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Idiopathic oligoasthenozoospermia (iOAZS) is one of the major causes of male infertility, and the ideal therapies for iOAZS have not been established yet. Traditional Chinese medicine (TCM), including Xianlu oral solution (XL), has been widely used as an adjunct treatment for male infertility in the clinic. However, the underlying mechanisms of XL treatment on iOAZS are still not known. Here, we found that XL treatment has therapeutic effects on ornidazole (ORN)-induced OAZS model rats through the amelioration of testis tissues spermatogenesis and the improvement of sperm concentration and motility. Moreover, XL treatment ameliorated the serum hormone levels, mitochondrial membrane potential, apoptosis status, and oxidative stress status in the testis tissues of iOAZS model rats. These findings identify a potential mechanism underlying the therapeutic effects of Xianlu oral solution on iOAZS, and Xianlu oral solution may be used as a traditional Chinese medicine (TCM) therapy for male infertility caused by iOAZS in clinical practice.

Background To achieve replicative immortality, most cancers develop a telomere maintenance mechanism, such as reactivation of telomerase or alternative lengthening of telomeres (ALT). There are limited data on the prevalence and clinical significance of ALT in pediatric brain tumors, and ALT-directed therapy is not available. Methods We performed C-circle analysis (CCA) on 579 pediatric brain tumors that had corresponding tumor/normal whole genome sequencing through the Open Pediatric Brain Tumor Atlas (OpenPBTA). We detected ALT in 6.9% (n = 40/579) of these tumors and completed additional validation by ultrabright telomeric foci in situ on a subset of these tumors. We used CCA to validate TelomereHunter for computational prediction of ALT status and focus subsequent analyses on pediatric high-grade gliomas (pHGGs) Finally, we examined whether ALT is associated with recurrent somatic or germline alterations. Results ALT is common in pHGGs (n = 24/63, 38.1%), but occurs infrequently in other pediatric brain tumors ( Conclusions We demonstrate that ATRX is mutated in only a subset of ALT+ pHGGs, suggesting other mechanisms of ATRX loss of function or alterations in other genes may be associated with the development of ALT in these patients. We show that germline variants in MMR are associated with the development of ALT in patients with pHGG.

To investigate the effects of acupuncture on phosphorylated P38 mitogen-activated protein kinase (p-P38MAPK), intercellular adhesion molecule-1 (ICAM-1), interferon γ (IFN-γ), and eosinophilic granulocytes (EOS) in lung tissue of asthmatic rats, and to explore the mechanism of acupuncture in regulating the apoptosis of EOS.Clean-grade male Wistar rats were randomly divided into normal, model, dexamethasone and acupuncture groups, 8 rats in each group. The asthmatic model was established by intraperitoneal injection of mixture suspension (1 mL) of 10% ovalbumin and 10% Al(OH)_3+ normal saline, followed by inhalation of atomized 1% ovalbumin solution for 30 min, once daily for 2 weeks to trigger occurrence of asthmatic symptoms. The rats in dexamethasone group were intraperitoneally injected with 0.9 mg/kg dexamethasone since day 15 once a day for two consecutive weeks. In the acupuncture group, bilateral "Feishu" (BL13), "Pishu" (BL20), "Shenshu" (BL23), "Dingchuan" (EX-B1), and "Danzhong" (CV17) were selected for acupuncture treatment once every other day since day 15 for two consecutive weeks. Uniform reinforcing and reducing manipulation was carried out, and the needles were retained for 30 min. The pathological changes of the lung tissue were observed by hematoxylin-eosin (HE) staining. The apoptosis of EOS in the lung tissue of rats was detected by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. The expression of p-P38MAPK in the lung tissue was detected by Western blot. The protein and mRNA levels of ICAM-1 and IFN-γ in the lung tissue were determined by immunohistochemistry and real-time PCR, respectively.The results of HE staining showed that the pulmonary alveoli and surrounding tissues were intact with no inflammatory cell infiltration in the normal group. The model group showed massive exudation of inflammatory materials and thickened pulmonary interstitium. The dexamethasone group and acupuncture group showed less damage of the alveolar structure and only a small number of inflammatory cells around the airway. Compared with the normal group, the apoptosis rate of EOS in lung tissue was decreased (Acupuncture may inhibit the P38MAPK signaling pathway, down-regulate ICAM-1 expression, and up-regulate IFN-γ expression to promote the apoptosis of EOS and reduce EOS aggregation, thus alleviating the inflammatory response of airway in asthma.

