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This systematic review aimed to compare the influence of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on the efficacy and safety of elderly patients with type 2 diabetes and younger individuals. A comprehensive search of PubMed, Embase, and Web of Science databases was conducted up to September 2022. The summary standard means difference and odds ratios were calculated. Thirteen articles were included in the analysis. The incidence of adverse events (AEs) leading to discontinuation was higher in elderly patients (OR = 0.67, 95% CI 0.47 to 0.96, p = 0.028). However, no significant differences were observed in weight loss (SMD = 0.03, 95% CI –0.12 to 0.19, p = 0.686), HbA1c% (SMD = –0.02, 95% CI –0.11 to 0.08, p = 0.715), FBG levels (SMD = –0.03, 95% CI –0.11 to 0.06, p = 0.537), and the incidence of overall AEs (OR = 0.85, 95% CI 0.71 to 1.01, p = 0.072), serious AEs (OR = 0.68, 95% CI 0.45 to 1.04, p = 0.077), nausea (OR = 0.91, 95% CI 0.81 to 1.03, p = 0.140), vomiting (OR = 0.95, 95% CI 0.79 to 1.13, p = 0.532), diarrhea (OR = 0.86, 95% CI 0.72 to 1.02, p = 0.081), and hypoglycemia (OR = 1.22, 95% CI 0.90 to 1.65, p = 0.193). In conclusion, while certain AEs leading to discontinuation may be more prevalent in older patients, GLP-1RAs are effective for weight loss and lead to decreased glucose concentrations with a low rate of complications in elderly patients.

BackgroundCurrently, evidence regarding the causal relationship between primary immunodeficiency-related genes and varicella-zoster virus reactivation syndrome is limited and inconsistent. Therefore, this study employs Mendelian randomization (MR) methodology to investigate the causal relationship between the two.MethodsThis study selected 110 single-nucleotide polymorphisms (SNPs) of primary immunodeficiency-related genes as instrumental variables (IVs). Genetic associations of primary immunodeficiency-related genes were derived from recent genome-wide association studies (GWAS) data on human plasma protein levels and circulating immune cells. Data on genes associated with varicella-zoster virus reactivation syndrome were obtained from the GWAS Catalog and FINNGEN database, primarily analyzed using inverse variance weighting (IVW) and sensitivity analysis.ResultsThrough MR analysis, we identified 9 primary immunodeficiency-related genes causally associated with herpes zoster and its subsequent neuralgia; determined causal associations of 20 primary immunodeficiency-related genes with three vascular lesions (stroke, cerebral aneurysm, giant cell arteritis); revealed causal associations of 10 primary immunodeficiency-related genes with two ocular diseases (retinopathy, keratitis); additionally, three primary immunodeficiency-related genes each were associated with encephalitis, cranial nerve palsy, and gastrointestinal infections.ConclusionsThis study discovers a certain association between primary immunodeficiency-related genes and varicella-zoster virus reactivation syndrome, yet further investigations are warranted to explore the specific mechanisms underlying these connections.

Neuropathic pain (NeP) is a condition charactesized by nervous system injury or dysfunction that affects a significant portion of the population. Current treatments are ineffective, highlighting the need for novel therapeutic approaches. Mahuang Fuzi Xixin decoction (MFXD) has shown promise for treating pain conditions in clinical practice; however, its potential against NeP and the underlying mechanisms remain unclear. This study identified 35 compounds in MFXD using ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS). The analgesic effects of MFXD on chronic constriction injury (CCI) rats were evaluated through the detection of mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL). The analgesic effects of MFXD in rats with chronic constriction injury (CCI) were evaluated by measuring the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL). Low-dose MFXD (L-MFXD) group (4.8 g/kg) and high-dose MFXD (H-MFXD) group (9.6 g/kg) exhibited significantly higher MWT and TWL values than the CCI group on days 11 and 15 post-CCI surgery, substantiating the remarkable analgesic efficacy of MFXD. Network pharmacology analysis identified 58 key targets enriched in pathways such as long-term potentiation (LTP) and glutamatergic synapse. The MCODE algorithm further identified core targets with significant enrichment in LTP. Molecular docking revealed that mesaconitine, rosmarinic acid, and delgrandine from MFXD exhibited high binding affinity with NMDAR2B (−11 kcal/mol), CaMKIIα (−14.3 kcal/mol), and ERK (−10.8 kcal/mol). Western blot and immunofluorescence confirmed that H-MFXD significantly suppressed the phosphorylation levels of NMDAR2B, CaMKIIα, ERK, and CREB in the spinal cord tissue of CCI rats. In conclusion, this study demonstrates that MFXD possesses potent analgesic effects on NeP by suppressing the NMDAR2B/CaMKIIα/ERK/CREB signalling pathway. This study unlocks a path toward potentially revolutionising NeP treatment with MFXD, encouraging further research and clinical development.

Salidroside (SAL), belonging to a kind of the main active ingredient of Rhodiola rosea, is extensively utilized for anti-hypoxia and prevention of altitude sickness in the plateau region of China. However, the research on the systemic changes induced by SAL at intracellular protein level is still limited, especially at protein phosphorylation level. These limitations hinder a comprehensive understanding of the regulatory mechanisms of SAL. This study aimed to investigate the potential molecular mechanism of SAL in ameliorating the acute myocardial hypoxia induced by cobalt chloride using integrated proteomics and phosphoproteomics. We successfully identified 165 differentially expressed proteins and 266 differentially expressed phosphosites in H9c2 cells following SAL treatment under hypoxic conditions. Bioinformatics analysis and biological experiment validation revealed that SAL significantly antagonized CoCl2-mediated cell cycle arrest by downregulating CCND1 expression and upregulating AURKA, AURKAB, CCND3 and PLK1 expression. Additionally, SAL can stabilize the cytoskeleton through upregulating the Kinesin Family (KIF) members expression. Our study systematically revealed that SAL had the ability to protect myocardial cells against CoCl2-induced hypoxia through multiple biological pathways, including enhancing the spindle stability, maintaining the cell cycle, relieving DNA damage, and antagonizing cell apoptosis. This study supplies a comprehension perspective on the alterations at protein and protein phosphorylation levels induced by SAL treatment, thereby expanded our knowledge of the anti-hypoxic mechanisms of SAL. Moreover, this study provides a valuable resource for further investigating the effects of SAL.

We report a 42-year-old male patient who was diagnosed with acute myocardial infarction (AMI), and subsequently underwent percutaneous coronary intervention (PCI) for revascularization. The patient was transferred to the cardiac intensive care unit for intra-aortic balloon pump (IABP) due to frequent malignant arrhythmia after PCI. Then the patient experienced the most severe complications of IABP, including multiple organ embolism and intestinal necrosis. This report highlights the rare serious complications of IABP and the challenges encountered in handling this complex case.

