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Abstract Vesicular monoamine transporter 2 (VMAT2) belongs to the major facilitator superfamily (MFS), and mediates cytoplasmic monoamine packaging into presynaptic vesicles. Here, we present two cryo-EM structures of VMAT2, with a frog VMAT2 adopting a canonical MFS fold and an engineered sheep VMAT2 adopting a non-canonical fold. Both VMAT2 proteins mediate uptake of a selective fluorescent VMAT2 substrate into cells. Molecular docking, substrate binding and transport analysis reveal potential substrate binding mechanism in VMAT2. Meanwhile, caution is advised when interpreting engineered membrane protein structures.

Abstract The sigma-1 receptor (σ1R) is a non-opioid membrane receptor, which responds to a diverse array of synthetic ligands to exert various pharmacological effects. Meanwhile, candidates for endogenous ligands of σ1R have also been identified. However, how endogenous ligands bind to σ1R remains unknown. Here, we present crystal structures of σ1R from Xenopus laevis (xlσ1R) bound to two endogenous neurosteroid ligands, progesterone (a putative antagonist) and dehydroepiandrosterone sulfate (DHEAS) (a putative agonist), at 2.15-3.09 Å resolutions. Both neurosteroids bind to a similar location in xlσ1R mainly through hydrophobic interactions, but surprisingly, with opposite binding orientations. DHEAS also forms hydrogen bonds with xlσ1R, whereas progesterone interacts indirectly with the receptor through water molecules near the binding site. Binding analyses are consistent with the xlσ1R-neurosteroid complex structures. Furthermore, molecular dynamics simulations and structural data reveal a potential water entry pathway. Our results provide insight into binding of two endogenous neurosteroid ligands to σ1R.

Abstract Breast cancer is the most commonly diagnosed malignancy and benefits from endocrine agents such as tamoxifen. However, the development of drug resistance in cancerous cells often leads to recurrence, thus limiting the therapeutic benefit. Identification of potential biomarkers that can predict response to tamoxifen and recognize patients who will clinically benefit from this therapy is urgently needed. In this study, we report that high collagen type XI alpha 1 (COL11A1) expression was associated with poor therapeutic response and prognosis in breast cancer patients treated with tamoxifen. To confirm the role of COL11A1 in the development of tamoxifen resistance, we established MCF-7/COL11A1 and T47D/COL11A1 cell lines, which stably expressed COL11A1. Compared with parental MCF-7 and T47D, MCF-7/COL11A1 and T47D/COL11A1 cells were more resistant to 4-OHT-induced growth inhibition. Moreover, the level of COL11A1 expression was upregulated in tamoxifen-resistant MCF-7/TamR and T47D/TamR cell lines, and depletion of COL11A1 markedly sensitized the cells to 4-OHT in vitro and in vivo. Interestingly, the level of estrogen receptor α (ERα) expression was elevated, probably due to the increased COL11A1 in TamR cells. In addition, knockdown of COL11A1 decreased the expression of ERα and its downstream target genes. Overall, our findings suggest that overexpressed COL11A1 contributes to tamoxifen resistance, and targeting COL11A1 holds great promise for reversing endocrine resistance.

Since the first discovery of grapevine brown leaf spot disease in Turpan, Xinjiang, China, in 2007, it has been a common occurrence in grapevine-growing regions. Grapevine brown leaf spot seriously decreases fruit yield and has become one of the most important leaf diseases in the Turpan region. However, thus far, there have been no reports on the evaluation of grapevine germplasm resources for resistance to brown leaf spot disease. In addition, the response mechanism of grapevine leaves to brown leaf spot infection has not been revealed. To better understand the resistance of grapevine germplasm resources to brown leaf spot disease, we first evaluated resistance in grapevine varieties. On this basis, the most susceptible variety ‘Sultanina’ was selected as the experimental material for this study. Transcriptome analysis and carbohydrate content analysis were performed on ‘Sultanina’ leaves with different levels of disease susceptibility. As the severity of the disease increased, the content of fructose gradually decreased, while the content of trehalose gradually increased. Transcriptome data revealed that differentially expressed genes were enriched in the pentose and glucuronate interchange pathway. These results suggest that the sugar trehalose may play an important role in the response of ‘Sultanina’ leaves to brown leaf spot infection. In addition, the pentose and glucuronate interchange pathway may be involved in the response mechanism of brown leaf spot disease. Our work provides new insights into the mechanism of the ‘Sultanina’ leaf response to brown leaf spot infection.

Silicosis is the most common type of pneumoconiosis, having a high incidence in workers chronically exposed to crystalline silica (CS). No specific medication exists for this condition. GHK, a tripeptide naturally occurring in human blood and urine, has antioxidant effects. We aimed to investigate the therapeutic effect of GHK-Cu on silicosis and its potential underlying molecular mechanism. An experimental silicosis mouse model was established to observe the effects of GHK-Cu on lung inflammation and fibrosis. Moreover, the effects of GHK-Cu on the alveolar macrophages (AM) were examined using the RAW264.7 cell line. Its molecular target, peroxiredoxin 6 (PRDX6), has been identified, and GHK-Cu can bind to PRDX6, thus attenuating lung inflammation and fibrosis in silicosis mice without significant systemic toxicity. These effects were partly related to the inhibition of the CS-induced oxidative stress in AM induced by GHK-Cu. Thus, our results suggest that GHK-Cu acts as a potential drug by attenuating alveolar macrophage oxidative stress. This, in turn, attenuates the progression of pulmonary inflammation and fibrosis, which provides a reference for the treatment of silicosis.

Abstract Nucleic acids are not only essential biomolecules that drive critical life processes such as growth, development, reproduction, inheritance, and mutation, but also serve as significant markers for disease diagnosis, pathogen identification, and cancer screening. Nevertheless, several challenges have hindered the widespread use of nucleic acids in biomedicine, such as susceptibility to degradation, limited cellular uptake efficiency, potential toxicity, and uncontrollable activity. Photo‐regulation offers an effective solution to address these challenges. It allows for the precise control of nucleic acid structure and function and enhances the stability and safety of their application in biomedicine. In this review, we systematically review the structural characteristics of the three primary photosensitive groups commonly used in the regulation of nucleic acid molecules (i.e., photocleavable molecules, photoisomerization molecules, and photo‐crosslinking molecules) under light irradiation. Subsequently, recent research advances in the development and application of photo‐modulation strategies based on these photosensitive molecules in antisense oligonucleotides, RNA interference, nucleic acid amplification, and CRISPR/Cas systems are outlined. Finally, we discuss the challenges faced in the widespread application of these photo‐regulatory strategies and outline potential future directions for their development.

Summary: Neurons in the neocortex are generated during embryonic development. While the adult ventricular-subventricular zone (V-SVZ) contains cells with neural stem/progenitors’ characteristics, it remains unclear whether it has the capacity of producing neocortical neurons. Here, we show that generating neurons with transcriptomic resemblance to upper layer neocortical neurons continues in the V-SVZ of mouse models of a human condition known as periventricular heterotopia by abrogating Flna and Flnb. We found such surplus neurogenesis was associated with V-SVZ’s upregulation of oxidative phosphorylation, mitochondrial biogenesis, and vascular abundance. Additionally, spatial transcriptomics analyses showed V-SVZ’s neurogenic activation was coupled with transcriptional enrichment of genes in diverse pathways for energy metabolism, angiogenesis, cell signaling, synaptic transmission, and turnovers of nucleic acids and proteins in upper cortical layers. These findings support the potential of generating neocortical neurons in adulthood through boosting brain-wide vascular circulation, aerobic adenosine triphosphate synthesis, metabolic turnover, and neuronal activity.

