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ObjectiveAlthough extensive structural and functional abnormalities have been reported in schizophrenia, the gray matter volume (GMV) covariance of the amygdala remain unknown. The amygdala contains several subregions with different connection patterns and functions, but it is unclear whether the GMV covariance of these subregions are selectively affected in schizophrenia.MethodsTo address this issue, we compared the GMV covariance of each amygdala subregion between 807 schizophrenia patients and 845 healthy controls from 11 centers. The amygdala was segmented into nine subregions using FreeSurfer (v7.1.1), including the lateral (La), basal (Ba), accessory-basal (AB), anterior-amygdaloid-area (AAA), central (Ce), medial (Me), cortical (Co), corticoamygdaloid-transition (CAT), and paralaminar (PL) nucleus. We developed an operational combat harmonization model for 11 centers, subsequently employing a voxel-wise general linear model to investigate the differences in GMV covariance between schizophrenia patients and healthy controls across these subregions and the entire brain, while adjusting for age, sex and TIV.ResultsOur findings revealed that five amygdala subregions of schizophrenia patients, including bilateral AAA, CAT, and right Ba, demonstrated significantly increased GMV covariance with the hippocampus, striatum, orbitofrontal cortex, and so on (permutation test, P< 0.05, corrected). These findings could be replicated in most centers. Rigorous correlation analysis failed to identify relationships between the altered GMV covariance with positive and negative symptom scale, duration of illness, and antipsychotic medication measure.ConclusionOur research is the first to discover selectively impaired GMV covariance patterns of amygdala subregion in a large multicenter sample size of patients with schizophrenia.

Low back pain caused by disc herniation and spinal stenosis imposes an enormous medical burden on society due to its high prevalence and refractory nature. This is mainly due to the long-term inflammation and degradation of the extracellular matrix in the process of intervertebral disc degeneration (IVDD), which manifests as loss of water in the nucleus pulposus (NP) and the formation of fibrous disc fissures. Biomaterial repair strategies involving hydrogels play an important role in the treatment of intervertebral disc degeneration. Excellent biocompatibility, tunable mechanical properties, easy modification, injectability, and the ability to encapsulate drugs, cells, genes, etc. make hydrogels good candidates as scaffolds and cell/drug carriers for treating NP degeneration and other aspects of IVDD. This review first briefly describes the anatomy, pathology, and current treatments of IVDD, and then introduces different types of hydrogels and addresses “smart hydrogels”. Finally, we discuss the feasibility and prospects of using hydrogels to treat IVDD.

Enteric fistula (EF), a serious complication after abdominal surgery, refers to unnatural communication between the gastrointestinal tract and the skin or other hollow organs. It is associated with infection, massive fluid/electrolyte loss, and malnutrition, resulting in an unhealed course. Despite advances in surgical techniques, wound care, infection control, and nutritional support, EF remains associated with considerable morbidity and mortality. Autologous platelet-rich plasma (PRP) containing elevated platelet concentrations has been proposed to promote healing in many tissues. However, the mechanism of action of PRP in EF treatment remains unclear owing to its complicated clinical manifestations. In this review, we summarized the clinical approaches, outlined the principal cytokines involved in the healing effects, and discussed the advantages of PRP for EF therapy. In addition, we defined the mechanism of autologous PRP in EF management, which is essential for further developing EF therapies.

BackgroundDue to the low incidence of adult fibrosarcoma (AFS), it is difficult for clinicians to assess cancer-specific survival (CSS) in elderly patients based on this study. The study aimed to develop nomograms capable of accurately predicting 3-, 5-, and 8-year CSS in patients over 40 years of age with AFS.MethodsData were collected from The Surveillance, Epidemiology, and End Results (SEER) registry. 586 patients were included in this study. Univariate as well as multivariate Cox regression analyses were applied to identify independent risk factors. A nomogram was constructed and validated to predict the 3-, 5-, and 8-year CSS of patients.ResultsFive variables including age, sex, stage, grade, and chemotherapy status were considered independent risk factors and were used to construct the nomogram. The nomogram was well validated. The C-indexes of the training cohort and the validation cohort are 0.766 and 0.780, respectively. In addition, the area under the curves for 3-, 5- and 8-year CSS are 0.824, 0.846 and 0.840 in the training cohort, 0.835, 0.806 and 0.829 in the validation cohort. Calibration curves were also plotted to show that predicted endings have a well fit for the true endings. Finally, decision curve analysis demonstrates that the nomogram can bring a high benefit to patients.ConclusionWe successfully constructed a highly accurate nomogram to predict the CSS of AFS patients at 3-, 5-, and 8 years. The nomogram can greatly help clinicians and patients with AFS.

It has been confirmed that platelets play a key role in tumorigenesis. Tumor-activated platelets can recruit blood cells and immune cells to migrate, establish an inflammatory tumor microenvironment at the sites of primary and metastatic tumors. On the other hand, they can also promote the differentiation of mesenchymal cells, which can accelerate the proliferation, genesis and migration of blood vessels. The role of platelets in tumors has been well studied. However, a growing number of studies suggest that interactions between platelets and immune cells (e.g., dendritic cells, natural killer cells, monocytes, and red blood cells) also play an important role in tumorigenesis and tumor development. In this review, we summarize the major cells that are closely associated with platelets and discuss the essential role of the interaction between platelets with these cells in tumorigenesis and tumor development.

Tea (Camellia sinensis) is one of the significant cash crops in China. As a leaf crop, nitrogen supply can not only increase the number of new shoots and leaves but also improve the tenderness of the former. However, a conundrum remains in science, which is the molecular mechanism of nitrogen use efficiency, especially long non-coding RNA (lncRNA). In this study, a total of 16,452 lncRNAs were identified through high-throughput sequencing analysis of lateral roots under nitrogen stress and control conditions, of which 9,451 were differentially expressed lncRNAs (DE-lncRNAs). To figure out the potential function of nitrogen-responsive lncRNAs, co-expression clustering was employed between lncRNAs and coding genes. KEGG enrichment analysis revealed nitrogen-responsive lncRNAs may involve in many biological processes such as plant hormone signal transduction, nitrogen metabolism and protein processing in endoplasmic reticulum. The expression abundance of 12 DE-lncRNAs were further verified by RT-PCR, and their expression trends were consistent with the results of RNA-seq. This study expands the research on lncRNAs in tea plants, provides a novel perspective for the potential regulation of lncRNAs on nitrogen stress, and valuable resources for further improving the nitrogen use efficiency of tea plants.