Arterial spin labeling (ASL) can be used to detect differences in perfusion for multiple brain regions thought to be important in major depressive disorder (MDD). However, the potential of cerebral blood flow (CBF) to predict MDD and its correlations between the blood lipid levels and immune markers, which are closely related to MDD and brain function change, remain unclear. The 451 individuals − 298 with MDD and 133 healthy controls who underwent MRI at a single time point with arterial spin labelling and a high resolution T1-weighted structural scan. A proportion of MDD also provided blood samples for analysis of lipid and immune markers. We performed CBF case-control comparisons, random forest model construction, and exploratory correlation analyses. Moreover, we investigated the relationship between gray matter volume (GMV), blood lipids, and the immune system within the same sample to assess the differences in CBF and GMV. We found that the left inferior parietal but supramarginal and angular gyrus were significantly different between the MDD patients and HCs (voxel-wise P

Anxious depression is a common subtype of major depressive disorder (MDD) associated with adverse outcomes and severely impaired social function. It is important to clarify the underlying neurobiology of anxious depression to refine the diagnosis and stratify patients for therapy. Here we explored associations between anxiety and brain structure/function in MDD patients. A total of 260 MDD patients and 127 healthy controls underwent three-dimensional T1-weighted structural scanning and resting-state functional magnetic resonance imaging. Demographic data were collected from all participants. Differences in gray matter volume (GMV), (fractional) amplitude of low-frequency fluctuation ((f)ALFF), regional homogeneity (ReHo), and seed point-based functional connectivity were compared between anxious MDD patients, non-anxious MDD patients, and healthy controls. A random forest model was used to predict anxiety in MDD patients using neuroimaging features. Anxious MDD patients showed significant differences in GMV in the left middle temporal gyrus and ReHo in the right superior parietal gyrus and the left precuneus than HCs. Compared with non-anxious MDD patients, patients with anxious MDD showed significantly different GMV in the left inferior temporal gyrus, left superior temporal gyrus, left superior frontal gyrus (orbital part), and left dorsolateral superior frontal gyrus; fALFF in the left middle temporal gyrus; ReHo in the inferior temporal gyrus and the superior frontal gyrus (orbital part); and functional connectivity between the left superior temporal gyrus(temporal pole) and left medial superior frontal gyrus. A diagnostic predictive random forest model built using imaging features and validated by 10-fold cross-validation distinguished anxious from non-anxious MDD with an AUC of 0.802. Patients with anxious depression exhibit dysregulation of brain regions associated with emotion regulation, cognition, and decision-making, and our diagnostic model paves the way for more accurate, objective clinical diagnosis of anxious depression.

We describe MGARD, a software providing MultiGrid Adaptive Reduction for floating-point scientific data on structured and unstructured grids. With exceptional data compression capability and precise error control, MGARD addresses a wide range of requirements, including storage reduction, high-performance I/O, and in-situ data analysis. It features a unified application programming interface (API) that seamlessly operates across diverse computing architectures. MGARD has been optimized with highly-tuned GPU kernels and efficient memory and device management mechanisms, ensuring scalable and rapid operations.

Purpose The main treatment options of neurogenic bladder remains catheterization and long-term oral medications. Metabolic interventions have shown good therapeutic results in many diseases. To date, no studies have characterized the metabolites of the detrusor muscle during neurogenic bladder. Using metabolomics, new muscle metabolomic signatures were identified to reveal the temporal metabolic profile of muscle during disease progression. Methods We used 42 Sprague-Dawley rats (200±20 g, males) for T10 segmental spinal cord injury modeling and collected detrusor tissue and performed nontargeted metabolomics after sham surgery, 30-minute, 6-hour, 12-hour, 24-hour, 5-day, and 2-week postmodelling, to identify the dysregulated metabolic pathways and key metabolites. Results By comparing mzCloud, mzVault, MassList, we identified a total of 1,271 metabolites and enriched a total of 12 metabolism-related pathways with significant differences (P

Background: Oral squamous cell carcinoma (OSCC) is one of the most common types of cancer worldwide. Although overall losses of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) have been previously observed, a genome-wide, single-base-resolution, and simultaneous mapping of 5mC and 5hmC in OSCC is still unaccomplished. Similarly, the mechanism of how 5mC and 5hmC collectively lead to abnormal gene expression in OSCC is largely unexplored. Using parallel whole-genome bisulfite sequencing (WGBS) and whole-genome oxidative bisulfite sequencing (oxWGBS), we characterized 5mC- and 5hmC-profiles at single-nucleotide resolution in paired primary OSCC samples and their normal adjacent tissues (NATs). We also analyzed the effect of 5mC- and 5hmC-modifications on differential gene expression in OSCC using multi-omics analysis.Results: An overall reduction of both 5mC and 5hmC in various genomic regions have been observed in OSCC samples. At promoter regions, a total of 6,921 differentially methylated regions and 1,024 differentially hydroxymethylated regions were identified in OSCC. Interestingly, compared to bidirectional modification with 5mC and 5hmC, unidirectional modification with 5mC and 5hmC at the promoters is associated with bigger change in the gene expression. Additionally, genes bearing unidirectional modification with 5mC and 5hmC at the promoters are enriched in signaling pathways like cell proliferation, cell differentiation, and receptor tyrosine kinase pathway that are essential for the tumorigenesis. Finally, the grouped expression signature of top 20 genes bearing promoter-unidirectional-modification with 5mC and 5hmC tends to correlate with the clinical outcome of certain subtypes of head and neck squamous cell carcinoma.Conclusion: Using parallel WGBS and oxWGBS analyses, we observed an overall reduction of 5mC- and 5hmC-modifications at various genomic regions in OSCC. Unidirectional modification with 5mC and 5hmC at the promoters is associated with enhanced changes in gene expression in OSCC tissues. Furthermore, such differentially expressed genes bearing unidirectional modifications with 5mC and 5hmC at the promoters might have clinical relevance to the outcome of OSCC.

Mesenchymal stem cells (MSCs) are pluripotent stem cells derived from a variety of tissues, such as umbilical cord, fat, and bone marrow. Today, MSCs are widely recognized for their prominent anti-inflammatory properties in a variety of acute and chronic inflammatory diseases. In inflammatory diseases, monocytes/macrophages are an important part of the innate immune response in the body, and the alteration of the inflammatory phenotype plays a crucial role in the secretion of pro-inflammatory/anti-inflammatory factors, the repair of injured sites, and the infiltration of inflammatory cells. In this review, starting from the effect of MSCs on the monocyte/macrophage phenotype, we have outlined in detail the process by which MSCs influence the transformation of the monocyte/macrophage inflammatory phenotype, emphasizing the central role of monocytes/macrophages in MSC-mediated anti-inflammatory and damage site repair. MSCs are phagocytosed by monocytes/macrophages in various physiological states, the paracrine effect of MSCs and mitochondrial transfer of MSCs to macrophages to promote the transformation of monocytes/macrophages into anti-inflammatory phenotypes. We also review the clinical applications of the MSCs-monocytes/macrophages system and describe novel pathways between MSCs and tissue repair, the effects of MSCs on the adaptive immune system, and the effects of energy metabolism levels on monocyte/macrophage phenotypic changes.

Abstract Background Little is known about the association between the preoperative low-density lipoprotein cholesterol (LDL-C) level and prognosis in patients with renal cell carcinoma (RCC) after nephrectomy, and its prognostic value needs to be elucidated. Methods The clinical and follow-up data of 737 RCC patients who underwent nephrectomy were retrospectively analyzed. The optimal cut-off LDL-C level was determined using X-tile, and then patients were divided into low and high LDL-C groups. The association between LDL-C levels and survival of RCC patients was assessed using the Kaplan-Meier method and Cox regression analysis. Results The optimal cut-off LDL-C level was 1.93 mmol/L, and patients were divided into the low (≤ 1.93 mmol/L) and high LDL-C (> 1.93 mmol/L) groups. The Kaplan-Meier analysis showed that patients in the low LDL-C group had significantly shorter overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS) than those in the high LDL-C group (P = 0.001, P = 0.001, and P = 0.003, respectively). The COX univariate analysis showed that the preoperative LDL-C level was closely associated with OS, CSS, and RFS in RCC patients (P = 0.002, P = 0.003, and P = 0.005, respectively). The multivariate analysis showed that the preoperative LDL-C level was an independent factor for predicting survival (OS, CSS and RFS) in RCC patients after nephrectomy. The low preoperative LDL-C levels predicted worse OS (hazard ratio [HR]: 2.337; 95% confidence interval [CI]: 1.192–4.581; P = 0.013), CSS (HR: 3.347; 95% CI: 1.515–7.392; P = 0.003), and RFS (HR: 2.207; 95% CI: 1.178–4.132; P = 0.013). Conclusions The preoperative LDL-C level is an independent factor for the prognosis of RCC patients after nephrectomy, and low preoperative LDL-C levels predict worse survival (OS, CSS, and RFS).