Abstract Background Astaxanthin (AXT) is a keto-carotenoid with a variety of biological functions, including antioxidant and antifibrotic effects. Small airway remodeling is the main pathology of chronic obstructive pulmonary disease (COPD) and is caused by epithelial-to-mesenchymal transition (EMT) and fibroblast differentiation and proliferation. Effective therapies are still lacking. This study aimed to investigate the role of AXT in small airway remodeling in COPD and its underlying mechanisms. Methods First, the model of COPD mice was established by cigarette smoke (CS) exposure combined with intraperitoneal injection of cigarette smoke extract (CSE). The effects of AXT on the morphology of CS combined with CSE -induced emphysema, EMT, and small airway remodeling by using Hematoxylin-eosin (H&E) staining, immunohistochemical staining, and western blot. In addition, in vitro experiments, the effects of AXT on CSE induced-EMT and fibroblast function were further explored. Next, to explore the specific mechanisms underlying the protective effects of AXT in COPD, potential targets of AXT in COPD were analyzed using network pharmacology. Finally, the possible mechanism was verified through molecular docking and in vitro experiments. Results AXT alleviated pulmonary emphysema, EMT, and small airway remodeling in a CS combined with CSE -induced mouse model. In addition, AXT inhibited the EMT process in airway cells and the differentiation and proliferation of fibroblasts. Mechanistically, AXT inhibited myofibroblast activation by directly binding to and suppressing the phosphorylation of AKT1. Therefore, our results show that AXT protects against small airway remodeling by inhibiting AKT1. Conclusions The present study identified and illustrated a new food function of AXT, indicating that AXT could be used in the therapy of COPD-induced small airway remodeling.

Abstract Background Small airway remodelling is a vital characteristic of chronic obstructive pulmonary disease (COPD), which is mainly caused by epithelial barrier dysfunction and epithelial-mesenchymal transition (EMT). Recent studies have indicated that histone deacetylase 6 (HDAC6) plays an important role in the dysregulation of epithelial function. In this study, we investigated the therapeutic effects and underlying mechanisms of an inhibitor with high selectivity for HDAC6 in COPD. Methods Cigarette smoke (CS) exposure was used to establish a CS-induced COPD mouse model. CAY10603 at doses of 2.5 and 10 mg/kg was injected intraperitoneally on alternate days. The protective effects of CAY10603 against CS-induced emphysema, epithelial barrier function and small airway remodeling were evaluated using hematoxylin and eosin (H&E) staining, Masson’s trichrome staining, immunohistochemical staining, and western blot. The human lung bronchial epithelial cell line (HBE) was used to elucidate the underlying molecular mechanism of action of CAY10603. Results HDAC6 levels in the lung homogenates of CS-exposed mice were higher than that those in control mice. Compared to the CS group, the mean linear intercept (MLI) of the CAY10603 treatment group decreased and the mean alveolar number (MAN)increased. Collagen deposition was reduced in groups treated with CAY10603. The expression of α-SMA was markedly upregulated in the CS group, which was reversed by CAY10603 treatment. Conversely, E-cadherin expression in the CS group was further downregulated, which was reversed by CAY10603 treatment. CAY10603 affects the tight junction protein expression of ZO-1 and occludin. ZO-1 and occludin expression were markedly downregulated in the CS group. After CAY10603treatment, the protein expression level of ZO-1 and occludin increased significantly. In HBE cells, Cigarette smoke extract (CSE) increased HDAC6 levels. CAY10603 significantly attenuated the release of TGF-β1 induced by CSE. CAY10603 significantly increased the E-cadherin levels in TGF-β1 treated HBE cells, while concurrently attenuated α-SMA expression. This effect was achieved through the suppression of Smad2 and Smad3 phosphorylation. CAY10603 also inhibited TGF-β1 induced cell migration. Conclusions These findings suggested that CAY10603 inhibited CS induced small airway remodelling by regulating epithelial barrier dysfunction and reversing EMT via the TGF-β1/Smad2/3 signalling pathway.

Background The performance of host immune responses biomarkers and clinical scores was compared to identify infection patient populations at risk of progression to sepsis, ICU admission and mortality.Methods Immune response biomarkers were measured and NEWS, SIRS, and MEWS. Logistic and Cox regression models were employed to evaluate the strength of association.Results IL-10 and NEWS had the strongest association with sepsis development, whereas IL-6 and CRP had the strongest association with ICU admission and in-hospital mortality. IL-6 [HR (95%CI) = 2.68 (1.61–4.46)] was associated with 28-day mortality. Patient subgroups with high IL-10 (≥ 5.03 pg/ml) and high NEWS (> 5 points) values had significantly higher rates of sepsis development (88.3% vs 61.1%; p

Abstract Background Acute heart failure (AHF) is often associated with diffuse insufficiency and arterial hypoxemia, requiring respiratory support for rapid and effective correction. We aimed to compare the effects of high-flow nasal cannula(HFNC) with those of conventional oxygen therapy(COT) or non-invasive ventilation(NIV) on the prognosis of patients with AHF. Methods We performed the search using PubMed, Embase, Web of Science, MEDLINE, the Cochrane Library, CNKI, Wanfang, and VIP databases from the inception to August 31, 2023 for relevant studies in English and Chinese. We included controlled studies comparing HFNC with COT or NIV in patients with AHF. Primary outcomes included the intubation rate, respiratory rate (RR), heart rate (HR), and oxygenation status. Results From the 1288 original papers identified, 16 studies met the inclusion criteria, and 1333 patients were included. Compared with COT, HFNC reduced the intubation rate (odds ratio [OR]: 0.29, 95% CI: 0.14–0.58, P = 0.0005), RR (standardized mean difference [SMD]: -0.73 95% CI: -0.99 – -0.47, P

Abstract Background Sarcopenia and obesity are two abnormal body composition phenotypes, and sarcopenic obesity (SO) is characterized by both low skeletal muscle mass (sarcopenia) and high adiposity (obesity). SO negatively influences the clinical status of patients with chronic obstructive pulmonary disease (COPD). However, the studies exploring the prevalence and clinical effects of SO in COPD patients are limited. Our study aimed to elucidate the prevalence and impact of SO on COPD patients. Methods In this cross-sectional study, the pulmonary function, St. George’s Respiratory Questionnaire, exercise tolerance, body composition, and serum levels of resistin and TNF-α were assessed in 198 COPD patients. The clinical value of serum resistin and TNF-α for predicting SO in patients with COPD was evaluated. Results In the 198 patients with COPD, the prevalence rates of sarcopenia, obesity, and SO in COPD patients were 27.27%, 29.8%, and 9.6%, respectively. Patients with SO experienced more severe symptoms of dyspnea and worse health related quality of life. The expression of resistin increased in patients with SO compared to other patients. The AUC value of serum resistin level for predicting SO was 0.870 (95% CI: 0.799–0.940). BMI (OR: 1.474, 95% CI: 1.124–1.934) and resistin (OR: 1.001, 95% CI: 1.000-1.002) levels were independent risk factors of SO in patients with COPD in Multivariate analysis. Conclusion The prevalence rates of SO in COPD patients was 9.6%. COPD accompanied by SO is significantly associated with worse pulmonary function and poor physical performance. Serum resistin may be a potential adjunct for predicting SO in COPD patients.