Alzheimer's disease (AD) is a neurodegenerative disorder that causes memory degradation and cognitive function impairment in elderly people. The irreversible and devastating cognitive decline brings large burdens on patients and society. So far, there is no effective treatment that can cure AD, but the process of early-stage AD can slow down. Early and accurate detection is critical for treatment. In recent years, deep-learning-based approaches have achieved great success in Alzheimer's disease diagnosis. The main objective of this paper is to review some popular conventional machine learning methods used for the classification and prediction of AD using Magnetic Resonance Imaging (MRI). The methods reviewed in this paper include support vector machine (SVM), random forest (RF), convolutional neural network (CNN), autoencoder, deep learning, and transformer. This paper also reviews pervasively used feature extractors and different types of input forms of convolutional neural network. At last, this review discusses challenges such as class imbalance and data leakage. It also discusses the trade-offs and suggestions about pre-processing techniques, deep learning, conventional machine learning methods, new techniques, and input type selection.

BackgroundThe relationship between smoking and depression remains controversial. This study aimed to investigate the association between smoking and depression from three aspects: smoking status, smoking volume, and smoking cessation.MethodsData from adults aged ≥20 who participated in the National Health and Nutrition Examination Survey (NHANES) between 2005 and 2018 were collected. The study gathered information about the participants' smoking status (never smokers, previous smokers, occasional smokers, daily smokers), smoking quantity per day, and smoking cessation. Depressive symptoms were assessed using the Patient Health Questionnaire (PHQ-9), with a score ≥10 indicating the presence of clinically relevant symptoms. Multivariable logistic regression was conducted to evaluate the association of smoking status, daily smoking volume, and smoking cessation duration with depression.ResultsPrevious smokers [odds ratio (OR) = 1.25, 95% confidence interval (CI): 1.05–1.48] and occasional smokers (OR = 1.84, 95% CI: 1.39–2.45) were associated with a higher risk of depression compared with never smokers. Daily smokers had the highest risk of depression (OR = 2.37, 95% CI: 2.05–2.75). In addition, a tendency toward a positive correlation was observed between daily smoking volume and depression (OR = 1.65, 95% CI: 1.24–2.19) (P for trend < 0.05). Furthermore, the longer the smoking cessation duration, the lower the risk of depression (OR = 0.55, 95% CI: 0.39–0.79) (P for trend < 0.05).ConclusionsSmoking is a behavior that increases the risk of depression. The higher the smoking frequency and smoking volume, the higher the risk of depression, whereas smoking cessation is associated with decreased risk of depression, and the longer the smoking cessation duration, the lower the risk of depression.

IntroductionNeurological impairment during spinal deformity surgery is the most serious possible complication. When confronting intraoperative neurophysiological monitoring alerts, various surgical management methods such as the release of implants and decompression of the spinal cord are always performed. Transvertebral transposition of the spinal cord is rarely performed, and its role in the management of acute paraplegia is seldom reported.Case descriptionThe authors present two patients with kyphoscoliosis who experienced neurological deficits and abnormal neurological monitoring intraoperatively or post-operatively that were detected during correction surgery. Acute paraplegia was confirmed by a wake-up test. Subsequent spinal cord transposition was performed. Intraoperative neurophysiological monitoring motor-evoked potentials (MEPs) and somatosensory-evoked potentials (SEPs) were performed to detect the changes during the process. After transvertebral transposition of the spinal cord, the MEPs and SEPs were significantly improved in both patients during surgery. The spinal cord function was restored post-operatively and recovered to normal at the final follow-up in two patients.ConclusionThis case demonstrated that instead of decreasing the correction ratio of kyphoscoliosis, transvertebral transposition of the spinal cord under intraoperative neurophysiological monitoring may be an alternative therapeutic strategy for acute spinal cord dysfunction caused by deformity correction surgeries.

Human papillomaviruses (HPVs) have been recognized as the etiologic agents of various cancers and are called HPV-driven cancers. Concerning HPV-mediated carcinogenic action, gene therapy can cure cancer at the molecular level by means of the correction of specific genes or sites. CRISPR-Cas9, as a novel genetic editing technique, can correct errors in the genome and change the gene expression and function in cells efficiently, quickly, and with relative ease. Herein, we overviewed studies of CRISPR-mediated gene remedies for HPV-driven cancers and summarized the potential applications of CRISPR-Cas9 in gene therapy for cancer.

BackgroundAs a rare tumor, surgery is the best treatment for primary spinal tumors. However, for elderly patients who cannot undergo surgery, the prognosis is often difficult to evaluate. The purpose of this study was to identify the risk factors that may lead to death and predict the prognosis of elderly patients with primary spinal tumors who have not undergone surgical treatment. MethodsIn this study, 426 patients aged 60 years or older diagnosed with a primary spinal tumor between 1975 and 2015 were selected and included from the Surveillance, Epidemiology, and End Results database. A retrospective analysis was performed by using the Cox regression algorithm to identify independent prognostic factors. A nomogram model was developed based on the results. Multiple evaluation methods (calibration curve, receiver operating characteristic curve, and decision curve analyses) were used to evaluate and validate the performance of the nomogram.ResultsA nomogram was developed, with age, histological type, and stage as independent prognostic factors. The results indicated that the prognostic risk tended to increase significantly with age and tumor spread. Osteosarcoma was found to have the most prominent risk prognosis in this patient group, followed by chondrosarcoma and chordoma. The area under the curve and the C-index of the model were both close to or greater than 0.7, which proved the high-differentiation ability of the model. The calibration curve and decision curve analyses showed that the model had high predictive accuracy and application value.ConclusionsWe successfully established a practical nomogram to assess the prognosis of elderly patients with primary spinal tumors who have not undergone surgical treatment, providing a scientific basis for clinical management.

BackgroundReliable biomarkers are needed to improve preeclampsia (PE) prediction accuracy. With the investigational tool of peptidomics, we aimed to identify and validate potential serum peptide biomarkers in cohorts suspected for PE development in middle or late pregnancy.MethodsTotally 195 serum samples were prospectively collected from pregnant women with PE-related syndromes who were followed up for PE development until delivery. Serum peptidomic analysis was performed in the discovery cohort of 115 samples using matrix-assisted laser desorption ionization-time of flight coupled with Linear Trap Quadropole Orbitrap mass spectrometry. The candidate biomarkers were further validated using an in-house developed liquid chromatography tandem mass spectrometry (LC-MS/MS) method in an independent validation cohort of 80 serum samples.ResultsWe identified 8 peptides that were differentially expressed and originated from fibrinogen alpha chain (FGA), inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) and complement component 3. In the subsequent LC-MS/MS quantitation analysis, the levels of the three peptides (FGA-1033.4, ITIH4-2026.9, ITIH4-2051.1) exhibited a significant difference between the PE-positive and PE-negative groups. Further, the three-peptide panel yielded an area under the ROC curve (AUC) of 0.985 [95% confidence interval (CI) 0.965–1.000] and 0.923 (95% CI 0.845–1.000) in the discovery and validation cohorts respectively, with negative predictive values of 98.1–98.8% and positive predictive values of 73.1–85.3% that were much improved when compared with that of soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio.ConclusionsWe have discovered and validated a novel three-peptide biomarker panel predictive for the occurrence PE in pregnant women.

