent upturn. We defined three subgroups according to the nadir platelet counts within 7 days: ≤50, 50–130, and ≥130 × 109/L, corresponding to high, intermediate, and low ICU mortality. A decreased platelet count was associated with increased ICU mortality (intermediate vs. low: 1.676 [1.285–2.187]; high vs. low: 3.632 [2.611–5.052]). In conclusion, during the first 7 days, platelet counts decreased after ICU admission, while increased subsequently in the survivors but not in the non-survivors. ICU mortality risk increased as nadir platelet count decreased below 130 × 109/L, and further boosted when it reached below 50 × 109/L.

Abstract Background Recent studies have shown that chronic kidney disease (CKD) prevalence is significantly higher in patients with hepatic steatosis (HS); however, it remains unclear whether HS is associated with serum creatinine (SCr). We aimed to explore the association between SCr levels and HS in a Chinese population. Methods We performed a cross-sectional study among 56,569 Chinese individuals. SCr level, other clinical and laboratory parameters, abdominal ultrasound and noninvasive fibrosis scores were extracted, and the fibrosis 4 score (FIB-4) was calculated. Results A total of 27.1% of the subjects had HS. After 1:1 propensity score matching (PSM) according to sex and age, we included 13,301 subjects with HS and 13,301 subjects without HS. SCr levels were significantly higher in the HS group than in the non-HS group [73.19 ± 15.14(μmoI/L) vs. 71.75 ± 17.49(μmoI/L), p

Stem cell therapy is of great therapeutical potential for anti-aging treatment. Lysates of dental pulp stem cells (DPSC) are rich in numerous cytokines, which can improve the cell growth environment and enhance collagen synthesis in the skin. Frequently, the instability of protein growth factors severely restricts their applications in living systems. In this study, a strategy for delivering the growth factors of DPSC lysate via protein-encapsulated zeolitic imidazolate framework-8 (ZIF-8) nanoparticles was developed. Using ZIF-8 as protein-encapsulated nanoparticles, a ZIF-8@DPSC lysate (ZIF-8@DL) with pH-responsive drug release was produced. ZIF-8@DL demonstrated superior cutaneous uptake, cutaneous penetration, and retention capacity in vivo compared to DPSC lysate. Moreover, ZIF-8@DL demonstrated excellent in vitro and in vivo biocompatibility. Subcutaneous microneedle injection of ZIF-8@DL into a mouse photoaging model resulted in significantly improved epidermal thickness, dermal collagen deposition, and cutaneous inflammation, with no apparent adverse effects. This study provides a safe and efficient method for enhancing the therapeutic application of DPSC lysate. It has the potential to expedite the clinical implementation of lysate-based anti-photoaging therapy.

Abstract Background Heart rate (HR) related parameters, such as HR variability, HR turbulence, resting HR, and nighttime mean HR have been recognized as independent predictors of mortality. However, the influence of circadian changes in HR on mortality remains unclear in intensive care units (ICU). The study is designed to evaluate the relationship between the circadian variation in HR and mortality risk among critically ill patients. Methods The present study included 4,760 patients extracted from the Multiparameter Intelligent Monitoring in Intensive Care II database. The nighttime mean HR/daytime mean HR ratio was adopted as the circadian variation in HR. According to the median value of the circadian variation in HR, participants were divided into two groups: group A (≤ 1) and group B (> 1). The outcomes included ICU, hospital, 30-day, and 1-year mortalities. The prognostic value of HR circadian variation was investigated by multivariable logistic regression models and Cox proportional hazards models. Results Patients in group B (n = 2,471) had higher mortality than those in group A (n = 2,289). Multivariable models revealed that the higher circadian variation in HR was associated with ICU mortality (odds ratio [OR], 1.393; 95% confidence interval [CI], 1.112–1.745; P = 0.004), hospital mortality (OR, 1.393; 95% CI, 1.112–1.745; P = 0.004), 30-day mortality (hazard ratio, 1.260; 95% CI, 1.064–1.491; P = 0.007), and 1-year mortality (hazard ratio, 1.207; 95% CI, 1.057–1.378; P = 0.005), especially in patients with higher SOFA scores. Conclusions The circadian variation in HR might aid in the early identification of critically ill patients at high risk of associated with ICU, hospital, 30-day, and 1-year mortalities.