Abstract Background Atopic dermatitis is one of the most common skin disorders. Evidence has suggested an association between skin disorders, such as atopic dermatitis, and Parkinson's disease (PD). However, whether atopic dermatitis has a causal effect on PD remains unknown. Methods The study aimed to determine whether their association between atopic dermatitis and PD is causal, using a bidirectional two‐sample Mendelian randomization method. Genetic variants from the public genome‐wide association studies for atopic dermatitis (n = 10788 cases and 30047 controls) were selected to evaluate their causal effects on the risk of PD (33,674 cases and 449,056 controls). The inverse variance weighted (IVW) method was used as the primary analysis. Results The IVW results indicated that atopic dermatitis was associated with decreased risk of PD {fixed effects: odds ratio [OR] [95% confidence interval (CI)]: .905 [.832–.986], p = .022; OR [95% CI]: .905 [.827–.991], p = .032}. However, we failed to detect the causal effects of PD on risk of atopic dermatitis in the reverse causation analysis. Conclusion This study indicated causal association of genetically proxied atopic dermatitis with the risk of PD. Future studies are warranted to explore the underlying mechanism and investigate the targeting effect of atopic dermatitis on PD.

Crop resilience measures must be strengthened in response to the global climate impact. Temperature stress exacerbates the impact on crop growth and grain yield, threatening the sustainability of grapevine production and dependent wine industries. Grape (Vitis spp.) is one of the most widely cultivated fruit crops in the world, as well as the most economically important fruit. However, grape yield and quality are highly dependent on environmental conditions, particularly temperature stress. Understanding the molecular mechanisms that control grapevine responses to environmental stresses and the development of stress-resilient varieties have markedly advanced through the rapid evolution of high-throughput sequencing technologies, state-of-the-art multi-omics analytic platforms, and automated phenotyping facilities. In the current review, we summarized recent genomic progress and omics-based breakthroughs in grapes that have contributed to abiotic stress tolerance via genetic strategies during the last decades. Furthermore, we delve into prospective challenges and opportunities pertaining to the use of multi-omics-based breeding strategies aimed at designing climate-resilient grape varieties. Advances in highly efficient de novo or re-domestication histories, as well as the characterization of numerous trait genes using various omics tools, are also discussed. By describing the underlying mechanisms of crop adaptability and future breeding strategies to meet demand due to population bursts in the following decades while keeping climate change in mind, the information will offer potential solutions for sustainable grape and wine businesses.

Sickle cell nephropathy (SCN) is a leading cause of morbidity and mortality in sickle cell disease (SCD). Early intervention is crucial for mitigating its effects. However, current diagnostic methods rely on generic tests and may not detect SCN until irreversible renal damage occurs. Therefore, specific biomarkers for early diagnosis of SCN are needed. Urinary exosomes, membrane-bound vesicles secreted by renal podocytes and epithelial cells, contain both common and cell type-specific membrane and cytosolic proteins, reflecting the physiologic and pathophysiologic states of the kidney. Using proteomics, we analyzed the proteomes of urinary exosomes from humanized SCD mice at 2 months (without albuminuria) and 4 months (with albuminuria) of age. Excretion of 164 proteins were significantly increased and 176 proteins was significantly decreased in the exosomes when mice developed albuminuria. Based on the relevance to SCD, chronic kidney disease and Western blot confirmation in mice, we analyzed protein abundance of heparanase, cathepsin C, α2-macroglobulin and sarcoplasmic endoplasmic Ca2+ ATPase-3 (SERCA3) in the urinary exosomes and urine of 18 SCD subjects without albuminuria and 12 subjects with albuminuria using Western blot analyses. Both male and female subjects increased or tended to increase the excretion of these proteins in their urinary exosomes upon developing albuminuria, but female subjects demonstrated stronger correlations between the excretion of these proteins and urine albumin creatinine ratio (UACR) compared to male subjects. In contrast, exosomal excretion of Tamm-Horsfall protein, β-actin and SHP-1 was independent of albuminuria. These findings provide a foundation for a time-course study to determine whether increases in the levels of these proteins precede the onset of albuminuria in patients, which will help determine the potential of these proteins as biomarkers for early detection of SCN.

Background: Little is known about the association between sarcopenia and multimorbidity among middle-aged and older adults. This study investigated whether sarcopenia is associated with multimorbidity in middle-aged and older Chinese individuals. Materials and methods: A total of 12,760 participants from China Health and Retirement Longitudinal Study (CHARLS) 2015, with data on 14 specified chronic diseases and sarcopenia status were included in the cross-sectional analysis. A total of 7345 participants without multimorbidity from the CHARLS 2015 were included and followed up in 2018 in the longitudinal analysis. Logistic regression models were used in a cross-sectional investigation to assess the association between sarcopenia status and multimorbidity. In a longitudinal analysis, the relationships between sarcopenia status and multimorbidity were investigated using Cox proportional hazards models. Results: Multimorbidity was prevalent in the no sarcopenia, possible sarcopenia, and sarcopenia groups at 38.8 % (3765/9713), 56.6 % (1199/2118), and 48.5 % (451/929), respectively. Multivariable regression revealed that both possible sarcopenia (β = 0.088, P

Abstract Background The sedative dexmedetomidine has been shown to reduce mortality in adult patients with severe sepsis, but it is not known whether children benefit. This study explored the effects of dexmedetomidine on the outcomes of children with severe sepsis with mechanical ventilation. Methods In this retrospective cohort study, children with severe sepsis requiring mechanical ventilation from 2016 to 2020 were categorized as dexmedetomidine and non-dexmedetomidine group. The propensity score matching was performed to match cases in both groups. The primary outcome was 28-day mortality, and the secondary outcomes were acute kidney injury, ventilator-free days, lengths of PICU and hospital stays. The Kaplan-Meier method and was the log-rank test used to estimate the 28-day mortality rate and assess between-group differences. Results In total, 250 patients were eligible patients: 138 in the dexmedetomidine group and 112 in the non-dexmedetomidine group. After 1:1 propensity score matching, 61 children in each group. dexmedetomidine group showed more lower 28-day mortality (9.84% vs. 26.23%, P = 0.008). During the 7-day observation period after PICU admission, the dexmedetomidine group showed significantly lower neurological and renal sub-scores at day 7 and serum creatinine level at day 3 and day 7. There were no statistical differences in the incidence of acute kidney injury, ventilator-free days, lengths of PICU and hospital stays between the two groups. Conclusions dexmedetomidine treatment in children with severe sepsis is associated with better outcomes and should therefore be considered for the sedation strategy.

3,4-disubstituted maleimides find wide applications in various pharmacologically active compounds. This study presents a highly effective approach for synthesizing derivatives of 3,4-disubstituted maleimides through the direct isomerization of α-succinimide-substituted allenoates, followed by a cascade γ′-addition and aryl imines using PR3 as a catalyst. The resulting series of 3,4-disubstituted maleimides exhibited excellent stereoselectivities, achieving yields of up to 86%. To our knowledge, the phosphine-mediated γ′-addition reaction of allenoates is seldom reported.

In this paper, an interesting γ′-carbon 1,6-conjugate addition for phosphine-catalyzed α-succinimide substituted allenoates has been disclosed. A wide array of substrates was found to participate in the reaction, resulting in the production of diverse 4-diarylmethylated 3,4-disubstituted maleimides with satisfactory to outstanding yields. Furthermore, a plausible mechanism for the reaction was proposed by the investigators.