Abstract Background Neutrophil extracellular traps (NETs) is the key means for neutrophils to resist bacterial invasion. Sepsis is a systemic inflammatory response syndrome caused by infection. Methods In our study, qRT-PCR was used to detect the gene expression in neutrophils, Western blot was used to detect the protein expression in mouse tissues and neutrophils, flow cytometry was used to detect the purity of neutrophils in the whole blood and immunofluorescence was used to detect the NETs formation. Results In this study, we analyzed the NETs formation in the blood of patients with sepsis. The results showed that a large number of NETs appeared. And the expression of GPR109A in neutrophils of patients with sepsis was significantly up regulated. Then we collected neutrophils from WT mice and GPR109A−/− mice and found that GPR109A knockout could significantly inhibit the early NETs formation of neutrophils. The results also showed that knockout of GPR109A or inhibition of the NETs formation could increase the inflammatory response of liver, spleen, lung and kidney in mice, thus affecting the disease process of sepsis. Then we observed the death of mice in 16 days. The results showed that inhibiting the NETs formation could significantly affect the early mortality of mice, while knocking out GPR109A could directly affect the mortality of the whole period. Conclusions This study confirmed the regulatory effect of GPR109A on early NETs formation for the first time, and provided a new target for the treatment of sepsis.

Objectives: Bone marrow-derived mesenchymal stem cells (BMSCs) are considered to have potential clinical application value in the treatment of acute lung injury (ALI). Myeloid-derived growth factor (MYDGF) can promote the proliferation of stem cell. We hypothesized that MYDGF may play a role in reducing lung injury in vitro and in vivo through bone marrow mesenchymal stem cells. Methods: An in vitro model of lipopolysaccharide (LPS)(MLE-12) was established, which was divided into five groups: A: MLE-12; B: MLE-12+LPS; C: MLE-12+LPS + BMSCs; D: MLE-12+LPS + MYDGF; and E: MLE-12+LPS + BMSCs + MYDGF. A Cell Counting Kit-8 was used to detect the OD value. And an ALI model was constructed by inducing mice with a lipopolysaccharide. Forty male Balb/c mice were randomly divided into five groups: A control group; B: model group; C: LPS + BMSCs; D: LPS + MYDGF; E: LPS +BMSCs +MYDGF. Specimens were collected after 24 h. Hematoxylin-eosin (HE)-staining was performed on the tissue sections. The protein concentration in the alveolar lavage fluid was measure by bicinchoninic acid (BCA). The NF-κB, p-Akt, Bax, and Bcl-2 protein expression was detected through Western blotting, and Enzyme linked immunosorbent assay (ELISA) was used to measure the expression of serum interleukin-6, interleukin-10, and TNF-α. Results: Compared with the model group, BMSCs and MYDGF can alleviate the ALI induced by lipopolysaccharide in vitro and vivo ( p < .05). Conclusion: We found that the combined treatment effect of MYDGF and BMSCs was better than using MYDGF or BMSCs alone. We speculate that a pretreatment with MYDGF after ALI in mice may improve the survival and growth of transplanted MSCs, thereby improving the curative effect of cell transplantation.

Abstract In major depressive disorder (MDD) patients, nonsuicidal self-injury (NSSI) is a common comorbidity, and it is important to clarify the underlying neurobiology. Here, we investigated the association of NSSI with brain function and structure in MDD patients. A total of 260 MDD patients and 132 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging and three-dimensional T1-weighted structural scans. NSSI behaviour was assessed through interviews. Voxel-based morphometry analysis (VBM), regional homogeneity analysis (ReHo), functional connectome topology properties and network-based statistics were used to detect the differences in neuroimaging characteristics. Finally, the random forest method was used to evaluate whether these factors could predict NSSI in MDD. Compared with HCs, MDD patients with a history of NSSI showed significant right putamen grey matter volume (GMV), right superior orbital frontal cortex ReHo, left pallidum degree centrality, and putamen-centre function network differences. Compared to MDD subjects without NSSI, those with past NSSI showed significant right superior temporal gyrus (STG) GMV, right lingual gyrus ReHo, sigma and global efficiency, and cerebellum-centre function network differences. The right STG GMV and cerebellum-centre function network were more important than other factors in predicting NSSI behaviour in MDD. MDD patients with a history of NSSI have dysregulated spontaneous brain activity and structure in regions related to emotions, pain regulation, and the somatosensory system. Importantly, right STG GMV and cerebellar loops may play important roles in NSSI in MDD patients.

Abstract The perivascular epithelioid cell tumor (PEComa) is a rare tumor of interstitial origin characterized by several immunological and muscle cell markers. The clear cell sugar tumor (CCST) of the lung is a type of PEComa defined by thin cell walls and high levels of glycogen in the cytoplasm. We herein reported the case of a 48‐year‐old male with a recurrence of lung CCST. The preoperative diagnosis of the lung mass was performed by percutaneous needle biopsy. During the thoracoscopic resection, multiple adhesions in the thoracic cavity were described. The tumor invaded the chest wall, and the boundaries between the tumor and surrounding normal tissues were unclear. The mediastinal lymph nodes were significantly enlarged. No relevant gene mutations were detected. After concomitant chemoradiotherapy, the patient's condition was stable. We also conducted a literature review and discussed the overall findings.

Wave energy is a kind of renewable and clean energy. When waves meet the breakwaters, wave energy reflection will happen. In this paper, the modified mild slope equation for waves propagating over the permeable seabed is introduced, and the finite difference model to solve the equation is set up. The accuracy and applicability of the model is verified with Zeng et al’s analytical solution for wave reflection by the rectangular Bragg breakwaters on the impermeable seabed. Furthermore, in case of a permeable seabed, the effects of the seabed permeability, the bar width, the bar number and the submergence of the bars on wave reflection coefficient, as well as the difference with the case of an impermeable seabed, is studies in details. The results show the reflection coefficient of the Bragg resonant reflection increases with the increase in the bar number, but decreases with the increase in the seabed permeability and the submergence of the bars. When the bar number increases from 1 to 8, the Bragg resonance reflection coefficient increases from 0.146 to 0.772. When the permeability parameter of the seabed increases from 0.005 s to 0.03 s, the coefficient decreases from 0.403 to 0.347. When the bar submergence increases from 0.5 to 0.875, the coefficient decreases from 0.842 to 0.195. Moreover, there exists a particular value of the bar width, that is half of the distance between two adjacent rectangular bars that maximizes the wave energy reflection.

Abstract As sessile organisms, plants encounter diverse invasions from pathogens including viruses. To survive and thrive, plants have evolved multilayered defense mechanisms to combat virus infection. RNAi, also known as RNA silencing, is an across-kingdom innate immunity and gene regulatory machinery. Molecular framework and crucial roles of RNAi in antiviral defense have been well-characterized. However, it is largely unknown that how RNAi is transcriptionally regulated to initiate, maintain and enhance cellular silencing under normal or stress conditions. Recently, insights into the transcriptional and post-transcriptional regulation of RNAi-related genes in different physiological processes have been emerging. In this review, we integrate these new findings to provide updated views on how plants modulate RNAi machinery at the (post-) transcriptional level to respond to virus infection.

Summary: Neuropathic pain (NeP) remains a significant clinical challenge owing to insufficient awareness of its pathological mechanisms. We elucidated the aberrant metabolism of the cerebral cortex in NeP induced by the chronic constriction injury (CCI) using metabolomics and proteomics analyses. After CCI surgery, the values of MWT and TWL markedly reduced and maintained at a low level. CCI induced the significant dysregulation of 57 metabolites and 31 proteins in the cerebral cortex. Integrative analyses showed that the differentially expressed metabolites and proteins were primarily involved in alanine, aspartate and glutamate metabolism, GABAergic synapse, and retrograde endocannabinoid signaling. Targeted metabolomics and western blot analysis confirmed the alterations of some key metabolites and proteins in endogenous pain-modulatory system. In conclusion, our study revealed the alterations of endocannabinoids system and purinergic system in the CCI group, and provided a novel perspective on the roles of endogenous pain-modulatory system in the pathological mechanisms of NeP.