Background: Several clinical trials have demonstrated that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) reduce the incidence of non-fatal myocardial infarction (MI) in patients with type 2 diabetes mellitus (T2DM). However, the underlying mechanism remains unclear. In this study, we applied a network pharmacology method to investigate the mechanisms by which GLP-1RAs reduce MI occurrence in patients with T2DM.Methods: Targets of three GLP-1RAs (liraglutide, semaglutide, and albiglutide), T2DM, and MI were retrieved from online databases. The intersection process and associated targets retrieval were employed to obtain the related targets of GLP-1RAs against T2DM and MI. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genes (KEGG) enrichment analyses were performed. The STRING database was used to obtain the protein-protein interaction (PPI) network, and Cytoscape was used to identify core targets, transcription factors, and modules.Results: A total of 198 targets were retrieved for the three drugs and 511 targets for T2DM with MI. Finally, 51 related targets, including 31 intersection targets and 20 associated targets, were predicted to interfere with the progression of T2DM and MI on using GLP-1RAs. The STRING database was used to establish a PPI network comprising 46 nodes and 175 edges. The PPI network was analyzed using Cytoscape, and seven core targets were screened: AGT, TGFB1, STAT3, TIMP1, MMP9, MMP1, and MMP2. The transcription factor MAFB regulates all seven core targets. The cluster analysis generated three modules. The GO analysis for 51 targets indicated that the terms were mainly enriched in the extracellular matrix, angiotensin, platelets, and endopeptidase. The results of KEGG analysis revealed that the 51 targets primarily participated in the renin-angiotensin system, complement and coagulation cascades, hypertrophic cardiomyopathy, and AGE-RAGE signaling pathway in diabetic complications.Conclusion: GLP-1RAs exert multi-dimensional effects on reducing the occurrence of MI in T2DM patients by interfering with targets, biological processes, and cellular signaling pathways related to atheromatous plaque, myocardial remodeling, and thrombosis.

Seismic investigation revealed that a fault fracture zone is one of the most vulnerable areas of mountain tunnels in earthquakes. For the tunnel crossing secondary fault, the fault may be permanently dislocated by the causative faults during earthquakes, making the tunnel subject to combined action of seismic motion and fault dislocation, which makes the seismic response of the tunnel more complicated. In order to investigate the seismic response of fault-crossing tunnels in this case and explore the suitability of different aseismic measures, three-dimensional numerical models with different widths of faults and different aseismic measures were developed in this study. By inputting accelerogram considering permanent displacements, the seismic responses of fault-crossing tunnels under the combined action of seismic motion and fault dislocation were simulated. The results showed that the acceleration and stress of the tunnel-crossing narrow fault are larger than those crossing wide faults during earthquakes. Grouting reinforcement can reduce the acceleration and stress of the tunnel within the fault during earthquakes, while flexible joints will increase the acceleration of the tunnel within the fault and increase the stress of the tunnel-crossing wide fault. For fault-crossing tunnels, if the fault width is narrow than the tunnel diameter, the best aseismic measure installs grouting reinforcement and flexible joints; if the fault width is wider than 10 times of the tunnel diameter, the best aseismic measure installs grouting reinforcement.

Qiang Huang et al. fed C. elegans with E. coli containing phosphorothioate (PT) DNA or a control strain and evaluated the impact on animal physiology. They observed that worms fed PT( + ) diets exhibited low reactive oxygen species, more active movement, and a longer lifespan compared to controls, suggesting that PT-DNA may have a positive effect on animal health.

Abstract To determine the impact of initial vancomycin trough concentration (VTC) on mortality in adult patients in the intensive care unit (ICU) undergoing vancomycin therapy. During their first ICU stay, patients with initial VTC records after vancomycin treatment were recruited from the eICU Collaborative Research Database to this multicenter retrospective cohort study, and classified into four groups according to VTC: less than 10, 10–15, 15–20, and greater than 20 mg/L. Multivariable logistic regression and sensitivity analyses were performed to explore the association of VTC, as a continuous and categorical variable, with mortality. This study enrolled 7220 patients from 335 different ICUs at 208 hospitals. Multivariable logistic regression models indicated that VTC was positively correlated with ICU (odds ratio [OR], 1.028, 95% confidence interval [CI], 1.019–1.037) and hospital (OR 1.028, 95% CI, 1.020–1.036) mortalities. Moreover, compared with VTC less than 10 mg/L, VTCs of 10–15, 15–20, and greater than 20 mg/L were associated with a higher risk of ICU mortality (OR, 1.330, 95% CI, 1.070–1.653; OR, 1.596, 95% CI, 1.265–2.015; abd OR, 1.875, 95% CI, 1.491–2.357, respectively), and VTCs of 15–20 and greater than 20 mg/L were also correlated with increased hospital mortality (OR, 1.482, 95% CI, 1.225–1.793; and OR, 1.831, 95% CI, 1.517–2.210, respectively). Similar results persisted in patients with different Acute Physiology and Chronic Health Evaluation Ⅳ scores, creatinine clearance levels, ages, and body mass indexes. Our findings indicated a potential relationship of initial VTC with ICU and hospital mortalities in patients in the ICU. However, due to the retrospective nature of this study, future prospective studies or randomized controlled trials are needed to validate those results.