BackgroundThe long-term outcomes of ablation index (AI)-guided radiofrequency catheter ablation (RFCA) on atrial fibrillation (AF) and different subtypes of heart failure (HF) remain unknown. The aim of the study was to evaluate the long-term prognosis of AI-guided RFCA procedures in patients with AF and concomitant HF.MethodsWe retrospectively included consecutive patients with AF and HF who underwent the initial RFCA procedure with AI guidance from March 2018 to June 2021 in our institution. The patients were categorized into two groups: HF with preserved ejection fraction (HFpEF) group and HF with mid-range ejection fraction (HFmrEF) +HF with reduced ejection fraction (HFrEF) group.ResultsA total of 101 patients were included. HFpEF and HFmrEF + HFrEF groups consisted of 71 (70.3%) and 30 patients (29.7%), respectively. During a median follow-up of 32.0 (18.2, 37.6) months, no significant difference was detected in AF recurrence between groups (21.1 vs. 33.3%) after multiple procedures, whereas the incidence of the composite endpoint of all-cause death, thromboembolic events, and HF hospitalization was significantly lower in HFpEF group (9.9 vs. 25.0%, Log-rank p = 0.018). In multivariable analysis, a history of hypertension [hazard ratio (HR) 4.667, 95% confidence interval (CI) 1.433–15.203, p = 0.011], left ventricular ejection fraction (LVEF) < 50% (HR 5.390, 95% CI 1.911–15.203, p = 0.001) and recurrent AF after multiple procedures (HR 7.542, 95% CI 2.355–24.148, p = 0.001) were independently associated with the incidence of the composite endpoint.ConclusionLong-term success could be achieved in 75% of patients with AF and concomitant HF after AI-guided RFCA procedures, irrespective of different HF subtypes. Preserved LVEF was associated with a reduction in the composite endpoint compared with impaired LVEF. Patients with recurrent AF tend to have a poorer prognosis.

ImportanceMost healthcare institutions require employees to be vaccinated against SARS-CoV-2 and many also require at least one booster.ObjectiveWe determine the impact of vaccine type, demographics, and health conditions on COVID-19 vaccine side effects in healthcare professionals.DesignA COVID-19 immunity study was performed at the 2021 American Association for Clinical Chemistry Annual Scientific meeting. As part of this study, a REDCap survey with cascading questions was administered from September 9, 2021 to October 20, 2021. General questions included participant demographics, past and present health conditions, smoking, exercise, and medications. COVID-19 specific questions asked about SARS-CoV-2 vaccine status and type, vaccine-associated side effects after each dose including any boosters, previous infection with COVID-19, diagnostic testing performed, and type and severity symptoms of COVID-19.ResultsThere were 975 participants (47.1% male, median age of 50 years) who completed the survey. Pfizer was the most commonly administered vaccine (56.4%) followed by Moderna (32.0%) and Johnson & Johnson (7.1%). There were no significant differences in vaccine type received by age, health conditions, smoking, exercise, or type or number of prescription medications. Side effects were reported more frequently after second dose (e.g., Moderna or Pfizer) (54.1%) or single/only dose of Johnson & Johnson (47.8%). Males were significantly more likely to report no side effects (p < 0.001), while females were significantly more likely to report injection site reactions (p < 0.001), fatigue (p < 0.001), headache (p < 0.001), muscle pain (p < 0.001), chills (p = 0.001), fever (p = 0.007), and nausea (p < 0.001). There was a significant upward trend in participants reporting no side effects with increasing age (p < 0.001). There were no significant trends in side effects among different races, ethnicities, health conditions, medications, smoking status or exercise. In multivariate logistic regressions analyses, the second dose of Moderna was associated with a significantly higher risk of side effects than both the second dose of Pfizer and the single dose of Johnson & Johnson.Conclusions and relevanceYounger people, females, and those receiving the second dose of Moderna had more COVID-19 vaccine side effects that per self-report led to moderate to severe limitations. As reported in other studies, the increase in side effects from Moderna may be explained by higher viral mRNA concentrations but be associated with additional protective immunity.

Evidence suggests that perceived school culture is the most powerful predictor of teachers’ work performance. However, studies to date have paid little attention to the potential mechanisms behind this association. On the basis of the job demands–resources (JD–R) model, the present study explored the mediating role of affective empathy and the moderating role of job tenure in the association between perceived school culture and teachers’ work engagement. 647 primary and secondary school teachers completed questionnaires measuring perceived school culture, affective empathy, and work engagement. After gender and educational level were included as covariates, the results showed that perceived school culture positively correlated with teachers’ work engagement, and more importantly, this association was partially mediated by affective empathy. In addition, job tenure significantly moderated the direct association between perceived school culture and work engagement. Specifically, there was a stronger association between perceived school culture and work engagement for teachers with shorter job tenure than those with longer job tenure. The findings suggested the direct effect of perceived school culture on work engagement, and the indirect effect of perceived school culture on work engagement through the mediating role of affective empathy. These findings enrich our understanding of how perceived school culture associates with work engagement, and highlight the moderating role of job tenure in the direct association between perceived school culture and work engagement.

Background and AimsRadiation-induced lung injury (RILI) is the most common complication associated with chest tumors, such as lung and breast cancers, after radiotherapy; however, the pathogenic mechanisms are unclear. Single-cell RNA sequencing has laid the foundation for studying RILI at the cellular microenvironmental level. This study focused on changes during the acute pneumonitis stage of RILI at the cellular microenvironmental level and investigated the interactions between different cell types.MethodsAn acute RILI model in mice and a single-cell transcriptional library were established. Intercellular communication networks were constructed to study the heterogeneity and intercellular interactions among different cell types.ResultsA single-cell transcriptome map was established in a mouse model of acute lung injury. In total, 18,500 single-cell transcripts were generated, and 10 major cell types were identified. The heterogeneity and radiosensitivity of each cell type or subtype in the lung tissues during the acute stage were revealed. It was found that immune cells had higher radiosensitivity than stromal cells. Immune cells were highly heterogeneous in terms of radiosensitivity, while some immune cells had the characteristics of radiation resistance. Two groups of radiation-induced Cd8+Mki67+ T cells and Cd4+Cxcr6+ helper T cells were identified. The presence of these cells was verified using immunofluorescence. The ligand-receptor interactions were analyzed by constructing intercellular communication networks. These explained the origins of the cells and revealed that they had been recruited from endothelial cells to the inflammatory site.ConclusionsThis study revealed the heterogeneity of in vivo radiosensitivity of different cell types in the lung at the initial stage post irradiation

Background: Recent studies have shown that alpha-1,3-mannosyltransferase (ALG3) promoted tumorigenesis and progression in multiple cancer types. Our study planned to explore the clinical implication and potential function of ALG3 in hepatocellular carcinoma.Materials and Methods: Data from public databases were used to analyze the ALG3 expression and its impact on the clinical significance of patients with HCC. The ALG3 expression was confirmed by qRT-PCR and Western blot. Immunohistochemistry was used to confirm the ALG3 expression and explore its clinical implication in HCC. KEGG, GO, and GSEA enrichment analyses were utilized to explore the biological pathways related to ALG3 in HCC. TIMER2.0 was applied to assess the association between ALG3 and immune infiltration. CCK8, MTT, and transwell assays were used to investigate the role of ALG3 downregulation in HCC cell lines.Results: qRT-PCR, WB, and IHC proved ALG3 was highly overexpressed in HCC tissues. The Kaplan–Meier analysis verified the overexpression of ALG3 was related to poor overall survival (p < 0.001). Multivariate cox regression analysis showed that the high ALG3 expression was an independent risk prognostic factor. GSEA and TIMER2.0 predicted that ALG3 participates in cell differentiation and cycle and correlates with immune cell infiltration. Transwell assay results showed that ALG3 silencing also impaired the invasion ability of HCC cells.Conclusion: ALG3 was overexpressed and considered a potential indicator of survival in HCC, and our findings provided a novel therapeutic target for HCC.