Abstract The cell adhesion molecule nectin3 and its presynaptic partner nectin1 have been linked to early-life stress-related cognitive disorders, but how the nectin1-nectin3 system contributes to stress-induced neuronal, circuit, and cognitive abnormalities remains to be studied. Here we show that in neonatally stressed male mice, temporal order and spatial working memories, which require the medial entorhinal cortex (MEC)-CA1 pathway, as well as the structural integrity of CA1 pyramidal neurons were markedly impaired in adulthood. These cognitive and structural abnormalities in stressed mice were associated with decreased nectin levels in entorhinal and hippocampal subregions, especially reduced nectin1 level in the MEC and nectin3 level in the CA1. Postnatal suppression of nectin1 but not nectin3 level in the MEC impaired spatial memory, whereas conditional inactivation of nectin1 from MEC excitatory neurons reproduced the adverse effects of early-life stress on MEC-dependent memories and neuronal plasticity in CA1. Our data suggest that early-life stress disrupts presynaptic nectin1-mediated interneuronal adhesion in the MEC-CA1 pathway, which may in turn contribute to stress-induced synaptic and cognitive deficits.

Temperature control is a critical aspect for the semiconductor material growth of the Molecular Beam Epitaxy system. The growth rate depends on the temperature of the beam source, and the quality of epi-layers heavily depends on the temperature of the substrate. In this paper, we reported an intelligent temperature control algorithm based on the BP neural network, which is specially optimized for the Molecular Beam Epitaxy system. After training the BP neural network by the collected temperature data of the Molecular Beam Epitaxy, the intelligent temperature control algorithm keeps the temperature error within 0.1°C. Moreover, this intelligent algorithm in the field of Molecular Beam Epitaxy achieves a better control effect, reduces the regulation time of the system and makes the system overshoot to zero.

Abstract Aims The aim of this study was to analyze the sensitivity and specificity of a shortened Hasegawa Dementia Scale Revised (shortened HDS‐R) questionnaire and explore its utility for the rapid screening and diagnosis of Alzheimer’s disease (AD). Methods We included 113 patients over the age of 60 years who visited our hospital from June 2018 to January 2021 including 70 subjects with AD and 43 healthy subjects. AD was diagnosed in accordance with the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and the standard HDS‐R questionnaire was used as a neuropsychological examination. The shortened HDS‐R questionnaire was composed of the first seven subdomains (1 to 7) of the HDS‐R questionnaire and excluded subdomains 8 and 9. Magnetic resonance imaging (MRI) was performed to calculate the degree of atrophy of the whole brain, hippocampus, and parahippocampal gyrus. Results The cumulative contribution ratio of subdomains 1 to 7 of the HDS‐R questionnaire was as high as 94%, indicating that the construct validity of the shortened HDS‐R was very good. The correlation coefficient of the total scores of the shortened HDS‐R and the HDS‐R was 0.96, indicating that the criterion‐related validity was also very good. Furthermore, the shortened HDS‐R was significantly negatively correlated with the degree of atrophy in the whole brain, hippocampus, and parahippocampal gyrus, indicating that its concurrent validity was very good in relation to imaging parameters. Cronbach’s α coefficient of the shortened HDS‐R was 0.76, and the correlation coefficient of the item‐total correlation analysis was between 0.68 and 0.76, indicating that this questionnaire has high internal consistency and reliability. The total shortened HDS‐R score of the normal group (17.0 ± 1.9) was significantly higher than that of the AD group (8.6 ± 3.8), demonstrating that the total shortened HDS‐R score can be used to identify healthy individuals and patients with AD. When the cutoff score was 14 of 15, the sensitivity was 92.9% and the specificity was 88.4%. The diagnostic ability of the shortened HDS‐R was 91.2%, which indicates that it is similar to the full HDS‐R questionnaire as an AD screening tool. Conclusion As a neuropsychological examination questionnaire for the screening and diagnosis of AD, the shortened HDS‐R had very high validity and reliability. Its sensitivity, specificity, and diagnostic ability were similar to those of the gold standard HDS‐R; therefore, it can be considered a concise and useful questionnaire for AD screening and diagnosis in the older population.

Background: There is a high correlation between the risk of major depressive disorder (MDD) and adverse childhood experiences (ACEs) such as adverse parenting (AP). While there appears to be an association between ACEs and changes in brain structure and function, there have yet to be multimodal neuroimaging studies of associations between parenting style and brain developmental changes in MDD patients. To explore the effect of AP on brain structure and function. Methods: In this cross-sectional study, 125 MDD outpatients were included in the study and divided into the AP group and the optimal parenting (OP) group. Participants completed self-rating scales to assess depressive severity, symptoms, and their parents’ styles. They also completed magnetic resonance imaging within one week of filling out the instruments. The differences between groups of gender, educational level, and medications were analyzed using the chi-squared test and those of age, duration of illness, and scores on scales using the independent samples t-test. Differences in gray matter volume (GMV) and resting-state functional connectivity (RS-FC) were assessed between groups. Results: AP was associated with a significant increase in GMV in the right superior parietal lobule (SPL) and FC between the right SPL and the bilateral medial superior frontal cortex in MDD patients. Limitations: The cross-cultural characteristics of AP will result in the lack of generalizability of the findings. Conclusions: The results support the hypothesis that AP during childhood may imprint the brain and affect depressive symptoms in adulthood. Parents should pay attention to the parenting style and avoid a style that lacks warmth.

Summary: Wounding evokes transient increases in cytosolic calcium (Ca2+) concentration. Visualizing real-time Ca2+ flux provides new insights into Ca2+-signaling pathways. Here, we outline a protocol to detect insect feeding-induced Ca2+ flux elevation in Nicotiana benthamiana leaves based on the GCaMP3 reporter system by Leica fluorescence stereo microscopes (LFSM). LFSM combines super-fast manual screening with high-end imaging capabilities. Through this protocol, we can clearly observe the calcium flow after aphid’s piercing-sucking. Additionally, we describe a protocol to quantify Ca2+ level using LFSM.For complete details on the use and execution of this protocol, please refer to Wang et al. (2021).

Heat stress (HS) in summer will seriously affect the health and performance of dairy cows. To alleviate the injury to dairy cows caused by HS, we added the rumen-bypassed tributyrin to the feed. We determined whether cows were in a heat-stressed environment by testing the temperature humidity index in the morning, at noon, and in the evening. The detection of anal temperature and respiratory frequency further proved the HS state of the dairy cows. The quantificational real time PCR results showed that tributyrin could significantly reduce the relative expression of tumor necrosis factor α, interleukin 1β, and Interleukin 6. Western blot results showed that tributyrin could alleviate the lymphocyte inflammatory response by inhibiting the mitogen-activated protein kinase and nuclear factor-кB signaling pathways. To further detect the effect of tributyrin on HS in dairy cows, routine biochemical and blood tests were carried out. The results showed that the contents of aspartate aminotransferase, total bilirubin, creatinine, albumin, and globulin were significantly reduced by tributyrin. The results showed that tributyrin could significantly alleviate the liver and kidney injury induced by heat stress in dairy cows. Moreover, tributyrin could also significantly reduce the numbers of intermediate cells and increase the level of hemoglobin. Tributyrin could also improve the performance of dairy cows. These results suggested that tributylglycerol may have a positive effect on breast health of dairy cows. In conclusion, these results indicated that tributyrin could relieve HS and increase the production performance of dairy cows by reducing the inflammatory responses of lymphocytes.