Parkinson’s disease (PD) has a characteristically unilateral pattern of symptoms at onset and in the early stages; this lateralization is considered a diagnostically important diagnosis feature. We aimed to compare the graph-theoretical properties of whole-brain networks generated by using resting-state functional MRI (rs-fMRI), diffusion tensor imaging (DTI), and the resting-state-informed structural connectome (rsSC) in patients with left-onset PD (LPD), right-onset PD (RPD), and healthy controls (HCs). We recruited 26 patients with PD (13 with LPD and 13 with RPD) as well as 13 age- and sex-matched HCs. Rs-fMRI and DTI were performed in all subjects. Graph-theoretical analysis was used to calculate the local and global efficiency of a whole-brain network generated by rs-fMRI, DTI, and rsSC. Two-sample t-tests and Pearson correlation analysis were conducted. Significantly decreased global and local efficiency were revealed specifically in LPD patients compared with HCs when the rsSC network was used; no significant intergroup difference was found by using rs-fMRI or DTI alone. For rsSC network analysis, multiple network metrics were found to be abnormal in LPD. The degree centrality of the left precuneus was significantly correlated with the Unified Parkinson’s Disease Rating Scale (UPDRS) score and disease duration (p = 0.030, r = 0.599; p = 0.037, r = 0.582). The topological properties of motor-related brain networks can differentiate LPD and RPD. Nodal metrics may serve as important structural features for PD diagnosis and monitoring of disease progression. Collectively, these findings may provide neurobiological insights into the lateralization of PD onset.

Recently, it has become popular to study the use of extracellular vesicles (EVs) secreted by stem cells to repair damaged tissues or lost cells. Various cell types and physiological fluids release EVs, and they play an important role in cell-to-cell communication. Moreover, EVs have been implicated in important processes, such as immune responses, homeostasis maintenance, coagulation, inflammation, cancer progression, angiogenesis, and antigen presentation. Thus, EVs participate in both physiological and pathological progression. The main classes of EVs include exosomes, microvesicles (MVs), and apoptotic bodies (ApoBDs). Exosomes, which carry a mass of signal molecules such as RNA, DNA, proteins, and lipids, are the most important of these EVs subsets. Currently, exosomes are generating substantial interest in the scientific community. Exosomes loaded hydrogels or under different cultural environments exhibit different properties and functions. Therefore, the exosomes obtained from different sources and conditions are worth reviewing. More importantly, no review article has compared the different EVs, such as exosomes, MVs, ApoBDs, and mesenchymal stem cell (MSC) lysates, which are special soluble substances. The differentiation between EVs and MSC lysates is a logical approach. Accordingly, this review provides an update on the latest progress in studying the roles of culture-condition stimulated exosomes or their loaded hydrogels and the differentiation between exosomes, MVs, ApoBDs, and MSC lysates. Published studies were retrieved from the PubMed® database for review.

BackgroundDecreased serum albumin level (SAL) is associated with adverse clinical outcomes. We designed the present study to further assess the prognostic value of SAL in critically ill patients based on data from large intensive care unit (ICU) databases.MethodsThis retrospective cohort study recruited 18,353 patients from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Restricted cubic splines (RCS) were performed to visualize the association of SAL at admission with ICU and hospital mortalities. The prognostic value of SAL was analyzed using logistic regression models and receiver operating characteristic (ROC) curves in overall patients and subgroups.ResultsRestricted cubic splines revealed rapid increasing risks in ICU and hospital mortalities when SAL declined to below 30 g/l. Patients with SAL