BackgroundThe study of hemodynamics regarding thoracic endovascular aortic repair (TEVAR) is helpful to improve the surgical efficacy.ObjectiveCorrelations between hemodynamic changes and branch stent extension length and interference factors for branch stent extension length of in situ fenestration TEVAR (ISF-TEVAR) involving the left subclavian artery (LSA) were evaluated.Materials and MethodsThis study retrospectively analyzed 196 patients with Stanford type B aortic dissection who received in situ laser fenestrated thoracic endovascular aortic repair with LSA fenestration from April 2014 to March 2021. Branch stent extension to the main stent graft was evaluated by the computed tomographic angiography (CTA). Hemodynamic change of LSA was defined as a 20 mmHg interbrachial systolic pressure difference. The factors affecting the extension of the branch stent were also evaluated.ResultsAll patients underwent ISF-TEVAR with LSA fenestration, and there was no recurrence during the follow-up. The mean length of the branch stent extension was 10.37 ± 0.34 mm, which was used to divide the patients into long and short groups. Asymptomatic hemodynamic changes (defined as a 20 mmHg interbrachial systolic pressure difference) in LSA were observed in 61 patients undergoing ISF-TEVAR involving LSA fenestration. The Spearman correlation analysis showed extension length of a branch stent >1.5 cm elevated the risk of hemodynamic changes.ConclusionOverall, we conclude that branch stent extension length >1.5 cm induced LSA hemodynamic changes. Appropriate shortening of the stent extension length can improve the curative effect of ISF-TEVAR, especially when faced with a type II/III aortic arch and stent angles of

As an efficient and durable engine, a diesel engine has a broad application. However, soot particles (PM) and nitrogen oxides (NOx) coming from diesel engines are the main causes of air pollution, so it is necessary to design and prepare an effective catalyst for the simultaneous elimination of PM and NOx. In this work, a novel 3DOM ZrTiO4 support and a series of WxCeMnOδ/3DOM ZrTiO4 catalysts (where x indicates the wt% of W) were designed and fabricated by the colloidal crystal template technique. Among the as-prepared catalysts, the W1CeMnOδ/3DOM ZrTiO4 catalyst exhibits the highest NO conversion rate (52%) at the temperature of maximum CO2 concentration (474°C) and achieves 90% NO conversion in the temperature range of 250–396°C. The excellent catalytic performance is associated with the macroporous structure, abundant oxygen vacancies, sufficient acid sites, and the synergistic effect among the active components. The possible reaction mechanisms of WxCeMnOδ/3DOM ZrTiO4 catalysts were also discussed based on the characterization results.

The pathophysiologic mechanisms underpinning idiopathic normal pressure hydrocephalus (iNPH), a clinically diagnosed dementia-causing disorder, continue to be explored. An increasing body of evidence implicates multiple systems in the pathogenesis of this condition, though a unifying causative etiology remains elusive. Increased knowledge of the aberrations involved has shed light on the iNPH phenotype and has helped to guide prognostication for treatment with cerebrospinal fluid diversion. In this review, we highlight the central role of the cerebrovasculature in pathogenesis, from hydrocephalus formation to cerebral blood flow derangements, blood-brain barrier breakdown, and glymphatic pathway dysfunction. We offer potential avenues for increasing our understanding of how this disease occurs.

Immunotherapy using monoclonal antibodies targeting the PD-1/PD-L1 interaction has shown enormous success for various cancers. Despite their encouraging results in clinics, antibody-based checkpoint inhibitors have several limitations, such as poor tumor penetration. To address these limitations of monoclonal antibodies, there is a growing interest in developing low-molecular-weight checkpoint inhibitors, such as antibody fragments. Several antibody fragments targeting PD-1/PD-L1 were recently discovered using phage libraries from camel or alpaca. However, animal-derived antibody fragments may elicit unwanted immune responses, which limit their therapeutic applications. For the first time, we used a human domain antibody phage library and discovered anti-human PD-L1 human single-domain antibodies (dAbs) that block the PD-1/PD-L1 interaction. Among them, the CLV3 dAb shows the highest affinity to PD-L1. The CLV3 dAb also exhibits the highest blocking efficacy of the PD-1/PD-L1 interaction. Moreover, the CLV3 dAb significantly inhibits tumor growth in mice implanted with CT26 colon carcinoma cells. These results suggest that CLV3 dAb can be potentially used as an anti-PD-L1 inhibitor for cancer immunotherapy.

BackgroundThromboangiitis obliterans (TAO, Buerger's disease) is an inflammatory and obstructive vasculopathy, which leads to limb ischemic rest pain and ulcerations in the acute stage.ObjectivesThis study aimed to assess the feasibility of excimer laser-assisted balloon angioplasty (BA) for patients with acute infrapopliteal TAO.MethodThis was a single-center retrospective cohort study. In this study, 220 patients with 210 target limbs between January 2012 and September 2021 were involved. Among them, 52 target limbs have received endovascular excimer laser-assisted balloon angioplasty from January 2017. The ankle brachial index (ABI), rest pain score, ulcer, Rutherford classification, and TASC II classification were assessed. The follow-up time was 6 months.ResultsThe technical success rate of laser + BA and BA groups was 71.15 and 65.82% (p = 0.5021), respectively. After intervention, the ABI of two groups were 0.85 ± 0.20 and 0.77 ± 0.20 (p = 0.0419), and the rest pain score was 1.00 ± 1.43 and 1.71 ± 2.25 (p = 0.0449). During the 6 months follow-up, the ABI of two groups was 0.76 ± 0.17 and 0.75 ± 0.23 (p = 0.8539), the rest pain score was 1.43 ± 1.82 and 2.24 ± 2.06 (p = 0.0783), and the ulcer rate was 23.68 and 40.98% (p = 0.0867), respectively. The proportion of patients who were assessed as TASC II C/D or Rutherford 4–6 in laser +BA group was significantly lower than that in BA group, indicating that the former had better efficacy. The rate of critical limb ischemia and restenosis in the laser +BA group was lower than that in the BA group (47.36 vs. 67.22%; 21.05 vs. 34.43%) during follow-up. In the laser + BA group, the reintervention rate was lower than that in the BA group (2.70 vs. 8.20%, p = 0.0425). No serious adverse events (AEs) occurred.ConclusionExcimer laser debulking-assisted angioplasty is a feasible, effective, and safe method to treat acute infrapopliteal TAO.