Abstract The occurrence of cardiac surgery-associated acute kidney injury (CSA-AKI) increases hospital stay and mortality. MicroRNAs has a crucial role in AKI. This objective of the current study is to explore the function of hsa-miR-494-3p in inflammatory response in human kidney tubular epithelial (HK2) cells with hypoxia/reoxygenation. According to KDIGO standard, patients after cardiac surgery with cardiopulmonary bypass were divided into two groups: AKI (n = 10) and non-AKI patients (n = 8). HK2 were raised in the normal and hypoxia/reoxygenation circumstances and mainly treated by overexpression ofmiR-494-3p and HtrA3. The relationship between miR-494-3p and HtrA3 was determined by dual-luciferase reporter assay. Our result showed that Hsa-miR-494-3p was elevated in the serum of patients with CSA-AKI, and also induced in hypoxic reoxygenated HK2 cells. Hsa-miR-494-3p also increased a hypoxia-reoxygenation induced inflammatory response in HK2 cells. Moreover, as a target gene of miR-494-3p, overexpression of HtrA3 downregulated the hypoxia-reoxygenation induced inflammatory response in HK2 cells. Overexpression of hsa-miR-494-3p-induced inflammatory response was inhibited by overexpression of HtrA3. Collectively, we identified that hsa-miR-494-3p, a miRNA induced in both circulation of AKI patients and hypoxia-reoxygenation-treated HK2 cells, enhanced renal inflammation by targeting HtrA3, which may suggest a possible role as a new therapeutic target for CSA-AKI.

The reliability-centered maintenance (RCM) analysis method and the RCM implementation process for dynamic equipment in petrochemical ammonia-related systems were introduced. The operation situation, key roles, and potential risks were clarified through data analysis and system screening in ammonia dynamic equipment, and FMEA was used to analyze the failure mode. Then the risk of each failure mode was managed hierarchically, a suitable risk assessment standard and risk matrix were developed for the enterprise, and a suitable maintenance strategy was formulated for the risk level of each failure mode.

Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease characterized by pulmonary vascular remodeling and right heart enlargement the pathogenesis of PAH is complicated; no biologic-based therapy is available for the treatment of PAH, but recent studies suggest that inflammatory response and abnormal proliferation of pulmonary artery smooth muscle cells are the main pathogenic mechanism, while the role of immune-related long non-coding RNAs (lncRNAs) remains unclear. The aim of this study was to systematically analyze immune-related lncRNAs in PAH. Here, we downloaded a publicly available microarray data from PAH and control patients (GSE113439). A total of 243 up-regulated and 203 down-regulated differentially expressed genes (DEGs) were screened, and immune-related DEGs were further obtained from ImmPort. The immune-related lncRNAs were obtained by co-expression analysis of immune-related mRNAs. Then, immune-related lncRNAs-mRNAs network including 2 lncRNAs and 6 mRNAs was constructed which share regulatory miRNAs and have significant correlation. Among the lncRNA-mRNA pairs, one pair (JPX-RABEP1) was verified in the validating dataset GSE53408 and PAH mouse model. Furthermore, the immune cell infiltration analysis of the GSE113439 dataset revealed that the JPX-RABEP1 pair may participate in the occurrence and development of PAH through immune cell infiltration. Together, our findings reveal that the lncRNA-mRNA pair JPX-RABEP1 may be a novel biomarker and therapeutic target for PAH.

Touch can positively modulate cognitive performance and emotional response. Here the authors demonstrate that enriched tactile experience improves memory and reduces anxiety in adult mice by remodelling the pathway from the primary somatosensory cortex to the dentate gyrus.

The lasing characteristics of InP-based InAs/In0.53Ga0.47As quantum well (QW) lasers with different ridge widths are investigated. Two groups of lasers are grown for comparison, one with active triangular QW regions and the other with rectangular QW regions. Their output powers, characteristic temperatures (T0), external differential quantum efficiencies (ηd) and junction temperatures (Tj) are analyzed and compared. The parameter of ridge width is found to play an important role in the performance of the lasers. In triangular QW lasers, by broadening the ridge width from 8 to 12 μm, output power and ηd of the lasers are decreased for the temperature range of 100–320 K due to heating effect. But by broadening the ridge width from 8 to 100 μm in rectangular QW lasers, output power has about 3.5 time increase at 100 K and ηd also has a little increase for temperatures from 100 to 180 K due to much larger emission area and much faster heat dissipation. Tj, the real temperature of the active region, is also found to have accelerated increase at high injection current and heat sink temperature. Besides, compared to the rectangular QW laser of the same ridge width, the improved thermal performance of triangular QW laser is also demonstrated.

Smoking is an important factor in the pathogenesis of chronic obstructive pulmonary disease (COPD), which is commonly characterised by cellular senescence and inflammation. Recently, miR-200b has emerged as an important target to cure lung disease; however, the function of miR-200b in reducing cellular senescence and inflammatory responses has not been reported. In this study, we found that miR-200b was downregulated in the lungs of COPD model mice, and its expression is correlated with cellular senescence and inflammatory responses. We hypothesised that miR-200b may be a potential novel therapy for treating COPD. We performed senescence-Associated-β-galactosidase (SA-β-GAL) staining, western blot, qRT-PCR and ELISA; our data suggested that miR-200b is an anti-aging factor in the lungs that is involved in inflammatory responses. We also confirmed that ZEB2 (Zinc finger E-box binding homeobox 2) is a target gene of miR-200b using luciferase reporter assay. In addition, we verified the function of ZEB2 in cellular senescence and inflammatory responses through transfection experiments. Moreover, we found that the protective effects of miR-200b are inhibited when cells overexpress the ZEB2 protein. In conclusion, our results suggest that miR-200b may attenuate cellular senescence and inflammatory responses by targeting ZEB2 in pulmonary emphysema.

The treatment of cancer of unknown primary (CUP) is a huge challenge for clinicians. Gene expression profiling can help identify the tissue origin of tumors by detecting the expression levels of specific genes in tumor tissues. Herein, we report four CUP cases. All of them have been successfully identified with the corresponding primary tumor sites through gene expression profiling analysis. Then all patients received accurate treatment, providing reference to guide therapeutic decisions to treat CUP tumors in the future.

Objective: We aimed to: (1) explore the risk factors that affect the prognosis of cardiac surgery-associated acute kidney injury (CS-AKI) in patients undergoing renal replacement therapy (RRT) and (2) investigate the predictive value of the Acute Physiology and Chronic Health Evaluation (APACHE) III score, Sequential Organ Failure Assessment (SOFA) score, and Vasoactive-Inotropic Score (VIS) for mortality risk in patients undergoing RRT.Methods: Data from patients who underwent cardiac surgery from January 2015 through February 2021 were retrospectively reviewed to calculate the APACHE III score, SOFA score, and VIS on the first postoperative day and at the start of RRT. Various risk factors influencing the prognosis of the patients during treatment were evaluated; the area under the receiver operating characteristics curve (AUCROC) was used to measure the predictive ability of the three scores. Independent risk factors influencing mortality were analyzed using multivariable binary logistic regression.Results: A total of 90 patients were included in the study, using 90-day survival as the end point. Of those patients, 36 patients survived, and 54 patients died; the mortality rate reached 60%. At the start of RRT, the AUCROC of the APACHE III score was 0.866 (95% CI: 0.795–0.937), the VIS was 0.796 (95% CI: 0.700–0.892), and the SOFA score was 0.732 (95% CI: 0.623–0.842). The AUCROC-value of the APACHE III score on the first postoperative day was 0.790 (95% CI: 0.694–0.885). After analyzing multiple factors, we obtained the final logistic regression model with five independent risk factors at the start of RRT: a high APACHE III score (OR: 1.228, 95% CI: 1.079–1.397), high VIS (OR: 1.147, 95% CI: 1.021–1.290), low mean arterial pressure (MAP) (OR: 1.170, 95% CI: 1.050–1.303), high lactate value (OR: 1.552, 95% CI: 1.032–2.333), and long time from AKI to initiation of RRT (OR: 1.014, 95% CI: 1.002–1.027).Conclusion: In this study, we showed that at the start of RRT, the APACHE III score and the VIS can accurately predict the risk of death in patients undergoing continuous RRT for CS-AKI. The APACHE III score on the first postoperative day allows early prediction of patient mortality risk. Predictors influencing patient mortality at the initiation of RRT were high APACHE III score, high VIS, low MAP, high lactate value, and long time from AKI to the start of RRT.