Abstract Neck dissection for oral squamous-cell carcinoma (OSCC) is a clinically controversial issue and has therefore been the subject of abundant research. However, no one has performed a bibliometric study on this topic to date. The aim of this study was to assess the development of research on neck dissection for OSCC in terms of the historical evolution, current hotspots and future directions, particularly including research trends and frontiers from 2010 to 2019. Literature records related to research on neck dissection for OSCC were retrieved from the Web of Science Core Collection (WoSCC). CiteSpace was used as a tool to perform a bibliometric analysis of this topic. The survey included 2 096 papers. “Otorhinolaryngology” was the most popular research area. The most active institutions and countries were Memorial Sloan Kettering Cancer Center and the USA, respectively. Shah J.P. was the most cited author. Among the six identified “core journals”, Head & Neck ranked first. The top three trending keywords were ‘invasion’, ‘upper aerodigestive’ and ‘negative neck’. ‘D’Cruz AK (2015)’ was the most cited and the strongest burst reference in the last decade. The study evaluated the effect on survival of elective versus therapeutic neck dissection in patients with lateralized early-stage OSCC. The depth of invasion and the management of N0 OSCC were research frontiers in this field. The present study provides a comprehensive bibliometric analysis of research on neck dissection for OSCC, which will assist investigators in exploring potential research directions.

Abstract Evidence indicates that glucose variation (GV) plays an important role in mortality of critically ill patients. We aimed to investigate the relationship between the coefficient of variation of 24-h venous blood glucose (24-hVBGCV) and mortality among patients with acute respiratory failure. The records of 1625 patients in the Multiparameter Intelligent Monitoring in Intensive Care II (MIMIC II) database were extracted. The 24-hVBGCV was calculated as the ratio of the standard deviation (SD) to the mean venous blood glucose level, expressed as a percentage. The outcomes included ICU mortality and in-hospital mortality. Participants were divided into three subgroups based on tertiles of 24-hVBGCV. Multivariable logistic regression models were used to evaluate the relationship between 24-hVBGCV and mortality. Sensitivity analyses were also performed in groups of patients with and without diabetes mellitus. Taking the lowest tertile as a reference, after adjustment for all the covariates, the highest tertile was significantly associated with ICU mortality [odds ratio (OR), 1.353; 95% confidence interval (CI), 1.018–1.797] and in-hospital mortality (OR, 1.319; 95% CI, 1.003–1.735), especially in the population without diabetes. The 24-hVBGCV may be associated with ICU and in-hospital mortality in patients with acute respiratory failure in the ICU, especially in those without diabetes.

Background: Obesity is a principal risk factor for the development of type 2 diabetes and cardiovascular diseases. Natural plants and/or foods play an important role in the management of obesity. Acalypha australis L. (AAL) is a kind of potherb popular among Asian populations, and it is also consumed as a food ingredient and traditional herbal medicine. Objective: We investigated the effects of water extract from AAL on high-fat-diet (HFD)-induced obese mice and 3T3-L1 adipocytes to develop a new functional food material. Design: Nine-week-old male mice were randomly divided into control (chow diet, n = 6) and HFD (n = 30) group. From 12-weeks onward, mice in the HFD group were further separated into model (saline, 6 mL/kg), simvastatin (0.11 mg/mL, 6 mL/kg), and AAL treatment (low, middle, and high dosage: 300, 600, and 900 mg/kg) group, with 6 animals per group, while mice in the control group were treated with saline (6 mL/kg). Food intake, body/fat weight, liver/kidney indexes, and lipid profiles were determined. Tissues were fixed with formalin for pathological examination. Western blotting and PCR were performed to evaluate the protein and mRNA expression in 3T3-L1 adipocytes. Oil Red O staining was used to determine lipid accumulation. Results: AAL administration significantly suppressed body weight gain, and reduced fat pad weight and Lee’s index in obese mice, but had no effect on liver/kidney index. AAL also reduced serum cholesterol, triglyceride, and LDL-C and increased HDL-C levels. Histological analysis revealed that AAL significantly ameliorated lipid accumulation in the liver and subcutaneous adipose tissue. In vitro, Oil Red O staining showed that AAL inhibited adipose differentiation by down-regulating the gene and protein expression of PPARγ and C/EBPα. AAL also reversed HFD-induced intestinal dysbacteriosis. Conclusion: AAL water-soluble extract has a significant anti-adipogenic effect in the HFD-induced obese mice model.