Osteoporosis is one of the most common diseases in the world which resulted in heavy socioeconomic burden and a public health threat. Glucocorticoid-induced osteoporosis (GIO) is the most common secondary reason of osteoporosis. Therapeutic strategies using traditional Chinese medicine are under investigation for osteoporosis, with efforts to improve efficacy and clarify the mechanism. The combination of Eucommia, Cuscuta, and Drynaria is widely used in traditional Chinese decoction for osteoporosis treatment, but the experimental efficacy and mechanism are still unclear. Administration of E.C.D. extracts (Eucommia, Cuscuta, and Drynaria) in experimental GIO rats resulted in decreased urinal calcium, phosphorus loss, and decreased expression of RANKL, CTX in serum, increased serum calcium, phosphorus, and OPG level. E.C.D. extracts also improved bone density, structural integrity, and biomechanical function in experimental GIO rats. These finding were associated with E.C.D. extracts’ treatment efficacy to GIO in vivo. The balance between osteoclast and osteoblast activity is essential for bone remodeling and bone related disease. The E.C.D. extracts inhibited Raw 264.7 cell differentiation to osteoclast in vitro. On the other hand, it promoted OPG expression of bone marrow mesenchymal stromal cells (MSCs) which can suppress the osteoclast genesis. E.C.D. extracts also increased the Wnt1 and Runx2 expression which are related to osteoblast formation. It also regulated the paracrine effect of MSC to inhibit osteoclast differentiation. The analysis of HPLC and comprehensive pharmacology identified the constituents of E.C.D. extracts and the potential osteoporosis-related targets mediated by E.C.D. extracts. The KEGG enrichment analysis suggested that PI3K/Akt pathway may be involved in the regulation osteoclast genesis by E.C.D. extracts and the result of Western blot of vitro assays proved it. Collectively, these data demonstrate E.C.D. extracts can inhibit osteoclast differentiation to foster experimental osteoporosis both in vivo and in vitro and it may exert the function of inhibiting osteoclast differentiation through PI3K/Akt pathway.

Malonic acid is used as a common component of many products and processes in the pharmaceutical and cosmetic industries. Here, we designed a novel artificial synthetic pathway of malonic acid, in which oxaloacetate, an intermediate of cytoplasmic reductive tricarboxylic acid (rTCA) pathway, is converted to malonic semialdehyde and then to malonic acid, sequentially catalyzed by a-keto decarboxylase and malonic semialdehyde dehydrogenase. After the systematic screening, we discovered the enzyme oxaloacetate decarboxylase Mdc, catalyzing the first step of the artificially designed pathway in vitro. Then, this synthetic pathway was functionally constructed in cellulolytic thermophilic fungus Myceliophthora thermophila. After enhancement of glucose uptake, the titer of malonic acid achieved 42.5 mg/L. This study presents a novel biological pathway for producing malonic acid from renewable resources in the future.

Vascular dementia (VaD) is the second most common form of dementia after Alzheimer’s disease (AD); where Alzheimer’s accounts for 60–70% of cases of dementia and VaD accounts for 20% of all dementia cases. VaD is defined as a reduced or lack of blood flow to the brain that causes dementia. VaD is also known occasionally as vascular contributions to cognitive impairment and dementia (VCID) or multi-infarct dementia (MID). VCID is the condition arising from stroke and other vascular brain injuries that cause significant changes to memory, thinking, and behavior, and VaD is the most severe stage while MID is produced by the synergistic effects caused by multiple mini strokes in the brain irrespective of specific location or volume. There are also subtle differences in the presentation of VaD in males and females, but they are often overlooked. Since 1672 when the first case of VaD was reported until now, sex and gender differences have had little to no research done when it comes to the umbrella term of dementia in general. This review summarizes the fundamentals of VaD followed by a focus on the differences between sex and gender when an individual is diagnosed. In addition, we provide critical evidence concerning sex and gender differences with a few of the main risk factors of VaD including pre-existing health conditions and family history, gene variants, aging, hormone fluctuations, and environmental risk factors. Additionally, the pharmaceutical treatments and possible mitigation of risk factors is explored.

Background: Tumor-derived exosomes (EXOs), commonly differentially expressed in circular RNAs, have been shown to be crucial determinants of tumor progression and may regulate the development and metastasis of hepatic carcinoma (HCC).Methods: Possibly differentially expressed circRNAs in patients with HCC were screened out from the Gene Expression Omnibus (GEO). EXOs were isolated from the culture medium of HCC cells and plasma of patients with HCC, followed by characterization by transmission electron microscope, NanHCCight, and western blotting. Additionally, RNA immunoprecipitation and luciferase reporter gene assays were carried out to explore the molecular mechanism of hsa_circRNA_103809 (circ-0072088) in HCC cells.Results: The screening results showed that circ-0072088 was highly expressed in patients with HCC, and its increase indicated unfavorable prognosis of patients according to quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Additionally, circ-0072088 was mainly secreted by HCC cells via EXOs in plasma of such patients, and its high level in plasma EXOs was closely associated with tumor node metastasis (TNM) staging and tumor size. Moreover, HCC-secreted EXOs mediated the degradation of miR-375 via circ-0072088 and upregulated MMP-16, thus suppressing the metastasis of HCC.Conclusion: Upregulated in patients with HCC, circ-0072088 may be an index for diagnosis and prognosis of HCC. In addition, HCC-derived EXOs coated with circ-0072088 might be a treatment for HCC, with the ability to inhibit the metastasis of HCC cells.

The roles of serine protease inhibitor Kazal type 1 (SPINK1) in multiple types of cancers have been significantly documented. However, its specific roles in hepatocellular carcinoma (HCC) remain to be investigated. This study found that SPINK1 is upregulated in HCC and its upregulation correlates with poor prognosis. Besides, functional assays revealed that SPINK1 promotes cell proliferation, cell cycle, and invasion in vitro. Through bioinformatics analysis, we speculate that circRPS16 regulates SPINK1 expression by sponging miR-876-5p. This was further verified by the dual-luciferase reporter and fluorescent in situ hybridization (FISH) assays. Subsequently, rescue assays verified that circRPS16 promotes cell proliferation, cell cycle, and invasion through miR-876-5p. Importantly, silencing circRPS16 inhibited tumor growth by downregulating SPINK1 expression in vivo. Collectively, our results confirm that SPINK1 is a downstream target of circRPS16. Besides, circRPS16 and SPINK1 are oncogenic factors in HCC progression; they provide novel diagnostic and therapeutic targets for HCC patients.