Ischemic cardiomyopathy (ICM), which increases along with aging, is the leading cause of heart failure. Currently, immune response is believed to be critical in ICM whereas the roles of immune-related lncRNAs remain vague. In this study, we aimed to systematically analyze immune-related lncRNAs in the aging-related disease ICM. Here, we downloaded publicly available RNA-seq data from ischemic cardiomyopathy patients and non-failing controls (GSE116250). Weighted gene co-expression network analysis (WGCNA) was performed to identify key ICM-related modules. The immune-related lncRNAs of key modules were screened by co-expression analysis of immune-related mRNAs. Then, a competing endogenous RNA (ceRNA) network, including 5 lncRNAs and 13 mRNAs, was constructed using lncRNA–mRNA pairs which share regulatory miRNAs and have significant correlation. Among the lncRNA–mRNA pairs, one pair (AC011483.1-CCR7) was verified in another publicly available ICM dataset (GSE46224) and ischemic cell model. Further, the immune cell infiltration analysis of the GSE116250 dataset revealed that the proportions of monocytes and CD8+ T cells were negatively correlated with the expression of AC011483.1-CCR7, while plasma cells were positively correlated, indicating that AC011483.1-CCR7 may participate in the occurrence and development of ICM through immune cell infiltration. Together, our findings revealed that lncRNA–mRNA pair AC011483.1-CCR7 may be a novel biomarker and therapeutic target for ICM.

Stable and resilient materials are in great demand for electromagnetic interference (EMI) shielding applications under extreme conditions. Here we present a facile method that could tailor and strengthen the pore structure of carbon nanotube (CNT) foams to obtain highly effective and reliable EMI absorbers that maintain their superior EMI effectiveness under heavy mechanical deformation and extremely high temperature. The hierarchical macro-to-micro pore structure and properties of CNT foam were tailored in a wide range via a secondary chemical vapor deposition (CVD) process. Benefiting from the multi-level reflection in hierarchical pore structures, the optimized CNT foam presents a high shielding efficiency (SE) of 84 dB and a specific SE (SSE/t) of 5.6 × 104 dB·cm2·g-1 in X-band. The tailoring process also provides outstanding stability and mechanical resilience, leading to 83.8% EMI SE maintained after 1000 compressive cycles. Moreover, the foams can keep 76.5% EMI SE after 30 min of 1000°C thermal-destruction process (in argon atmosphere). All these features demonstrate the potential of using the optimized CNT foam as an EMI shielding material under extreme conditions. These findings have essential inspiration for pore engineering in CNT-based EMI shielding materials, giving further guidance for the design of EMI shielding materials used in harsh conditions.

Scientific applications continue to grow and produce extremely large amounts of data, which require efficient compression algorithms for long-term storage. Compression errors in scientific applications can have a deleterious impact on downstream processing. Thus, it is crucial to preserve all the “known” Quantities of Interest (QoI) during compression. To address this issue, most existing approaches guarantee the reconstruction error of the original data or primary data (PD), but cannot directly control the problem of preserving the QoI. In this work, we propose a physics-informed compression technique that is composed of two parts: (i) reduction of the PD with bounded errors and (ii) preservation of the QoI. In the first step, we combine tensor decompositions, autoencoders, product quantizers, and error-bounded lossy compressors to bound the reconstruction error at high levels of compression. In the second step, we use constraint satisfaction post-processing followed by quantization to preserve the QoI. To illustrate the challenges of reducing the reconstruction errors of the PD and QoI, we focus on simulation data generated by a large-scale fusion code, XGC, which can produce tens of petabytes in a single day. The results show that our approach can achieve a high compression amount while accurately preserving the QoI within scientifically acceptable bounds.

Ischemic cardiomyopathy (ICM) caused by coronary artery disease always leads to myocardial infarction and heart failure. Identification of novel transcriptional regulators in ICM is an effective method to establish new diagnostic and therapeutic strategies. In this study, we used two RNA-seq datasets and one microarray dataset from different studies, including 25 ICM and 21 non-failing control (NF) samples of human left ventricle tissues for further analysis. In total, 208 differentially expressed genes (DEGs) were found by combining two RNA-seq datasets with batch effects removed. GO and KEGG analyses of DEGs indicated that the response to wounding, positive regulation of smooth muscle contraction, chromatin, PI3K-Akt signaling pathway, and transporters pathways are involved in ICM. Simple Enrichment Analysis found that NFIC-binding motifs are enriched in promoter regions of downregulated genes. The Gene Importance Calculator further proved that NFIC is vital. NFIC and its downstream genes were verified in the validating microarray dataset. Meanwhile, in rat cardiomyocyte cell line H9C2 cells, two genes (Tspan1 and Hopx) were confirmed, which decreased significantly along with knocking down Nfic expression. In conclusion, NFIC participates in the ICM process by regulating TSPAN1 and HOPX. NFIC and its downstream genes may be marker genes and potential diagnostic and therapeutic targets for ICM.

Abstract Background The glycogen synthase kinase 3/shaggy kinase (GSK3) is a serine/threonine kinase with important roles in animals. Although GSK3 genes have been studied for more than 30 years, plant GSK genes have been studied only since the last decade. Previous research has confirmed that plant GSK genes are involved in diverse processes, including floral development, brassinosteroid signaling, and responses to abiotic stresses. Result In this study, 20, 15 (including 5 different transcripts) and 10 GSK genes were identified in G. hirsutum, G. raimondii and G. arboreum, respectively. A total of 65 genes from Arabidopsis, rice, and cotton were classified into 4 clades. High similarities were found in GSK3 protein sequences, conserved motifs, and gene structures, as well as good concordance in gene pairwise comparisons (G. hirsutum vs. G. arboreum, G. hirsutum vs. G. raimondii, and G. arboreum vs. G. raimondii) were observed. Whole genome duplication (WGD) within At and Dt sub-genomes has been central to the expansion of the GSK gene family. Furthermore, GhSK genes showed diverse expression patterns in various tissues. Additionally, the expression profiles of GhSKs under different stress treatments demonstrated that many are stress-responsive genes. However, none were induced by brassinolide treatment. Finally, nine co-expression sub-networks were observed for GhSKs and the functional annotations of these genes suggested that some GhSKs might be involved in cotton fiber development. Conclusion In this present work, we identified 45 GSK genes from three cotton species, which were divided into four clades. The gene features, muti-alignment, conversed motifs, and syntenic blocks indicate that they have been highly conserved during evolution. Whole genome duplication was determined to be the dominant factor for GSK gene family expansion. The analysis of co-expressed sub-networks and tissue-specific expression profiles suggested functions of GhSKs during fiber development. Moreover, their different responses to various abiotic stresses indicated great functional diversity amongst the GhSKs. Briefly, data presented herein may serve as the basis for future functional studies of GhSKs.

Purpose - Extreme high temperatures are a significant feature of global climate change and have become more frequent and intense in recent years. These pose a significant threat to both human health and economic activity, and thus are receiving increasing research attention. Understanding the hazards posed by extreme high temperatures are important for selecting intervention measures targeted at reducing socioeconomic and environmental damage. Design/methodology/approach - In this study, detrended fluctuation analysis is used to identify extreme high-temperature events, based on homogenized daily minimum and maximum temperatures from nine meteorological stations in a major grassland region, Hulunbuir, China, over the past 56 years. Findings - Compared with the commonly used functions, Weibull distribution has been selected to simulate extreme high-temperature scenarios. It has been found that there was an increasing trend of extreme high temperature, and in addition, the probability of its indices increased significantly, with regional differences. The extreme high temperatures in four return periods exhibited an extreme low hazard in the central region of Hulunbuir, and increased from the center to the periphery. With the increased length of the return period, the area of high hazard and extreme high hazard increased. Topography and anomalous atmospheric circulation patterns may be the main factors influencing the occurrence of extreme high temperatures. Originality/value - These results may contribute to a better insight in the hazard of extreme high temperatures, and facilitate the development of appropriate adaptation and mitigation strategies to cope with the adverse effects.