Abstract Objectives This study aims to develop and validate a virtual biopsy model to predict microsatellite instability (MSI) status in preoperative gastric cancer (GC) patients based on clinical information and the radiomics of deep learning algorithms. Methods A total of 223 GC patients with MSI status detected by postoperative immunohistochemical staining (IHC) were retrospectively recruited and randomly assigned to the training (n = 167) and testing (n = 56) sets in a 3:1 ratio. In the training set, 982 high-throughput radiomic features were extracted from preoperative abdominal dynamic contrast-enhanced CT (CECT) and screened. According to the deep learning multilayer perceptron (MLP), 15 optimal features were optimized to establish the radiomic feature score (Rad-score), and LASSO regression was used to screen out clinically independent predictors. Based on logistic regression, the Rad-score and clinically independent predictors were integrated to build the clinical radiomics model and visualized as a nomogram and independently verified in the testing set. The performance and clinical applicability of hybrid model in identifying MSI status were evaluated by the area under the receiver operating characteristic (AUC) curve, calibration curve, and decision curve (DCA). Results The AUCs of the clinical image model in training set and testing set were 0.883 [95% CI: 0.822–0.945] and 0.802 [95% CI: 0.666–0.937], respectively. This hybrid model showed good consistency in the calibration curve and clinical applicability in the DCA curve, respectively. Conclusions Using preoperative imaging and clinical information, we developed a deep-learning-based radiomics model for the non-invasive evaluation of MSI in GC patients. This model maybe can potentially support clinical treatment decision making for GC patients. Graphical abstract

Abstract Background Skeletal muscle dysfunction is an important co‐morbidity in patients with chronic obstructive pulmonary disease (COPD) and is significantly associated with increased mortality. Oxidative stress has been demonstrated an important trigger for COPD‐related skeletal muscle dysfunction. Glycine‐histidine‐lysine (GHK) is an active tripeptide, which is a normal component of human plasma, saliva, and urine; promotes tissue regeneration; and acts as an anti‐inflammatory and antioxidant properties. The purpose of this study was to determine whether GHK is involved in COPD‐related skeletal muscle dysfunction. Methods The plasma GHK level in patients with COPD (n = 9) and age‐paired healthy subjects (n = 11) were detected using reversed‐phase high‐performance liquid chromatography. The complex GHK with Cu (GHK‐Cu) was used in in vitro (C2C12 myotubes) and in vivo experiments (cigarette smoking [CS]‐exposure mouse model) to explore the involvement of GHK in CS‐induced skeletal muscle dysfunction. Results Compared with healthy control, plasma GHK levels were decreased in patients with COPD (70.27 ± 38.87 ng/mL vs. 133.0 ± 54.54 ng/mL, P = 0.009). And plasma GHK levels in patients with COPD were associated with pectoralis muscle area (R = 0.684, P = 0.042), inflammatory factor TNF‐α (R = −0.696, P = 0.037), and antioxidative stress factor SOD2 (R = 0.721, P = 0.029). GHK‐Cu was found to rescue CSE‐induced skeletal muscle dysfunction in C2C12 myotubes, as evidenced by increased expression of myosin heavy chain, reduced expression of MuRF1 and atrogin‐1, elevated mitochondrial content, and enhanced resistance to oxidative stress. In CS‐induced muscle dysfunction C57BL/6 mice, GHK‐Cu treatment (0.2 and 2 mg/kg) reduces CS‐induced muscle mass loss (skeletal muscle weight (1.19 ± 0.09% vs. 1.29 ± 0.06%, 1.40 ± 0.05%; P

Hemorrhage is a leading cause of death in trauma. Tourniquets are effective at controlling extremity hemorrhage and have saved lives. However, tourniquets can cause ischemia reperfusion injury of limbs, leading to systemic inflammation and other adverse effects, which results in secondary damage to the kidney, lung, and liver. A clinically relevant animal model is critical to understanding the pathophysiology of this process and developing therapeutic interventions. Despite the importance of animal models, tourniquet-induced lower limb ischemia/reperfusion (TILLIR) models to date lack a hemorrhage component. We sought to develop a new TILLIR model that included hemorrhage and analyze the subsequent impact on kidney, lung and liver injuries. Four groups of mice were examined: group 1) control, group 2) hemorrhage, group 3) tourniquet application, and group 4) hemorrhage and tourniquet application. The hemorrhagic injury consisted of the removal of 15% of blood volume through the submandibular vein. The tourniquet injury consisted of orthodontic rubber bands applied to the inguinal area bilaterally for 80 min. Mice were then placed in metabolic cages individually for 22 h to collect urine. Hemorrhage alone did not significantly affect transcutaneous glomerular filtration rate (tGFR), blood urea nitrogen (BUN) or urinary kidney injury molecule-1 (KIM-1) levels. Without hemorrhage, TILLIR decreased tGFR by 46%, increased BUN by 162%, and increased KIM-1 by 27% (p < 0.05 for all). With hemorrhage, TILLIR decreased the tGFR by 72%, increased BUN by 395%, and increased urinary KIM-1 by 37% (p < 0.05 for all). These differences were statistically significant (p < 0.05). While hemorrhage had no significant effect on TILLIR-induced renal tubular degeneration and necrosis, it significantly increased TILLIR-induced lung total injury scores and congestion, and fatty liver. In conclusion, hemorrhage exacerbates TILLIR-induced acute kidney injury and structural damage in the lung and liver.

Abstract The YTH N 6 -methyladenosine RNA binding proteins (YTHDFs) mediate the functional effects of N 6 -methyladenosine (m6A) on RNA. Recently, a report proposed that all YTHDFs work redundantly to facilitate RNA decay, raising questions about the exact functions of individual YTHDFs, especially YTHDF1 and YTHDF2. We show that YTHDF1 and YTHDF2 differ in their low-complexity domains (LCDs) and exhibit different behaviors in condensate formation and subsequent physiological functions. Biologically, we also find that the global stabilization of RNA after depletion of all YTHDFs is driven by increased P-body formation and is not strictly m6A dependent.

Background: Apoptosis and pyroptosis are two types of programmed cell death related to the neuroinflammatory reaction after subarachnoid hemorrhage (SAH). Research indicates that triggering receptor expressed on myeloid cells 2 (TREM2) can regulate the SAH-induced inflammatory response. However, whether TREM2 regulates programmed cell death (apoptosis and pyroptosis) remains to be clarified. The purpose of the present study was to investigate the effects of TREM2 on cell death in SAH. Methods: SAH was induced in adult male C57BL/6J mice by endovascular perforation. An in-vitro cellular model of SAH was established by treating cocultured BV2 microglia and HT22 neuronal cells with oxyhemoglobin. TREM2 overexpression or knockdown was carried out by intraventricular lentivirus injection at 7 d before SAH induction in mice or lentiviral transfection, respectively. Neurobehavioral tests as well as western blot, reverse transcription–quantitative polymerase chain reaction (RT-qPCR), immunofluorescence, Evans blue (EB) staining, Nissl staining, and flow cytometry assays were performed to investigate the neuroprotective role of TREM2 after SAH. Results: After SAH, the TREM2 mRNA and protein levels were elevated in SAH mice, exhibiting a peak at 72 h. TREM2 overexpression improved the SAH-induced neurological deficits in mice, while TREM2 knockdown worsened them. In the brains of mice with TREM2 overexpression, less neuronal death and more neuronal survival were detected at 72 h post SAH. Meanwhile, TREM2 overexpression showed an inhibitory effect on microglial activation, neutrophil infiltration, and the expression of cell death marker proteins. Consistent results were obtained in vitro. Conclusions: Our research indicates the important role of TREM2 on cell death after SAH, suggesting that targeting TREM2 might be an effective approach for treating SAH.