BackgroundMeningioma invasion can be preoperatively recognized by radiomics features, which significantly contributes to treatment decision-making. Here, we aimed to evaluate the comparative performance of radiomics signatures derived from varying regions of interests (ROIs) in predicting BI and ascertaining the optimal width of the peritumoral regions needed for accurate analysis.MethodsFive hundred and five patients from Wuhan Union Hospital (internal cohort) and 214 cases from Taihe Hospital (external validation cohort) pathologically diagnosed as meningioma were included in our study. Feature selection was performed from 1,015 radiomics features respectively obtained from nine different ROIs (brain-tumor interface (BTI)2–5mm; whole tumor; the amalgamation of the two regions) on contrast-enhanced T1-weighted imaging using least-absolute shrinkage and selection operator and random forest. Principal component analysis with varimax rotation was employed for feature reduction. Receiver operator curve was utilized for assessing discrimination of the classifier. Furthermore, clinical index was used to detect the predictive power.ResultsModel obtained from BTI4mm ROI has the maximum AUC in the training set (0.891 (0.85, 0.932)), internal validation set (0.851 (0.743, 0.96)), and external validation set (0.881 (0.833, 0.928)) and displayed statistically significant results between nine radiomics models. The most predictive radiomics features are almost entirely generated from GLCM and GLDM statistics. The addition of PEV to radiomics features (BTI4mm) enhanced model discrimination of invasive meningiomas.ConclusionsThe combined model (radiomics classifier with BTI4mm ROI + PEV) had greater diagnostic performance than other models and its clinical application may positively contribute to the management of meningioma patients.

Background: Vertebrobasilar dolichoectasia (VBD) is one of the rare causes of trigeminal neuralgia (TN). The common surgical treatments for patients with TN caused by VBD (VBD-TN) are microvascular decompression (MVD) and Gamma Knife radiosurgery (GKRS). However, the therapeutic effects of the two methods have not been clinically compared, so this study was performed to evaluate the treatment outcomes of MVD and GKRS for patients with VBD-TN.Methods: The retrospective study was performed from March 2011 to March 2019 in Wuhan Union Hospital. A total of 80 patients diagnosed with VBD-TN were included in this study, and they were divided into the MVD group (n = 46) and GKRS group (n = 34) according to the surgical methods. The imaging data, intraoperative findings, treatment outcomes, and complications of the two groups were analyzed and compared. Meanwhile, the influencing factors of the treatment effect are also explored on the two groups.Results: Patients who underwent MVD were younger than patients who underwent GKRS (median ages were 61.1 and 65.4 years old, respectively, p = 0.03). The median follow-up was 61.1 months for the MVD group and 56.8 months for the GKRS group. The favorable outcomes [Barrow Neurological Institute (BNI) pain score, BNI scores I–II] occurred in 97.8% of patients treated with MVD and in 78.9% of patients treated with GKRS (p = 0.009). The favorable outcomes in the percentage of patients after MVD 1, 3, 5, and 7 years were 95.7, 85.1, 74.2, and 74.2%, respectively, whereas the corresponding percentages after GKRS were 76.5, 66.2, 56.6, and 47.2%, respectively (p = 0.031). The postoperative complications (except facial numbness) in the MVD group were higher than those in the GKRS group (p = 0.036), but the incidence of new and worsening facial numbness was lower in the GKRS group (p < 0.001).Conclusions: MVD is superior to GKRS in obtaining and maintaining favorable outcomes for patients with VBD-TN, but it also comes with more complications other than facial numbness. Thus, the treatment program can be tailored to a patient's unique condition and wishes.

BackgroundGiven the similarities in clinical manifestations of cystic-solid pituitary adenomas (CS-PAs) and craniopharyngiomas (CPs), this study aims to establish and validate a nomogram based on preoperative imaging features and blood indices to differentiate between CS-PAs and CPs.MethodsA departmental database was searched to identify patients who had undergone tumor resection between January 2012 and December 2020, and those diagnosed with CS-PAs or CPs by histopathology were included. Preoperative magnetic resonance imaging (MRI) features as well as blood indices were retrieved and analyzed. Radiological features were extracted from the tumor on contrast-enhanced T1 (CE-T1) weighted and T2 weighted sequences. The two independent samples t-test and principal component analysis (PCA) were used for feature selection, data dimension reduction, and radiomics signature building. Next, the radiomics signature was put in five classification models for exploring the best classifier with superior identification performance. Multivariate logistic regression analysis was then used to establish a radiomic-clinical model containing radiomics and hematological features, and the model was presented as a nomogram. The performance of the radiomics-clinical model was assessed by calibration curve, clinical effectiveness as well as internal validation.ResultsA total of 272 patients were included in this study: 201 with CS-PAs and 71 with CPs. These patients were randomized into training set (n=182) and test set (n=90). The radiomics signature, which consisted of 18 features after dimensionality reduction, showed superior discrimination performance in 5 different classification models. The area under the curve (AUC) values of the training set and the test set obtained by the radiomics signature are 0.92 and 0.88 in the logistic regression model, 0.90 and 0.85 in the Ridge classifier, 0.88 and 0.82 in the stochastic gradient descent (SGD) classifier, 0.78 and 0.85 in the linear support vector classification (Linear SVC), 0.93 and 0.86 in the multilayers perceptron (MLP) classifier, respectively. The predictive factors of the nomogram included radiomic signature, age, WBC count, and FIB. The nomogram showed good discrimination performance (with an AUC of 0.93 in the training set and 0.90 in the test set) and good calibration. Moreover, decision curve analysis (DCA) demonstrated satisfactory clinical effectiveness of the proposed radiomic-clinical nomogram.ConclusionsA personalized nomogram containing radiomics signature and blood indices was proposed in this study. This nomogram is simple yet effective in differentiating between CS-PAs and CPs and thus can be used in routine clinical practice.

Efficient biological conversion of all sugars from lignocellulosic biomass is necessary for the cost-effective production of biofuels and commodity chemicals. Galactose is one of the most abundant sugar in many hemicelluloses, and it will be important to capture this carbon for an efficient bioconversion process of plant biomass. Thermophilic fungus Myceliophthora thermophila has been used as a cell factory to produce biochemicals directly from renewable polysaccharides. In this study, we draw out the two native galactose utilization pathways, including the Leloir pathway and oxido-reductive pathway, and identify the significance and contribution of them, through transcriptional profiling analysis of M. thermophila and its mutants on galactose. We find that galactokinase was necessary for galactose transporter expression, and disruption of galK resulted in decreased galactose utilization. Through metabolic engineering, both galactokinase deletion and galactose transporter overexpression can activate internal the oxido-reductive pathway and improve the consumption rate of galactose. Finally, the heterologous galactose-degradation pathway, De Ley–Doudoroff (DLD) pathway, was successfully integrated into M. thermophila, and the consumption rate of galactose in the engineered strain was increased by 57%. Our study focuses on metabolic engineering for accelerating galactose utilization in a thermophilic fungus that will be beneficial for the rational design of fungal strains to produce biofuels and biochemicals from a variety of feedstocks with abundant galactose.