Substantial evidence indicates that brain-derived neurotrophic factor (BDNF) plays an important role in tumorigenesis, in addition to its primary role in neuronal activity. Gastrointestinal stromal tumors (GISTs), which are the most common mesenchymal neoplasms of the gastrointestinal tract, contain multiple types of tumor-infiltrating lymphocytes (TILs) that express relevant immune checkpoint proteins. However, no data have been reported on the role of BDNF in GISTs. This study aimed to investigate the expression pattern and prognostic value of BDNF in GIST patients with different degrees of risk, as well as the relationship between BDNF expression and immune checkpoints. Immunohistochemistry (IHC) demonstrated that higher BDNF expression was more likely to be present in high-risk patients and suggested a poor prognosis. A similar phenomenon was demonstrated in plasma. Even more interesting was that a positive correlation was present between BDNF and PD-L1+ expression on TILs. Moreover, high BDNF expression levels in combination with a high PD-L1+ TIL count predict extremely poor survival. The combination of BDNF expression and TIL PD-L1+ expression as a single biomarker was a powerful significant independent predictor of prognosis. Taken together, BDNF expression may serve as a significant prognostic factor, as the combination of BDNF expression and the PD-L1+ TIL subset led to superior prediction of GIST prognosis. Furthermore, our research coupled a neurotrophin with immunity, which provides novel evidence of neural and immune regulation in a clinical study of GIST.

Background Cancer immunotherapy has evolved from interferon-alpha (IFNα) and interleukin-2 in the 1980s to CTLA-4 and PD-1/PD-L1 checkpoint inhibitors (CPIs), the latter highlighting the importance of enhancing T-cell functions. While the search for novel immunomodulatory pathways continues, combination therapies augmenting multiple pathways can also increase efficacy. The association of autoimmune-related adverse events with clinical efficacy following CPI treatment has been inferred and suggests that breaking tolerance thresholds associated with autoimmunity may affect host immune responses for effective cancer immunotherapy.Results Here, we show that loss of autoimmune associated PTPN22, a key desensitization node for multiple signaling pathways, including IFNα receptor (IFNAR) and T-cell receptor, can augment tumor responses. Implantation of syngeneic tumors in Ptpn22-/- mice led to expansion and activation of peripheral and intratumoral T cells and, in turn, spontaneous tumor regression as well as enhanced responses in combination with anti-PD-L1 treatment. Using genetically modified mice expressing a catalytically inactive PTPN22 or the autoimmunity-associated human single-nucleotide polymorphism variant, augmentation of antitumor immunity was dependent on PTPN22 phosphatase activity and partially on its adaptor functions. Further, antitumor responses were dependent on both CD4+ and CD8+T cells and, in part, IFNAR function. Finally, we demonstrate that the autoimmune susceptibility Ptpn22(C1858T) variant is associated with lower risk of developing non-melanoma skin cancers, improved overall survival and increased risk for development of hyperthyroidism or hypothyroidism following atezolizumab (anti-PD-L1) treatment.Conclusions Together, these data suggest that inhibition of PTPN22 phosphatase activity may provide an effective therapeutic option for cancer immunotherapy and that exploring genetic variants that shift immune tolerance thresholds may serve as a paradigm for finding new cancer immunotherapy targets.

Translanguaging literature has broadly discussed translanguaging as fostering expressive and creative interactions within classroom contexts. Often overlooked, however, are the responses of students who are encouraged to translanguage in spaces they previously deemed to be reserved for the dominant language only. Using Linguistic Ethno-graphy, we investigate the interactions of eight Chinese university students in two classroom settings at an Australian university. We examine how explicit or implicit English only norms at this university, combined with students' beliefs about English use, affect translanguaging practices and how English as an additional language (LX) users incorporate various resources, including spatial repertoires, peer support, and silence, to varying degrees of success within two different classrooms. The pedagogical implications of this examination point toward academics needing to embrace and legitimize translanguaging practices, not only at classroom level, but at course, university and policy level. Teachers in pre-tertiary English language courses also need to incorporate such practices into their classrooms if EAL/D students are to be convinced of the legitimacy of translanguaging in the university classroom.

Abstract Background WUSCHEL-related homeobox (WOX) family members play significant roles in plant growth and development, such as in embryo patterning, stem-cell maintenance, and lateral organ formation. The recently published cotton genome sequences allow us to perform comprehensive genome-wide analysis and characterization of WOX genes in cotton. Results In this study, we identified 21, 20, and 38 WOX genes in Gossypium arboreum (2n = 26, A2), G. raimondii (2n = 26, D5), and G. hirsutum (2n = 4x = 52, (AD)t), respectively. Sequence logos showed that homeobox domains were significantly conserved among the WOX genes in cotton, Arabidopsis, and rice. A total of 168 genes from three typical monocots and six dicots were naturally divided into three clades, which were further classified into nine sub-clades. A good collinearity was observed in the synteny analysis of the orthologs from At and Dt (t represents tetraploid) sub-genomes. Whole genome duplication (WGD) and segmental duplication within At and Dt sub-genomes played significant roles in the expansion of WOX genes, and segmental duplication mainly generated the WUS clade. Copia and Gypsy were the two major types of transposable elements distributed upstream or downstream of WOX genes. Furthermore, through comparison, we found that the exon/intron pattern was highly conserved between Arabidopsis and cotton, and the homeobox domain loci were also conserved between them. In addition, the expression pattern in different tissues indicated that the duplicated genes in cotton might have acquired new functions as a result of sub-functionalization or neo-functionalization. The expression pattern of WOX genes under different stress treatments showed that the different genes were induced by different stresses. Conclusion In present work, WOX genes, classified into three clades, were identified in the upland cotton genome. Whole genome and segmental duplication were determined to be the two major impetuses for the expansion of gene numbers during the evolution. Moreover, the expression patterns suggested that the duplicated genes might have experienced a functional divergence. Together, these results shed light on the evolution of the WOX gene family, and would be helpful in future research.

Paeoniflorin (PF) is the primary component of total glucosides of paeony (TGP). It exerts multiple effects, including immunoregulatory and anti-inflammatory effects. Our previous study has found that PF has a remarkable renal-protective effect in diabetic mice, but exact mechanism has not been clarified. This study mainly explores whether PF affects macrophage infiltration and activation in diabetic kidney through TLR4 pathway. Thus, this study was conducted to investigate the effect of PF on a streptozotocin (STZ)-induced experimental DN model. The results suggested that the onset and clinical symptoms of DN in mice were remarkably ameliorated after the administration of PF. Moreover, the number of infiltrating macrophages in the mouse kidneys was also markedly decreased. Instead of inhibiting the activation of macrophages directly, PF could influence macrophages by suppressing iNOS expression as well as the production of TNF-α, IL-1β, and MCP-1 both in vivo and in vitro. These effects might be attributable to the inhibition of the TLR4 signaling pathway. The percentage of M1-phenotype cells as well as the mRNA levels of iNOS, TNF-α, IL-1β, and MCP-1 were downregulated when PF-treated polarized macrophages were cultured under conditions of high glucose (HG) levels. In addition, the expression of TLR4, along with that of downstream signaling molecule proteins, was also reduced. Our study has provided new insights into the potential of PF as a promising therapeutic agent for treating DN and has illustrated the underlying mechanism of PF from a new perspective.