Objective: To develop novel multiparametric models based on computed tomography enterography (CTE) scores to identify endoscopic activity and surgical risk in patients with Crohn's disease (CD). Methods: We analyzed 171 patients from 3 hospitals. Correlations between CTE outcomes and endoscopic scores were assessed using Spearman's rank correlation analysis. Predictive models for moderate to severe CD were developed, and receiver operating characteristic (ROC) curves were constructed to determine the area under the ROC curve (AUC). A combined nomogram based on CTE scores and clinical variables was also developed for predicting moderate to severe CD and surgery. Results: CTE scores were significantly correlated with endoscopy scores at the segment level. The global CTE score was an independent predictor of severe (HR = 1.231, 95% CI: 1.048–1.446, p = 0.012) and moderate-to-severe Simplified Endoscopic Scores for Crohn's Disease (SES-CD) (HR = 1.202, 95% CI: 1.090–1.325, p

The accurate prediction of electricity prices has great significance for the power system and the electricity market, regional electricity prices are difficult to predict due to congestion issues in regional transmission lines. A regional electricity price prediction framework is proposed based on an adaptive spatial–temporal convolutional network. The proposed framework is expected to better explore regional electricity prices’ spatial–temporal dynamic characteristics in the electricity spot market and improve the predictive accuracy of regional electricity prices. First, different areas of the electricity market are regarded as nodes. Then, each area’s historical electricity price data are used as the corresponding node’s characteristic information and constructed into a graph. Finally, a graph containing the spatial–temporal information on electricity prices is input to the adaptive spatial–temporal prediction framework to predict the regional electricity price. Operational data from the Australian electricity market are adopted, and the prediction results from the proposed adaptive spatial–temporal prediction framework are compared with those of existing methods. The numerical example results show that the predictive accuracy of the proposed framework is better than the existing baseline and similar methods. In the twelve-step forecast example in this paper, considering the spatial dependence of the spot electricity price can improve the forecast accuracy by at least 10.3% and up to 19.8%.

Cervical cancer (CC) is one of the most prevalent malignancies among females. Cytoprotective autophagy could confer cancer cell tolerance to hypoxic stress, promoting cell survival and adaptation. Aspartyl-tRNA synthetase 1 antisense 1 (DARS-AS1) is an oncogenic long non-coding RNA (lncRNA) in various cancers, but how DARS-AS1 regulates cytoprotective autophagy in hypoxic environment in CC remains unclear. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were conducted to explore the interaction between hypoxia-inducible factor 1 subunit alpha (HIF1α) and DARS-AS1 promoter. Methylated RNA immunoprecipitation (MeRIP) followed by quantitative real-time polymerase-chain reaction (RT-qPCR) detected methylated RNA level. The process of autophagic maturation was monitored by immunofluorescence staining. Higher DARS-AS1 expression was found in CC tissues and cytoprotective. We also uncovered that hypoxic exposure induced cytoprotective autophagy via HIF1α/DARS-AS1/DARS axis. Moreover, DARS-AS1 was validated to facilitate DARS translation via recruiting N6-adenosine-methyltransferase methyltransferase like 3 (METTL3) and methyltransferase like 14 (METTL14), which bound with DARS mRNA DARS mRNA 5’ untranslated region (5ʹUTR) and promoting its translation. The present study demonstrated that the ‘HIF1α/DARS-AS1/DARS/ATG5/ATG3’ pathway regulated the hypoxia-induced cytoprotective autophagy of CC and might be a promising target of therapeutic strategies for patients afflicted with CC.

Xinjiang is the largest grape-producing region in China and the main grape cultivation area in the world. The Eurasian grape resources grown in Xinjiang are very rich in diversity. The sugar composition and content are the main factors that determine the quality of berries. However, there are currently no systematic reports on the types and contents of sugars in grapes grown in Xinjiang region. In this research, we evaluated the appearance and fruit maturity indicators of 18 grape varieties during fruit ripening and determined their sugar content using GC-MS. All cultivars primarily contained glucose, D-fructose, and sucrose. The glucose content in varieties varied from 42.13% to 46.80% of the total sugar, whereas the fructose and sucrose contents varied from 42.68% to 50.95% and 6.17% to 12.69%, respectively. The content of trace sugar identified in grape varieties varied from 0.6 to 2.3 mg/g. The comprehensive assessment by principal component analysis revealed strong positive correlations between some sugar components. A comprehensive study on the content and types of sugar will provide the foundation to determine the quality of grape cultivars and effective ways to utilize resources to improve sugar content through breeding.

BackgroundSarcopenia often occurs as a comorbidity in many diseases which ultimately affects patient prognosis. However, it has received little attention in patients with idiopathic pulmonary fibrosis (IPF). This systematic review and meta-analysis aimed at determining the prevalence and risk factors of sarcopenia in patients with IPF.MethodsEmbase, MEDLINE, Web of Science, and Cochrane databases were searched using relevant MeSH terms until December 31, 2022. The Newcastle-Ottawa Scale (NOS) was used for quality assessment and data analysis were performed using Stata MP 17.0 (Texas, USA). A random effects model was adopted to account for differences between articles, and the I2 statistic was used to describe statistical heterogeneities. Overall pooled estimates obtained from a random effects model were estimated using the metan command. Forest plots were generated to graphically represent the data of the meta-analysis. Meta-regression analysis was used for count or continuous variables. Egger test was used to evaluate publication bias and, if publication bias was observed, the trim and fill method was used.Main resultsThe search results showed 154 studies, and five studies (three cross-section and two cohort studies) with 477 participants were finally included. No significant heterogeneity was observed among studies included in the meta-analysis (I2 = 16.00%) and our study's publication bias is low (Egger test, p = 0.266). The prevalence of sarcopenia in patients with IPF was 26% (95% CI, 0.22–0.31). The risk factors for sarcopenia in patients with IPF were age (p = 0.0131), BMI (p = 0.001), FVC% (p < 0.001), FEV1% (p = 0.006), DLco% (p ≤ 0.001), and GAP score (p = 0.003).ConclusionsThe pooled prevalence of sarcopenia in patients with IPF was 26%. The risk factors for sarcopenia in IPF patients were age, BMI, FVC%, FEV1%, DLco%, and GAP score. It is important to identify these risk factors as early as possible to improve the life quality of patients with IPF.

The occurrence of early brain injury (EBI) significantly contributes to the unfavorable prognosis observed in patients with subarachnoid hemorrhage (SAH). During the process of EBI, a substantial quantity of iron permeates into the subarachnoid space and brain tissue, thereby raising concerns regarding its metabolism. To investigate the role and metabolic processes of excessive iron in neurons, we established both in vivo and in vitro models of SAH. We substantiated that ferritinophagy participates in iron metabolism disorders and promotes neuronal ferroptosis using an in vivo model, as detected by key proteins such as ferritin heavy chain 1, glutathione peroxidase 4, autophagy related 5, nuclear receptor coactivator 4 (NCOA4), LC3B, and electron microscopy results. By interfering with NCOA4 expression in vitro and in vivo, we confirmed the pivotal role of elevated NCOA4 levels in ferritinophagy during EBI. Additionally, our in vitro experiments demonstrated that the addition of oxyhemoglobin alone did not result in a significant upregulation of NCOA4 expression. However, simultaneous addition of oxyhemoglobin and hypoxia exposure provoked a marked increase in NCOA4 expression and heightened ferritinophagy in HT22 cells. Using YC-1 to inhibit hypoxia signaling in in vitro and in vitro models effectively attenuated neuronal ferroptosis. Collectively, we found that the hypoxic microenvironment during the process of EBI exaggerates iron metabolism abnormalities, leading to poor prognoses in SAH. The findings also offer a novel and potentially effective foundation for the treatment of SAH, with the aim of alleviating hypoxia.