Ovarian hyperandrogenism is one of the characteristics of polycystic ovary syndrome (PCOS) and androgen receptor (AR) in ovarian granulosa cells (GCs) functions as an important element to the accumulation of androgens. This study verified the existence of alternative splicing variant of AR (AR-SVs) in the GCs of PCOS patients and found that the function of AR decreased significantly in the presence of AR-SVs. And compared to the normal individuals, the expression of Serine/arginine-rich splicing factor 2(SRSF2) was higher and the expression of SRSF3 was lower in the GCs of patients with AR-SVs. More importantly, we found that the expression of SRSF2 was inhibited and that the expression of AR was decreased after the successful upregulation of miRNA-183, and testostrone (T) concentrations in the culture medium were increased. The results also showed that the expression of SRSF3 decreased when miRNA-124 was successfully upregulated, while the expression of AR significantly increased; however, the function of AR was also inhibited when T concentration in the culture medium was increased. This study has proved that SRSFs are regulated by corresponding miRNAs, and the altered expression of SRSFs interferenced the alternative splicing process of AR and ultimately decreased the function of AR, leading to the accumulation of androgens in the ovary.

Oligonucleotides and nucleic acid analogues that alter gene expression are now showing therapeutic promise in human disease. Whilst the modification of synthetic nucleic acids to protect against nuclease degradation and to influence drug function is common practice, such modifications may also confer unexpected physicochemical and biological properties. Gapmer mixed-modified and DNA oligonucleotides on a phosphorothioate backbone can bind non-specifically to intracellular proteins to form a variety of toxic inclusions, driven by the phosphorothioate linkages, but also influenced by the oligonucleotide sequence. Recently, the non-antisense or other off-target effects of 2′ O- fully modified phosphorothioate linkage oligonucleotides are becoming better understood. Here, we report chemistry-specific effects of oligonucleotides composed of modified or unmodified bases, with phosphorothioate linkages, on subnuclear organelles and show altered distribution of nuclear proteins, the appearance of highly stable and strikingly structured nuclear inclusions, and disturbed RNA processing in primary human fibroblasts and other cultured cells. Phosphodiester, phosphorodiamidate morpholino oligomers, and annealed complimentary phosphorothioate oligomer duplexes elicited no such consequences. Disruption of subnuclear structures and proteins elicit severe phenotypic disturbances, revealed by transcriptomic analysis of transfected fibroblasts exhibiting such disruption. Our data add to the growing body of evidence of off-target effects of some phosphorothioate nucleic acid drugs in primary cells and suggest alternative approaches to mitigate these effects.

Although previous studies have indicated that older people with diabetes mellitus (DM) had an approximately two times larger white matter hyperintensity (WMH) load than those without DM, the influence of WMHs on cognition is uncertain and inconsistent in the literature. It is unclear whether the short-range fibers in the juxtacortical region, traditionally considered to be spared from WMH pathology, are enhanced as an adaptive response to deep WM degeneration in older diabetic people with normal cognition. Moreover, the specific effect of vitamin B12 deficiency, commonly accompanied by DM, remains to be investigated. This study implemented a specialized analysis of the superficial cortical short-range fiber connectivity density (SFiCD) based on a data-driven framework in 70 older individuals with DM and low serum vitamin B12. Moreover, the effects of time and vitamin B12 supplementation were assessed based on a randomized placebo-controlled trial in 59 individuals. The results demonstrated a higher SFiCD in diabetic individuals with a higher deep WMH load. Additionally, a significant interaction between DWMH load and homocysteine on SFiCD was found. During the 27-month follow-up period, a longitudinal increase in the SFiCD was observed in the bilateral frontal cortices. However, the observed longitudinal SFiCD change was not dependent on vitamin B12 supplementation; thus, the specific reason for the longitudinal cortical short fiber densification may need further study. Overall, these findings may help us better understand the neurobiology of brain plasticity in older patients with DM, as well as the interplay among DM, WMH, and vitamin B12 deficiency.