Viral interfering RNA (viRNA) has been identified from several viral genomes via directly deep RNA sequencing of the virus-infected cells, including zika virus (ZIKV). Once produced by endoribonuclease Dicer, viRNAs are loaded onto the Argonaute (AGO) family proteins of the RNA-induced silencing complexes (RISCs) to pair with their RNA targets and initiate the cleavage of target genes. However, the identities of functional ZIKV viRNAs and their viral RNA targets remain largely unknown. Our recent study has shown that ZIKV capsid protein interacted with Dicer and antagonized its endoribonuclease activity, which requires its histidine residue at the 41st amino acid. Accordingly, the engineered ZIKV-H41R loss-of-function (LOF) mutant virus no longer suppresses Dicer enzymatic activity nor inhibits miRNA biogenesis in NSCs. By combining AGO-associated RNA sequencing, deep sequencing analysis in ZIKV-infected human neural stem cells (NSCs), and miRanda target scanning, we defined 29 ZIKV derived viRNA profiles in NSCs, and established a complex interaction network between the viRNAs and their viral targets. More importantly, we found that viRNA production from the ZIKV mRNA is dependent on Dicer function and is a limiting factor for ZIKV virulence in NSCs. As a result, much higher levels of viRNAs generated from the ZIKV-H41R virus-infected NSCs. Therefore, our mapping of viRNAs to their RNA targets paves a way to further investigate how viRNAs play the role in anti-viral mechanisms, and perhaps other unknown biological functions.

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder associated with cognitive impairment and later dementia among the elderly. Mounting evidence shows that adverse maternal environments during the fetal development increase the risk of diseases later in life including neurological disorders, and suggests an early origin in the development of AD-related dementia (ADRD) in utero. In the present study, we investigated the impact of antenatal hypoxia and fetal stress on the initiation of AD-related pathology in offspring of 5xFAD mice. We showed that fetal hypoxia significantly reduced brain and body weight in the fetal and the early postnatal period, which recovered in young adult mice. Using spontaneous Y-maze, novel object recognition (NOR), and open field (OF) tasks, we found that antenatal hypoxia exacerbated cognitive decline in offspring of 5xFAD compared with normoxia control. Of interest, fetal hypoxia did not alter intraneuronal soluble amyloid-β (Aβ) oligomer accumulation in the cortex and hippocampus in 5xFAD mouse offspring, indicating that antenatal hypoxia increased the vulnerability of the brain to synaptotoxic Aβ in the disease onset later in life. Consistent with the early occurrence of cognitive decline, we found synapse loss but not neuronal death in the cerebral cortex in 5xFAD but not wild-type (WT) offspring exposed to antenatal hypoxia. Furthermore, we also demonstrated that antenatal hypoxia significantly increased microglial number and activation, and reactive astrogliosis in the cerebral cortex in WT offspring. Moreover, antenatal hypoxia resulted in an exacerbated increase of microgliosis and astrogliosis in the early stage of AD in 5xFAD offspring. Together, our study reveals a causative link between fetal stress and the accelerated onset of AD-related pathology, and provides mechanistic insights into the developmental origin of aging-related neurodegenerative disorders.

Mild traumatic brain injury (mTBI) represents more than 80% of total TBI cases and is a robust environmental risk factor for neurodegenerative diseases including Alzheimer’s disease (AD). Besides direct neuronal injury and neuroinflammation, blood–brain barrier (BBB) dysfunction is also a hallmark event of the pathological cascades after mTBI. However, the vascular link between BBB impairment caused by mTBI and subsequent neurodegeneration remains undefined. In this review, we focus on the preclinical evidence from murine models of BBB dysfunction in mTBI and provide potential mechanistic links between BBB disruption and the development of neurodegenerative diseases.

The mammalian neurovascular unit (NVU) is comprised of neurons, glia, and vascular cells. The NVU is the nexus between the cardiovascular and central nervous system (CNS). The central component of the NVU is the blood-brain barrier (BBB) which consists of a monolayer of tightly connected endothelial cells covered by pericytes and further surrounded by astrocytic endfeet. In addition to preventing the diffusion of toxic species into the CNS, the BBB endothelium serves as a dynamic regulatory system facilitating the transport of molecules from the bloodstream to the brain and vis versa. The structural integrity and transport functions of the BBB are maintained, in part, by an orchestra of membrane receptors and transporters including members of the superfamily of G protein-coupled receptors (GPCRs). Here, we provide an overview of GPCRs known to regulate mammalian BBB structure and function and discuss how dysregulation of these pathways plays a role in various neurodegenerative diseases.

Brains depend on blood flow for the delivery of oxygen and nutrients essential for proper neuronal and synaptic functioning. French physiologist Rouget was the first to describe pericytes in 1873 as regularly arranged longitudinal amoeboid cells on capillaries that have a muscular coat, implying that these are contractile cells that regulate blood flow. Although there have been >30 publications from different groups, including our group, demonstrating that pericytes are contractile cells that can regulate hemodynamic responses in the brain, the role of pericytes in controlling cerebral blood flow (CBF) has not been confirmed by all studies. Moreover, recent studies using different optogenetic models to express light-sensitive channelrhodopsin-2 (ChR2) cation channels in pericytes were not conclusive; one, suggesting that pericytes expressing ChR2 do not contract after light stimulus, and the other, demonstrating contraction of pericytes expressing ChR2 after light stimulus. Since two-photon optogenetics provides a powerful tool to study mechanisms of blood flow regulation at the level of brain capillaries, we re-examined the contractility of brain pericytes in vivo using a new optogenetic model developed by crossing our new inducible pericyte-specific CreER mouse line with ChR2 mice. We induced expression of ChR2 in pericytes with tamoxifen, excited ChR2 by 488 nm light, and monitored pericyte contractility, brain capillary diameter changes, and red blood cell (RBC) velocity in aged mice by in vivo two-photon microscopy. Excitation of ChR2 resulted in pericyte contraction followed by constriction of the underlying capillary leading to approximately an 8% decrease (p = 0.006) in capillary diameter. ChR2 excitation in pericytes substantially reduced capillary RBC flow by 42% (p = 0.03) during the stimulation period compared to the velocity before stimulation. Our data suggests that pericytes contract in vivo and regulate capillary blood flow in the aging mouse brain. By extension, this might have implications for neurological disorders of the aging human brain associated with neurovascular dysfunction and pericyte loss such as stroke and Alzheimer’s disease.