Conventional liquid cooling techniques may provide effective chip cooling but at the expense of high pumping power consumption. Considering that there is dynamic heat load in practice, a self-adaptive cooling technique is desired to reduce operational costs while preserving inherent cooling effectiveness. In this work, a novel self-adaptive cooling strategy is presented to balance the thermal and flow efficiency in accordance with the dynamic thermal load, based on temperature-regulated movement of the metal pillar array in a microfluidic channel. With an illustrative device, the effectiveness of such a strategy is investigated using multiphysics modeling and simulation. As a case study, the device is considered to be initiated with a chip power of 5 W and an inlet coolant velocity of 0.3 m/s. It is shown that the temperature-regulated movement of the metal pillar heat sink will be activated rapidly and equilibrate within 30 s. Parts of the metal pillars immerse into the coolant flow, resulting in significantly improved heat transfer efficiency. The diminished thermal resistance leads to a reduction in chip temperature rise from 225 K (without structural adaptation) to 91.86 K (with structural adaption). Meanwhile, the immersion of metal pillars into the coolant also causes an increased flow resistance in the microfluidic channel (i.e., pressure drop increases from 859.27 Pa to 915.98 Pa). Nevertheless, the flow resistance decreases spontaneously when the working power of the chip decreases. Comprehensive simulation has demonstrated that the temperature-regulated structure works well under various conditions. Therefore, it is believed that the presented self-adaptive cooling strategy offers simple and cost-effective thermal management for modern electronics with dynamic heat fluxes.

PurposeTo evaluate and compare the predictive performance of different deep learning models using gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI in predicting microvascular invasion (MVI) in hepatocellular carcinoma.MethodsThe data of 233 patients with pathologically confirmed hepatocellular carcinoma (HCC) treated at our hospital from June 2016 to June 2021 were retrospectively analyzed. Three deep learning models were constructed based on three different delineate methods of the region of interest (ROI) using the Darwin Scientific Research Platform (Beijing Yizhun Intelligent Technology Co., Ltd., China). Manual segmentation of ROI was performed on the T1-weighted axial Hepatobiliary phase images. According to the ratio of 7:3, the samples were divided into a training set (N=163) and a validation set (N=70). The receiver operating characteristic (ROC) curve was used to evaluate the predictive performance of three models, and their sensitivity, specificity and accuracy were assessed.ResultsAmong 233 HCC patients, 109 were pathologically MVI positive, including 91 men and 18 women, with an average age of 58.20 ± 10.17 years; 124 patients were MVI negative, including 93 men and 31 women, with an average age of 58.26 ± 10.20 years. Among three deep learning models, 2D-expansion-DL model and 3D-DL model showed relatively good performance, the AUC value were 0.70 (P=0.003) (95% CI 0.57–0.82) and 0.72 (P

The nonopioid sigma-1 receptor (σ1R) is localized to the endoplasmic reticulum (ER), interacts with multiple effector proteins and various synthetic ligands, and is implicated in many diseases. Here, authors provide structural and functional evidence to reveal the likely ligand entry pathway for σ1R.

Simple methods for attaching polynucleotides to gold nanoparticles are of interest for simplifying conjugation in a range of applications. Here, the authors report a microwave heating-based method for the fast, one-step attachment of a range of thiolated or non-thiolated DNA and RNA to gold nanoparticles.

Electricity-driven thermostatically controlled loads (TCLs), e.g., air conditioners (ACs), have been widely utilized in demand response (DR) to provide operating reserve for power systems. However, the rebound effects may occur during the recovery process of DR, which can limit the operating reserve quality of ACs or even affect the reliable operation of power systems. With the community-level smart energy hubs (EH), the traditional electricity-driven TCLs can be expanded into multi-energy driven thermostatically controlled loads (MTCLs), e.g., household radiators. Under this circumstance, integrated demand response (IDR) can be exploited to coordinate the operation of MTCLs and provide more operating reserve resources while mitigating rebound effects. To this end, this paper proposes a two-stage IDR strategy to fully excavate the operating reserve provided by MTCLs. The first stage is to coordinate the energy consumption of ACs and household radiators to maximize the end-users’ thermal comfort and mitigate the rebound effects. To quantify the end-users’ thermal comfort, a modified predicted percentage of dissatisfied (PPD) index related to thermal environment parameters is introduced and simplified. Based on the energy consumption determined in the first stage, the energy conversion in EH is optimized in the second stage. Through the optimization in these two stages, a series of indices is established to evaluate the operating reserve in terms of aggregate capacity, duration, ramp rate, and smoothness. The case studies demonstrate that the proposed two-stage IDR strategy can provide high-aggregate-capacity and long-duration reserve resources in power systems while mitigating the rebound effects to maintain supply-demand balance and reliable operation of power systems. The analysis results of the test system show that the reserve capacity and duration obtained by the proposed model are 1.85 and 2.61 times those of the model without considering the multi-energy conversion, respectively.

The evaluation of photosynthetic characteristics of plants is important for the success rate of germplasm introduction. To select grape varieties with higher adaptability and trait performance, this experiment is aimed at evaluating and comparing the photosynthetic indices, chlorophyll fluorescence parameters, photosynthetic pigment content, and leaf characteristics of five Chinese hybrid varieties. The results showed that under high light intensity stress, the leaf growth of ‘Ruidu Cuixia’ was most affected and its specific leaf weight was the lowest, while ‘Jing Hongbao’ had the highest chlorophyll content. The maximum net photosynthetic rate (Pnmax), maximum light quantum yield (Fv/Fm), and apparent quantum efficiency (AQE) were different among varieties. It was reported that the ‘Ruidu Zaohong’ variety had the highest Pnmax. ‘Ruidu Wuheyi’ was found to have the highest Fv/Fm, while the highest AQE was recorded for ‘Ruidu Cuixia’, with intercellular CO2 concentration (Ci) and stomatal conductance (gs) at 292.56 μmol·mol−1, 766.56 mmol·m−2·s−1, and 66.8 μmol·m−2·s−1, respectively. The indices of ABS/CSm, TRo/CSm, and DIo/CSm were significantly different among varieties, and these indices of ‘Ruidu Zaohong’ were the highest. Pn was positively correlated with Ci and Tr, gs were positively correlated with Fv and TRo/CSm. The specific leaf area was negatively correlated with Fv/Fm and ΦDIo. The results of the principal component analysis and TOPSIS comprehensive evaluation showed that ‘Jing Hongbao’ and ‘Ruidu Cuixia’ performed best. Overall, the measurement of the photosynthetic characteristics of the plants during the growing period provided valuable data for the varietal introduction strategies. The better photosynthetic performance of ‘Jing Hongbao’ and ‘Ruidu Cuixia’ indicates more adaptability to the long day, high light intensity, and the high-temperature climate of Xinjiang.