Background/Aims: Mastitis is an acute clinical inflammatory response. The occurrence and development of mastitis seriously disturb women's physical and mental health. Licochalcone A, a phenolic compound in Glycyrrhiza uralensis, has anti-inflammatory properties. Here, we examined the effect of licochalcone A on blood-milk barrier and inflammatory response in LPS-induced mice mastitis.Methods:In vivo, we firstly established mice models of mastitis by canal injection of LPS to mammary gland, and then detected the effect of licochalcone A on pathological indexes, inflammatory responses and blood-milk barrier in this model. In vivo, Mouse mammary epithelial cells (mMECs) were treated with licochalcone A prior to the incubation of LPS, and then the inflammatory responses, tight junction which is the basic structure of blood-milk barrier were analyzed. Last, we elucidated the anti-inflammatory mechanism by examining the activation of mitogen-activated protein kinase (MAPK) and AKT/NF-κB signaling pathways in vivo and in vitro.Result: The in vivo results showed that licochalcone A significantly decreased the histopathological impairment and the inflammatory responses, and improved integrity of blood-milk barrier. The in vitro results demonstrated that licochalcone A inhibited LPS-induced inflammatory responses and increase the protein levels of ZO-1, occludin, and claudin3 in mMECs. The in vivo and in vitro mechanistic study found that the anti-inflammatory effect of licochalcone A in LPS-induced mice mastitis was mediated by MAPK and AKT/NF-κB signaling pathways.Conclusions and Implications: Our experiments collectively indicate that licochalcone A protected against LPS-induced mice mastitis via improving the blood–milk barrier integrity and inhibits the inflammatory response by MAPK and AKT/NF-κB signaling pathways.

Von Willebrand factor-binding protein (vWbp), secreted by Staphylococcus aureus (S. aureus), can activate host prothrombin, convert fibrinogen to fibrin clots, induce blood clotting, and contribute to pathophysiology of S. aureus-related diseases, including infective endocarditis, staphylococcal sepsis and pneumonia. Therefore, vWbp is an promising drug target in the treatment of S. aureus-related infections. Here, we report that dryocrassin ABBA (ABBA), a natural compound derived from Dryopteris crassirhizoma, can significantly inhibit the coagulase activity of vWbp in vitro by directly interacting with vWbp without killing the bacteria or inhibiting the expression of the vWbp. Using molecular dynamics simulations, we demonstrate that ABBA binds to the “central cavity” in the elbow of vWbp by interacting with Arg-70, His-71, Ala-72, Gly-73, Tyr-74, Glu-75, Tyr-83, and Gln-87 in vWbp, thus interfering with the binding of vWbp to prothrombin. Furthermore, in vivo studies demonstrated that ABBA can attenuate injury and inflammation of mouse lung tissues caused by S. aureus and increase survival of mice. Together these findings indicate that ABBA is a promising lead drug for the treatment of S. aureus-related infections. This is the first report of potential inhibitor which inhibit the coagulase activity of vWbp by directly interacting with vWbp.

Mastitis is one of three bovine diseases recognized as a cause of substantial economic losses every year throughout the world. Niacin is an important feed additive that is used extensively for dairy cow nutrition. However, the mechanism by which niacin acts on mastitis is not clear. The aim of this study is to investigate the mechanism of niacin in alleviating the inflammatory response of mammary epithelial cells and in anti-mastitis. Mammary glands, milk, and blood samples were collected from mastitis cows not treated with niacin (n = 3) and treated with niacin (30 g/d, n = 3) and healthy cows (n = 3). The expression of GPR109A, IL-6, IL-1β, and TNF-α in the mammary glands of the dairy cows with mastitis was significantly higher than it was in the glands of the healthy dairy cows. We also conducted animal experiments in vivo by feeding rumen-bypassed niacin. Compared with those in the untreated mastitis group, the somatic cell counts (SCCs) and the expression of IL-6, IL-1β, and TNF-α in the blood and milk were lower. In vitro, we isolated the primary bovine mammary epithelial cells (BMECs) from the mammary glands of the healthy cows. The mRNA levels of IL-6, IL-1β, TNF-α, and autophagy-related genes were detected after adding niacin, shRNA, compound C, trans retinoic acid, 3-methyladenine to BMECs. Then GPR109A, AMPK, NRF-2, and autophagy-related proteins were detected by Western blot. We found that niacin can activate GPR109A and phosphorylate AMPK, and promote NRF-2 nuclear import and autophagy to alleviate LPS-induced inflammatory response in BMECs. In summary, we found that niacin can reduce the inflammatory response of BMECs through GPR109A/AMPK/NRF-2/autophagy. We also preliminarily explored the alleviative effect of niacin on mastitis in dairy cows.

In adulthood, chronic exposure to stressful experiences disrupts synaptic plasticity and cognitive function. Previous studies have shown that perirhinal cortex-dependent object recognition memory is impaired by chronic stress. However, the stress effects on molecular expression and structural plasticity in the perirhinal cortex remain unclear. In this study, we applied the chronic social defeat stress (CSDS) paradigm and measured the mRNA levels of nectin-1, nectin-3 and neurexin-1, three synaptic cell adhesion molecules (CAMs) implicated in the adverse stress effects, in the perirhinal cortex of wild-type (WT) and conditional forebrain corticotropin-releasing hormone receptor 1 conditional knockout (CRHR1-CKO) mice. Chronic stress reduced perirhinal nectin-1 mRNA levels in WT but not CRHR1-CKO mice. In conditional forebrain corticotropin-releasing hormone conditional overexpression (CRH-COE) mice, perirhinal nectin-1 mRNA levels were also reduced, indicating that chronic stress modulates nectin-1 expression through the CRH-CRHR1 system. Moreover, chronic stress altered dendritic spine morphology in the main apical dendrites and reduced spine density in the oblique apical dendrites of perirhinal layer V pyramidal neurons. Our data suggest that chronic stress disrupts cell adhesion and dendritic spine plasticity in perirhinal neurons, which may contribute to stress-induced impairments of perirhinal cortex-dependent memory.

Members of the YABBY gene family, a small plant-specific family of genes, have been proposed to function in specifying abaxial cell fate. Although to date little has been learned about cotton YABBY genes, completion of the cotton genome enables a comprehensive genome-wide analysis of YABBY genes in cotton. Here, a total of 12, 12, and 23 YABBY genes were identified in Gossypium arboreum (2n = 26, A2), G. raimondii (2n = 26, D5), and G. hirsutum (2n = 4x = 52, [AD]t), respectively. Sequence analysis showed that the N-terminal zinc-finger and C-terminal YABBY domains in YABBY proteins are highly conserved among cotton, Arabidopsis, and rice. Eighty-five genes from eight sequenced species naturally clustered into five groups, and the YAB2-like group could be divided into three sub-groups, indicating that YABBYs are highly conserved among the examined species. Orthologs from the At and Dt sub-genomes (where “t” indicates tetraploid) showed good collinearity, indicating that YABBY loci are highly conserved between these two sub-genomes. Whole-genome duplication was the primary cause of upland cotton YABBY gene expansion, segmental duplication played important roles in YABBY gene expansion within the At and Dt sub-genomes, and the YAB5-like group was mainly generated by segmental duplication. The long-terminal repeat retroelements Copia and Gypsy were identified as major transposable elements accompanying the appearance of duplicated YABBY genes, suggesting that transposable element expansion might be involved in gene duplication. Selection pressure analyses using PAML revealed that relaxed purifying selection might be the main impetus during evolution of YABBY genes in the examined species. Furthermore, exon/intron pattern and motif analyses indicated that genes within the same group were significantly conserved between Arabidopsis and cotton. In addition, the expression patterns in different tissues suggest that YABBY proteins may play roles in ovule development because YABBYs are highly expressed in ovules. The expression pattern of YABBY genes showed that approximately half of the YABBYs were down-regulated under different stress treatments. Collectively, our results represent a comprehensive genome-wide study of the YABBY gene family, which should be helpful in further detailed studies on the gene function and evolution of YABBY genes in cotton.