Pericytes are perivascular mural cells that enwrap brain capillaries and maintain blood-brain barrier (BBB) integrity. Most studies suggest that pericytes regulate cerebral blood flow (CBF) and oxygen delivery to activated brain structures, known as neurovascular coupling. While we have previously shown that congenital loss of pericytes leads over time to aberrant hemodynamic responses, the effects of acute global pericyte loss on neurovascular coupling have not been studied. To address this, we used our recently reported inducible pericyte-specific Cre mouse line crossed to iDTR mice carrying Cre-dependent human diphtheria toxin (DT) receptor, which upon DT treatment leads to acute pericyte ablation. As expected, DT led to rapid progressive loss of pericyte coverage of cortical capillaries up to 50% at 3 days post-DT, which correlated with approximately 50% reductions in stimulus-induced CBF responses measured with laser doppler flowmetry (LDF) and/or intrinsic optical signal (IOS) imaging. Endothelial response to acetylcholine, microvascular density, and neuronal evoked membrane potential responses remained, however, unchanged, as well as arteriolar smooth muscle cell (SMC) coverage and functional responses to adenosine, as we previously reported. Together, these data suggest that neurovascular uncoupling in this model is driven by pericyte loss, but not other vascular deficits or neuronal dysfunction. These results further support the role of pericytes in CBF regulation and may have implications for neurological conditions associated with rapid pericyte loss such as hypoperfusion and stroke, as well as conditions where the exact time course of global regional pericyte loss is less clear, such as Alzheimer’s disease (AD) and other neurogenerative disorders.

The 14-pods Cu7S4 hollow microcages wholly exposed with nanotwinned building blocks were successfully prepared by an ethanol-assisted sacrificial Cu2O template approach. Its photocatalytic activity for the degradation of methylene blue (MB) was determined. The results suggest that the Cu7S4 microcages with nanotwinned building blocks possess higher catalytic activity than the Cu7S4 microcages without the nanotwinned structures, suggesting that the special nanotwinned components can improve the catalytic performance of the multipod framework. Further investigate reveals that the nanotwins inside the Cu7S4 microcages can facilite the transport of free charges, decrease the recombination of photoinduced electrons and holes, and elongate the lifetime of the electron–hole pairs. Our work will provide powerful evidence that the nanotwinned building blocks of the synthesized Cu7S4 microcages play a crucial role for the high catalytic activity.

Abscisic acid responsive element binding factors (ABFs) play crucial roles in plant responses to abiotic stress. However, little is known about the roles of ABFs in alpine subnival plants, which can survive under extreme environmental conditions. Here, we cloned and characterized an ABF1 homolog, CbABF1, from the alpine subnival plant Chorispora bungeana. Expression of CbABF1 was induced by cold, drought, and abscisic acid. Subcellular localization analysis revealed that CbABF1 was located in the nucleus. Further, CbABF1 had transactivation activity, which was dependent on the N-terminal region containing 89 residues. A Snf1-related protein kinase, CbSnRK2.6, interacted with CbABF1 in yeast two-hybrid analysis and bimolecular fluorescence complementation assays. Transient expression assay revealed that CbSnRK2.6 enhanced the transactivation of CbABF1 on ABRE cis-element. We further found that heterologous expression of CbABF1 in tobacco improved plant tolerance to freezing and drought stress, in which the survival rates of the transgenic plants increased around 40 and 60%, respectively, compared with wild-type plants. Moreover, the transgenic plants accumulated less reactive oxygen species, accompanied by high activities of antioxidant enzymes and elevated expression of stress-responsive genes. Our results thus suggest that CbABF1 is a transcription factor that plays an important role in cold and drought tolerance and is a candidate gene in molecular breeding of stress-tolerant crops.

Programmed death ligand 1 (PD-L1) is not only an important molecule in mediating tumor immune escape, but also regulates inflammation development. Here we showed that PD-L1 was upregulated on neutrophils in lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS). Neutrophil specific knockout of PD-L1 reduced lung injury in ARDS model induced by intratracheal LPS injection. The level of NET release was reduced and autophagy is elevated by PD-L1 knockout in ARDS neutrophils both in vivo and in vitro. Inhibition of autophagy could reverse the inhibitory effect of PD-L1 knockout on NET release. PD-L1 interacted with p85 subunit of PI3K at the endoplasmic reticulum (ER) in neutrophils from ARDS patients, activating the PI3K/Akt/mTOR pathway. An extrinsic neutralizing antibody against PD-L1 showed a protective effect against ARDS. Together, PD-L1 maintains the release of NETs by regulating autophagy through the PI3K/Akt/mTOR pathway in ARDS. Anti-PD-L1 therapy may be a promising measure in treating ARDS. [ABSTRACT FROM AUTHOR]

The cerebrospinal fluid (CSF) immune responses in HIV-uninfected cryptococcal meningitis (CM) have not beenwell studied. In this study, we aimed to explore the phenotype of CSF immune response during the course of disease and to examine relationships between phenotypes and disease severity. We profiled the CSF immune response in 128 HIV-uninfected CM and 30 pulmonary cryptococcosis patients using a 27-plex Luminex cytokine kit. Principal component analyses (PCA) and logistic regression model were performed. Concentrations of 23 out of 27 cytokines and chemokines in baseline CSF were significantly elevated in CM patients compared with pulmonary cryptococcosis cases. In CM patients with Cryptococcus neoformans infection, IL-1ra, IL-9, and VEGF were significantly elevated in immunocompetent cases. Cytokine levels usually reached peaks within the first 2 weeks of antifungal treatment and gradually decreased over time. PCA demonstrated a co-correlated CSF cytokine and chemokine response consisting of Th1, Th2, and Th17 type cytokines. Prognostic analysis showed that higher scores for the PCs loading pro-inflammatory cytokines, IFN-g, TNF-a, and IL-12; and anti-inflammatory cytokine, IL-4; and chemokines, Eotaxin, FGF-basis, and PDGF-bb; as well as lower scores for the PCs loading RANTES were associated with disease severity, as defined by a Glasgow Coma Scale of <15 or death. In conclusion, combined inflammatory responses in CSF involving both pro- and anti-inflammatory cytokines and chemokines are upregulated in HIV-uninfected CM, and associated with disease severity. [ABSTRACT FROM AUTHOR]

Programmed death ligand 1 (PD-L1) is not only an important molecule in mediating tumor immune escape, but also regulates inflammation development. Here we showed that PD-L1 was upregulated on neutrophils in lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS). Neutrophil specific knockout of PD-L1 reduced lung injury in ARDS model induced by intratracheal LPS injection. The level of NET release was reduced and autophagy is elevated by PD-L1 knockout in ARDS neutrophils both in vivo and in vitro. Inhibition of autophagy could reverse the inhibitory effect of PD-L1 knockout on NET release. PD-L1 interacted with p85 subunit of PI3K at the endoplasmic reticulum (ER) in neutrophils from ARDS patients, activating the PI3K/Akt/mTOR pathway. An extrinsic neutralizing antibody against PD-L1 showed a protective effect against ARDS. Together, PD-L1 maintains the release of NETs by regulating autophagy through the PI3K/Akt/mTOR pathway in ARDS. Anti-PD-L1 therapy may be a promising measure in treating ARDS. [ABSTRACT FROM AUTHOR]