Abstract Background Ephrin receptors (Eph) and their ligands, called ephrins, function in various disease processes. However, the expression level and prognostic value of Eph/ephrins in lung adenocarcinoma (LUAD) are still unclear. Methods The Oncomine and GEPIA databases were used to explore the differential expression of Eph/ephrins in LUAD. Kaplan–Meier plotter was selected to explore the prognostic value of Eph/ephrins. The cBioPortal database was used to analyze the genetic variation of the EFNA3 gene. Immunohistochemistry was used to analyze the expression level and clinical value of ephrin-A3 protein in clinical LUAD tissue. Weighted coexpression network analysis (WGCNA) and gene set enrichment analysis (GSEA) identified the potential regulatory mechanism of EFNA3. CCK-8 assays and colony-forming experiments were used to investigate whether EFNA3 can regulate cell proliferation ability in LUAD. Analysis of lactate, ATP, and glucose uptake levels was used to explore the effect of EFNA3 on glycolysis ability. In addition, we investigated the relationship between EFNA3 and tumor infiltrating immune cells (TIICs). Finally, the potential immunotherapy response prediction value of EFNA3 was also explored. Results In this study, we found that EFNA3 expression was significantly correlated with both overall survival (OS) and progression-free survival (PFS) in LUAD patients based on a comprehensive analysis of the Eph/Ephrin family. Next, the expression of the EFNA3 protein was increased in LUAD tissues and was designated an independent prognostic risk factor. Mechanistically, EFNA3 may be involved in nuclear division, synaptic function, and ion channel activity-related pathways. In vitro experiments confirmed the role of EFNA3 in promoting LUAD cells and showed that it could regulate glycolytic capacity. Moreover, EFNA3 was negatively associated with immunity, stromal infiltration, and several TIICs. Finally, EFNA3 was found to be positively related to multiple immunotherapy biomarkers. Conclusions In conclusion, increased EFNA3 in LUAD patients predicted worse clinical prognosis, promoted LUAD cell proliferation and glycolysis ability, and was related to immunotherapy response.

ObjectiveTo develop a radiomics nomogram for predicting microvascular invasion (MVI) before surgery in hepatocellular carcinoma (HCC) patients.Materials and MethodsThe data from a total of 189 HCC patients (training cohort: n = 141; validation cohort: n = 48) were collected, involving the clinical data and imaging characteristics. Radiomics features of all patients were extracted from hepatobiliary phase (HBP) in 15 min. Least absolute shrinkage selection operator (LASSO) regression and logistic regression were utilized to reduce data dimensions, feature selection, and to construct a radiomics signature. Clinicoradiological factors were identified according to the univariate and multivariate analyses, which were incorporated into the final predicted nomogram. A nomogram was developed to predict MVI of HCC by combining radiomics signatures and clinicoradiological factors. Radiomics nomograms were evaluated for their discrimination capability, calibration, and clinical usefulness.ResultsIn the clinicoradiological factors, gender, alpha-fetoprotein (AFP) level, tumor shape and halo sign served as the independent risk factors of MVI, with which the area under the curve (AUC) is 0.802. Radiomics signatures covering 14 features at HBP 15 min can effectively predict MVI in HCC, to construct radiomics signature model, with the AUC of 0.732. In the final nomogram model the clinicoradiological factors and radiomics signatures were integrated, outperforming the clinicoradiological model (AUC 0.884 vs. 0.802; p

Abstract Background Reduced exercise tolerance is an important clinical feature of chronic obstructive pulmonary disease (COPD) and is associated with poor prognosis. The 6-min walk test (6MWT) is widely used to assess exercise capacity; however, it is not commonly administered in primary medical institutions because it requires a suitable site and professional training. Ultrasound has great potential for evaluating skeletal muscle dimensions in COPD. However, whether skeletal muscle ultrasound can predict impaired exercise tolerance is unclear. Methods The study included 154 stable patients with COPD, who were randomly divided into a development set and a validation set. The thickness (RFthick) and cross-sectional area (RFcsa) of the rectus femoris were measured using ultrasound. Standardized RFthick (STD- RFthick) and Standardized RFcsa (STD-RFcsa) were obtained via standardization of RFthick and RFcsa by patients' height. Results Strong correlations were observed between the 6MWD and RFthick (r = 0.84, p

Abstract Multiple proinflammatory conditions, including chemotherapy, radiotherapy, transplant rejection, and microbial infections, have been identified to induce involution of the thymus. However, the underlying cellular and molecular mechanisms of these inflammatory conditions inducing apoptosis of thymic epithelial cells (TECs), the main components of the thymus, remain largely unknown. In the circulation, mature dendritic cells (mDCs), the predominant initiator of innate and adaptive immune response, can migrate into the thymus. Herein, we demonstrated that mDCs were able to directly inhibit TECs proliferation and induce their apoptosis by activating the Jagged1/Notch3 signaling pathway. Intrathymic injection of either mDCs or recombinant mouse Jagged1-human Fc fusion protein (rmJagged1-hFc) into mice resulted in acute atrophy of the thymus. Furthermore, DAPT, a γ-secretase inhibitor, reversed the effects induced by mDC or rmJagged1-hFc. These findings suggest that acute or aging-related thymus degeneration can be induced either by mass migration of circulating mDCs in a short period of time or by a few but constantly homing mDCs.

The authors create synthetic dimensions in acoustic crystals composed of cavity arrays, strongly coupled through modulated channels. They provide evidence for 1D and 2D dynamic topological pumping, and show that the higher-order topological sound transport is robust against the geometrical imperfections.

Abstract Background Early and accurate identification of septic patients at high risk for ICU mortality can help clinicians make optimal clinical decisions and improve the patients’ outcomes. This study aimed to develop and validate (internally and externally) a mortality prediction score for sepsis following admission in the ICU. Methods We extracted data retrospectively regarding adult septic patients from one teaching hospital in Wenzhou, China and a large multi-center critical care database from the USA. Demographic data, vital signs, laboratory values, comorbidities, and clinical outcomes were collected. The primary outcome was ICU mortality. Through multivariable logistic regression, a mortality prediction score for sepsis was developed and validated. Results Four thousand two hundred and thirty six patients in the development cohort and 8359 patients in three validation cohorts. The Prediction of Sepsis Mortality in ICU (POSMI) score included age ≥ 50 years, temperature 35 breaths/min, MAP ≤ 50 mmHg, SpO2

It is generally agreed that the quality of institutions, the amount of energy consumed, and foreign direct investment are among the essential factors in sustainable development. On the other hand, these aspects are just as critical as the others when determining what causes environmental deterioration and how the climate changes globally. This research used the dataset of the BRICS countries, which are classified as emerging nations, intending to determine the nature of the relationship between foreign direct investment and institutional quality in terms of an interaction term, in addition to other independent variables and environmental quality. The objective of this study was to determine whether or not a Pollution Heaven or Environmental Kuznets curve (EKC) exists in the BRICS countries. To accomplish this objective, the Pooled Mean Group (PMG) technique of econometrics was utilized to estimate a 21-year dataset between 2000 and 2020. The Pollution Heaven theory was shown to be true after empirical research was conducted on the BRICS economies. In these economies, this finding verified the expansion of foreign direct investment and the proliferation of business rules were sources of environmental degradation. In addition, no evidence was discovered to support the presence of the EKC theory in any of the BRICS countries or areas. Based on these empirical outcomes, this research suggested that the introduction of appropriate commercial laws is required to translate the benefits of foreign direct investment into environmentally sustainable development.