The downward shortwave radiation (DSR) is a critical parameter of the surface radiation budget. Several DSR satellite products have been developed in recent years. In this study, five updated global satellite daily DSR products were evaluated using in situ measurements from 142 global sites with a special focus on high latitudes in 2004. These five products are Clouds and the Earth's Radiant Energy System Synoptic TOA and surface fluxes and clouds (CERES), Clouds, Albedo and Radiation Edition 2 data (CLARA), Global Land Surface Satellite Downward Shortwave Radiation (GLASS), Breathing Earth System Simulator (BESS) shortwave radiation product, and Moderate Resolution Imaging Spectroradiometer land surface Downward Shortwave Radiation (MCD18) with a spatial resolution of 100, 25, 5, 5, and 1 km, respectively. The CERES, BESS, and MCD18 provide full global coverage throughout the year, whereas CLARA and GLASS present different levels of seasonal data loss over high-latitude areas. The products were aggregated and compared at various spatial resolutions over different subareas. The overall accuracy increased after the products were aggregated to 100 km. However, the highest accuracy was achieved at a resolution of 25 km over high-latitude areas for GLASS and MCD18. When all products were evaluated at a resolution of 100 km, the global root-mean-square error of CERES, CLARA, GLASS, BESS, and MCD18 was 27.6, 29.1, 30.3, 29.6, and 31.6 W/m2, respectively, and the mean bias difference was 2.2, −1.5, −1.8, −3.4, and −8.0 W/m2. The accuracies of most products are ~7 W/m2 lower over high-latitude areas. A seasonal variation of the accuracies was observed for all products. It is particularly pronounced over high-latitude areas. With respect to the long term, both in situ data, BESS, and CERES show insignificant trends, while CLARA and GLASS present dimming trend. Besides, CLARA and GLASS exhibit slight annual changes of −0.250 and −0.387 W/m2 in the bias and 0.357 and 0.310 Wm−2 in the RMSE in the past two decades. GLASS and MCD18 exhibit a superior performance over coastal regions but degrade over snow-covered areas. Potential refinements of current high-resolution DSR retrieval algorithms are suggested, which will improve the retrieval accuracy. Highly accurate products with a long-term stability, especially over high-latitude areas, are required for future climate change analyses.

Background: It remains unclear whether the mean vancomycin trough concentration (VTC) derived from the entire course of therapy is of potential benefit for critically ill patients. This study was conducted to explore the association between mean serum VTC and mortality in intensive care units (ICUs).Methods: 3,603 adult patients with two or more VTC records after receiving vancomycin treatment in the eICU Collaborative Research Database were included in this multicenter retrospective cohort study. Mean VTC was estimated using all measured VTCs and investigated as a continuous and categorical variable. Patients were categorised into four groups according to mean VTC: 20 mg/L. Multivariable logistic regression and subgroup analyses were performed to investigate the relationship of mean VTC with mortality.Results: After adjusting for a series of covariates, logistic regression analyses indicated that mean VTC, as a continuous variable, was positively correlated with ICU (odds ratio, 1.038, 95% confidence interval, [1.014–1.063]) and hospital (1.025 [1.005–1.046]) mortalities. As a categorical variable, mean VTC of 10–15 mg/L was not associated with reduced ICU (1.705 [0.975–2.981]) and hospital (1.235 [0.829–1.841]) mortalities. Mean VTC of 15–20 mg/L was not correlated with a lower risk of hospital mortality (1.370 [0.924–2.029]). Moreover, mean VTCs of 15–20 and >20 mg/L were significantly associated with higher ICU mortality (1.924 [1.111–3.332]; 2.428 [1.385–4.258]), and mean VTC of >20 mg/L with higher hospital mortality (1.585 [1.053–2.387]) than mean VTC of

Background: Upper respiratory infections (URIs) are among the most common diseases. However, the related burden has not been comprehensively evaluated. Thus, we designed the present study to describe the global and regional burden of URIs from 1990 to 2019. Methods: A secondary analysis was performed on the incidence, mortality, and disability-adjusted life years (DALYs) of URIs in different sex and age groups, from 21 geographic regions, 204 countries and territories, between 1990 and 2019, using the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. Countries and territories were categorized according to Socio-demographic Index (SDI) quintiles. Findings: Globally, the incident cases of URIs reached 17·2 (95% uncertainty interval: 15·4 to 19·3) billion in 2019, which accounted for 42·83% (40·01% to 45·77%) cases from all causes in the GBD 2019 study. The age-standardized incidence rate remained stable from 1990 to 2019, while significant decreases were found in the mortality and DALY rate. The highest age-standardized incidence rates from 1990 to 2019 and the highest age-standardized DALY rates after 2011 were observed in high SDI regions. Among all the age groups, children under five years old suffered from the highest incidence and DALY rates, both of which were decreased with increasing age. Fatal consequences of URIs occurred mostly in the elderly and children under five years old. Interpretation: The present study provided comprehensive estimates of URIs burden for the first time. Our findings, highlighting the substantial incidence and considerable DALYs due to URIs, are expected to attract more attention to URIs and provide future explorations in the prevention and treatment with epidemiological evidence. Funding: The study was funded by the National Natural Science Foundation of China (81770057).