BackgroundBoth catheter left atrial appendage occlusion combined with ablation (COA) and thoracoscopic surgical left atrial appendage clipping combined with ablation (TCA) have shown favorable outcomes in management of patients with atrial fibrillation (AFib). However, studies comparing the endpoints of both techniques are still lacking. Herein, a meta-analysis of safety and efficacy outcomes of COA versus TCA was performed in patients with AFib.MethodsPubmed, Embase, Cochrane, and Web of Science databases were searched for retrieving potential publications. The primary outcome was the incidence of stroke during follow-up period of at least 12 months. Secondary outcomes were acute success rate of complete left atrial appendage (LAA) closure by COA or TCA, postprocedural mortality and complications, and all-cause mortality during follow-up period of at least 12 months.Results19 studies of COA containing 1,504 patients and 6 studies of TCA with 454 patients were eligible for analysis. No significant difference in stroke and all-cause mortality was found in patients undergoing COA versus TCA after at least a 12-month follow-up (stroke: p = 0.504; all-cause mortality: p = 0.611). COA group had a higher acute success rate compared with TCA group (p = 0.001). COA placed the patients at a higher risk of hemorrhage during the postprocedural period compared with TCA (p = 0.023). A similar risk of other postprocedural complications (stroke/transient ischemic attack and pericardial effusion) and mortality was found in the COA group in comparison with TCA group (p>0.05).ConclusionThis meta-analysis showed that COA and TCA did not differ in stroke prevention and all-cause mortality in patients with AFib after a follow-up of at least 12 months. Postprocedural complications and mortality were almost comparable between the two groups. In the near future, high-quality randomized controlled trials exploring the optimal surgical strategies for AFib and endpoints of different procedures are warranted.Systematic review registration[https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42022325497].

Addressing the conflict between fossil fuel exploitation, usage, and greenhouse gas emissions is a top priority for China’s low-carbon socioeconomic development. Scalable Axisymmetric Matrix “a computerized general equilibrium model” is used to assess the impact of carbon tax policies on energy usage, carbon pollution, and macroeconomic drivers at reduction levels of 10%, 20%, and 30% of emissions. In the meantime, we examine the impact of various carbon tax recycling schemes in line with the tax neutrality concept. Although the carbon tax successfully reduces carbon emissions, we conclude that it will have a detrimental effect on the economy and social well-being. To cope with China’s increasing pollution emissions and ecological imbalances, the Chinese government promulgated the environmental protection tax law of the people’s Republic of China, which was officially implemented in 2018. Although carbon dioxide is not included in the Taxable Pollutants and Single Quantity Table attached to this law, China has almost reached a consensus on taxing carbon emissions. In 2021, the State Council of China issued the opinions on completely, accurately, and comprehensively implementing the new development concept and doing a good job in carbon peak and carbon neutralization, which made a comprehensive deployment to achieve the “double carbon” goal and improved the carbon tax policy and legal system, which is an essential part of it. Therefore, based on fiscal neutrality, an effective carbon tax recycling scheme can mitigate the adverse effects of its adoption. However, due to the current development in China’s energy-generating and transportation sectors, even minor steps can have huge effects on emissions with marginal economic implications.

Quantitative estimation of growth patterns is important for diagnosis of lung adenocarcinoma and prediction of prognosis. However, the growth patterns of lung adenocarcinoma tissue are very dependent on the spatial organization of cells. Deep learning for lung tumor histopathological image analysis often uses convolutional neural networks to automatically extract features, ignoring this spatial relationship. In this paper, a novel fully automated framework is proposed for growth pattern evaluation in lung adenocarcinoma. Specifically, the proposed method uses graph convolutional networks to extract cell structural features; that is, cells are extracted and graph structures are constructed based on histopathological image data without graph structure. A deep neural network is then used to extract the global semantic features of histopathological images to complement the cell structural features obtained in the previous step. Finally, the structural features and semantic features are fused to achieve growth pattern prediction. Experimental studies on several datasets validate our design, demonstrating that methods based on the spatial organization of cells are appropriate for the analysis of growth patterns.

Background: Chronic obstructive pulmonary disease (COPD) is a common respiratory disorder manifested as chronic airway inflammation and persistent airflow limitation with the essential mechanism as inflammatory response and oxidative stress induced by toxic exposures such as cigarette smoke (CS). Glycyl-L-histidyl-L-lysine (GHK) is a nontoxic tripeptide involved in the process of healing and regeneration as a natural product. With the combination of Cu(II), glycyl-L-histidyl-L-lysine-Cu2+ (GHK-Cu) improves antioxidative and anti-inflammatory bioavailability, and they might offer potential therapeutic properties for COPD. Thus, the present study aimed to identify the potential effects of GHK-Cu on emphysema induced by cigarette smoke.Methods: In the in vivo experiment, C57BL/6J mice were exposed to CS for 12 weeks to induce pulmonary emphysema. GHK-Cu was injected intraperitoneally at doses of 0.2, 2 and 20 μg/g/day in 100 µl of saline on alternative days from the 1st day after CS exposure. The effects of GHK-Cu on the morphology of CS-induced emphysema, the inflammatory response and oxidative stress were evaluated. The antioxidative effect of GHK-Cu on human alveolar epithelial A549 cells was assessed in vitro.Results: GHK-Cu treatment attenuated the CS-induced emphysematous changes and partially reversed the matrix metalloprotein -9 (MMP-9)/tissue inhibitor of metalloproteinases-1 (TIMP-1) imbalance in the lung tissue. GHK-Cu reduced the inflammation and oxidation by decreasing the expression of inflammatory cytokines (IL-1β and TNF-α) in the bronchoalveolar lavage and the enzymatic activity of MPO and MDA in the lung homogenate while restoring the T-AOC and GSH content. Furthermore, administration of GHK-Cu reversed the increase in NF-κB expression induced by CS and increased the Nrf2 level, as an antioxidant defense component, in mice with chronic CS exposure. In CSE-exposed human alveolar epithelial A549 cells, GHK-Cu also inhibited oxidative stress by suppressing MDA levels and restoring T-AOC and GSH levels, which were modulated by upregulating Nrf2 expression.Conclusion: GHK-Cu treatment attenuated CS-induced emphysema by anti-inflammation by downregulating NF-κB and antioxidation via upregulation of the Nrf2/Keap1 in lung tissues.

Summary: Aging is an intricate process characterized by multiple hallmarks including stem cell exhaustion, genome instability, epigenome alteration, impaired proteostasis, and cellular senescence. Whereas each of these traits is detrimental at the cellular level, it remains unclear how they are interconnected to cause systemic organ deterioration. Here we show that abrogating Brap, a BRCA1-associated protein essential for neurogenesis, results in persistent DNA double-strand breaks and elevation of histone H2A mono- and poly-ubiquitination (H2Aub). These defects extend to cellular senescence and proteasome-mediated histone H2A proteolysis with alterations in cells’ proteomic and epigenetic states. Brap deletion in the mouse brain causes neuroinflammation, impaired proteostasis, accelerated neurodegeneration, and substantially shortened the lifespan. We further show the elevation of H2Aub also occurs in human brain tissues with Alzheimer’s disease. These data together suggest that chromatin aberrations mediated by H2Aub may act as a nexus of multiple aging hallmarks and promote tissue-wide degeneration.