Abstract Background Mounting evidences have demonstrated that HCC patients with or without cirrhosis possess different clinical characteristics, tumor development and prognosis. However, few studies directly investigated the underlying molecular mechanisms between non-cirrhotic HCC and cirrhotic HCC. Methods The clinical information and RNA-seq data were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) of HCC with or without cirrhosis were obtained by R software. Functional annotation and pathway enrichment analysis were performed by Enrichr. Protein–protein interaction (PPI) network was established through STRING and mapped to Cytoscape to identify hub genes. MicroRNAs were predicted through miRDB database. Furthermore, correlation analysis between selected genes and miRNAs were conducted via starBase database. MiRNAs expression levels between HCC with or without cirrhosis and corresponding normal liver tissues were further validated through GEO datasets. Finally, expression levels of key miRNAs and target genes were validated through qRT-PCR. Results Between 132 non-cirrhotic HCC and 79 cirrhotic HCC in TCGA, 768 DEGs were acquired, mainly involved in neuroactive ligand-receptor interaction pathway. According to the result from gene expression analysis in TCGA, CCL19, CCL25, CNR1, PF4 and PPBP were renamed as key genes and selected for further investigation. Survival analysis indicated that upregulated CNR1 correlated with worse OS in cirrhotic HCC. Furthermore, ROC analysis revealed the significant diagnostic values of PF4 and PPBP in cirrhotic HCC, and CCL19, CCL25 in non-cirrhotic HCC. Next, 517 miRNAs were predicted to target the 5 key genes. Correlation analysis confirmed that 16 of 517 miRNAs were negatively regulated the key genes. By detecting the expression levels of these key miRNAs from GEO database, we found 4 miRNAs have high research values. Finally, potential miRNA-mRNA networks were constructed based on the results of qRT-PCR. Conclusion In silico analysis, we first constructed the miRNA-mRNA regulatory networks in non-cirrhotic HCC and cirrhotic HCC.

Abstract Background Previous studies have found a connection between left coronary artery dominance and worse prognoses in patient with acute coronary syndrome, which remains a predominant cause of morbidity and mortality globally. The aim of this study was to investigate whether coronary dominance is associated with the incidence of acute inferior myocardial infarction (MI). Methods Between January 2011 and November 2014, 265 patients with acute inferior MI and 530 age-matched and sex-matched controls were recruited for a case-control study in the Second Affiliated Hospital of Xi’an Jiaotong University in Xi’an, China. All participants underwent coronary angiography. The exclusion criteria included history of coronary artery bypass graft surgery, chronic or systemic diseases (including hepatic failure, kidney failure, hypothyroidism and Grave’s disease), ventricular fibrillation, and known allergy to iodinated contrast agent. Patients with left- or co-dominant anatomies were placed into the LD group and those with right-dominant anatomy were included in the RD group. The association of acute inferior MI and coronary dominant anatomy were assessed using multivariable conditional logistic regression, and to estimate the odds ratio (OR) and 95% confidence interval (95%CI). Results Distributions of right dominance were significantly different between the acute inferior MI group and control group (94.0% vs. 87.9%, P = 0.018). Univariable conditional logistic regression revealed that right dominance may be a risk factor for the incident acute inferior MI (OR: 2.137; 95% CI: 1.210–3.776; P = 0.009). After adjusting for baseline systolic blood pressure, heart rate, smoking status, diabetes mellitus, hypertension, hyperlipidaemia, and family history of coronary artery disease, results of multivariate conditional logistic regression showed that right dominance was associated with the incidence of acute inferior MI (OR: 2.396; 95% CI: 1.328–4.321; P = 0.004). Conclusions Right coronary dominance may play a disadvantageous role in the incidence of acute inferior MI. However, further studies are needed to verify our findings, especially with regard to the underlying mechanisms.

Cancer cell survival, function and fate strongly depend on endoplasmic reticulum (ER) proteostasis. Although previous studies have implicated the ER stress signaling network in all stages of cancer development, its role in cancer metastasis remains to be elucidated. In this study, we investigated the role of Gremlin-1 (GREM1), a secreted protein, in the invasion and metastasis of colorectal cancer (CRC) cells in vitro and in vivo. Firstly, public datasets showed a positive correlation between high expression of GREM1 and a poor prognosis for CRC. Secondly, GREM1 enhanced motility and invasion of CRC cells by epithelial–mesenchymal transition (EMT). Thirdly, GREM1 upregulated expression of activating transcription factor 6 (ATF6) and downregulated that of ATF4, and modulation of the two key players of the unfolded protein response (UPR) was possibly through activation of PI3K/AKT/mTOR and antagonization of BMP2 signaling pathways, respectively. Taken together, our results demonstrate that GREM1 is an invasion-promoting factor via regulation of ATF6 and ATF4 expression in CRC cells, suggesting GREM1 may be a potential pharmacological target for colorectal cancer treatment.

Background Previous studies have suggested that sleep timing is associated with cardiovascular risk factors. However, there is no evidence on the relationship between sleep timing and congestive heart failure (CHF). We aimed to examine this relationship in this study. Methods and Results We recruited 4765 participants (2207 men; mean age, 63.6±11.0 years) from the SHHS (Sleep Heart Health Study) database in this multicenter prospective cohort study. Follow‐up was conducted until the first CHF diagnosis between baseline and the final censoring date. Sleep timing (bedtimes and wake‐up times on weekdays and weekends) was based on a self‐reported questionnaire. Cox proportional hazard models were constructed to investigate the association between sleep timing and CHF. During the mean follow‐up period of 11 years, 519 cases of CHF (10.9%) were reported. The multivariable Cox proportional hazards models revealed that participants with weekday bedtimes >12:00 am (hazard ratio [HR], 1.56; 95% CI, 1.15–2.11; P=0.004) and from 11:01 pm to 12:00 am (HR, 1.25; 95% CI, 1.00–1.56; P=0.047) had an increased risk of CHF compared with those with bedtimes from 10:01 pm to 11:00 pm. After stratified analysis, the association was intensified in participants with a self‐reported sleep duration of 6 to 8 hours. Furthermore, wake‐up times >8:00 am on weekdays (HR, 1.53; 95% CI, 1.07–2.17; P=0.018) were associated with a higher risk of incident CHF than wake‐up times ≤6:00 am. Conclusions Delayed bedtimes (>11:00 pm) and wake‐up times (>8:00 am) on weekdays were associated with an increased risk of CHF.

Background Disrupted circadian rhythm of blood pressure is commonly observed in patients in the intensive care unit (ICU). This study assessed the association of nocturnal mean arterial pressure rising (NMAPR) with short‐ and long‐term mortality in critically ill adult patients. Methods and Results Adult patients with a complete record of mean arterial pressure monitoring during the first 24 hours of ICU stay in the Multiparameter Intelligent Monitoring in Intensive Care II (MIMIC‐II) database were included in this retrospective cohort study. All patients were divided into the non‐NMAPR group (≤1) or the NMAPR group (>1), according to the value of mean nighttime divided by daytime mean arterial pressure. The associations of NMAPR with ICU, hospital, 28‐day, and 1‐year mortality were assessed using multivariable logistic regression or a Cox proportional hazards model. Interaction and subgroup analyses were performed for those patients who had a first Sequential Organ Failure Assessment (SOFA) score of ≥8 or

This article uses one year’s worth of daily travel distance data for 252 Seattle households’ vehicles to ascertain that one day’s distance (plus day of week and month of year information) accounts for 10.7% of the variability in that vehicle’s annual (total) distance traveled, while two and seven consecutive days’ distance values predict 16.7% and 33.6%, respectively. In analyzing Gini coefficients (which average 0.546 + / − 0.117 across these instrumented vehicles), one finds that full-time employed females have the most stable day-to-day driving patterns, allowing for shorter-duration surveys of such households.

Increasing evidence suggests that epilepsy is the result of synaptic reorganization and pathological excitatory loop formation in the central nervous system; however, the mechanisms that regulate this process are not well understood. We proposed that microRNA-132 (miR-132) and p250GAP might play important roles in this process by activating the downstream Rho GTPase family. We tested this hypothesis using a magnesium-free medium-induced epileptic model of cultured hippocampal neurons. We investigated whether miR-132 regulates GTPase activity through p250GAP and found that Cdc42 was significantly activated in our experimental model. Silencing miR-132 inhibited the electrical excitability level of cultured epileptic neurons, whereas silencing p250GAP had an opposite effect. In addition, we verified the effect of miR-132 in vivo and found that silencing miR-132 inhibited the aberrant formation of dendritic spines and chronic spontaneous seizure in a lithium-pilocarpine-induced epileptic mouse model. Finally, we confirmed that silencing miR-132 has a neuroprotective effect on cultured epileptic neurons; however, this effect did not occur through the p250GAP pathway. Generally, silencing miR-132 may suppress spontaneous seizure activity through the miR-132/p250GAP/Cdc42 pathway by regulating the morphology and electrophysiology of dendritic spines; therefore, miR-132 may serve as a potential target for the development of antiepileptic drugs.