BackgroundTo achieve replicative immortality, most cancers develop a telomere maintenance mechanism, such as reactivation of telomerase or alternative lengthening of telomeres (ALT). There are limited data on the prevalence and clinical significance of ALT in pediatric brain tumors, and ALT-directed therapy is not available.MethodsWe performed C-circle analysis (CCA) on 579 pediatric brain tumors that had corresponding tumor/normal whole genome sequencing through the Open Pediatric Brain Tumor Atlas (OpenPBTA). We detected ALT in 6.9% (n=40/579) of these tumors and completed additional validation by ultrabright telomeric fociin situon a subset of these tumors. We used CCA to validateTelomereHunterfor computational prediction of ALT status and focus subsequent analyses on pediatric high-grade glioma (pHGG) Finally, we examined whether ALT is associated with recurrent somatic or germline alterations.ResultsALT is common in pHGG (n=24/63, 38.1%), but occurs infrequently in other pediatric brain tumors (ATRXmutations occur in 50% of ALT+ pHGG and in 30% of ALT-pHGG. Rare pathogenic germline variants in mismatch repair (MMR) genes are significantly associated with an increased occurrence of ALT. Conclusions: We demonstrate thatATRXis mutated in only a subset of ALT+ pHGG, suggesting other mechanisms ofATRXloss of function or alterations in other genes may be associated with the development of ALT in these patients. We show that germline variants in MMR are associated with development of ALT in patients with pHGG.Key PointsATRX alterations are frequent, but not required, for an ALT phenotype in pHGGspHGG patients with germline mismatch repair variants have higher rate of ALT + tumorsTelomereHunteris validated to predict ALT in pHGGsImportance of the StudyWe performed orthogonal molecular and computational analyses to detect the presence of alternative lengthening of telomeres in a highly characterized cohort of pediatric brain tumors. We demonstrate that many pHGG utilize ALT without a mutation in ATRX, suggesting either loss of function of ATRX via an alternative mechanism or an alternate means of development of ALT. We show that germline variants in MMR genes are significantly associated with ALT in pHGG. Our work adds to the biological understanding of the development of ALT and provides an approach to stratify patients who may benefit from future ALT-directed therapies in this patient population.

Understanding the immune microenvironment in pediatric low-grade glioma (pLGG) patients may help in identification of the patients who benefit from anti-tumor immunotherapies. However, surgical resection is not feasible for many pLGG tumors in certain anatomical locations. Therefore, developing non-invasive tools that characterize the tumor microenvironment prior to therapeutic interventions could contribute to stratification and enrollment of the patients into relevant clinical trials. In this work, we derived radiomic signatures of immune profiles (radioimmunomics) based on machine learning (ML) analysis of readily available conventional MRI scans. Transcriptomic data for a cohort of 197 subjects was retrospectively collected from Open Pediatric Brain Tumor Atlas (OpenPBTA). The patients were categorized into three groups (Group1-3) based on their immunological profiles using consensus clustering algorithm. This analysis revealed greater immune cell infiltration in non-BRAF mutated pLGGs. Group1 showed more enrichment in M1 macrophages, and microenvironment and immune scores compared to Group2 and Group3. Elevated tumor inflammation score (TIS), as a predictor of clinical response to anti-PD-1 blockade, was observed in Group1 compared to Group2 (p= 1.4e-7) and Group3 (p= 0.0054). Radiomic features, including volumetric, morphologic, histogram, and texture descriptors, were extracted from the segmented tumor regions on multiparametric MRI (mpMRI) scans of 71 (of 197) patients. Multivariate ML models were trained to predict the three immunological groups based on radiomic features using cross-validated random forest classifier along with recursive feature elimination, which yielded AUC of 0.72 for this multi-class classification problem. Our findings indicate the presence of distinct immunological groups in pLGG tumors, with possibly more favorable response to immunotherapies in Group1 tumors. Furthermore, we developed radioimmunomic signatures based on pre-operative conventional mpMRI that can potentially stratify the patients based on their immune tumor microenvironment. Based on these initial promising results, we are exploring additional features to increase the accuracy of radioimmunomics model.

The relationship between inflammation and age-related neurocognitive changes is significant, which may relate to the age-related immune dysfunctions characterized by the senescence of immune cells and elevated inflammatory markers in the peripheral circulation and the central nervous system. In this review, we discuss the potential mechanisms, including the development of vascular inflammation, neuroinflammation, organelle dysfunctions, abnormal cholesterol metabolism, and glymphatic dysfunctions as well as the role that the key molecules play in the immune-cognition interplay. We propose potential therapeutic pharmacological and behavioral strategies for ameliorating age-related neurocognitive changes associated with inflammation. Further research to decipher the multidimensional roles of chronic inflammation in normal and pathological aging processes will help unfold the pathophysiological mechanisms underpinning neurocognitive disorders. The insight gained will lay the path for developing cost-effective preventative measures and the buffering or delaying of age-related neurocognitive decline.

SUMMARY OBJECTIVE: The aim of this study was to explore the efficacy of imipenem combined with glutamine in the treatment of severe acute pancreatitis with abdominal infection in mainland China using meta-analysis. METHODS: We searched China National Knowledge Network, Wanfang Medical Network, Chinese Science Citation Database, PubMed, and Embase Databases for publications of imipenem combined with glutamine in the treatment of severe acute pancreatitis abdominal infection. The search time limit was from the establishment of the database to April 10, 2021. Stata software version 12.0 was used for statistical analysis; the combined effect size odds ratio and standardized mean difference values were calculated for the count data and measurement data, respectively; and the heterogeneity test was performed in this study. RESULTS: A total of five randomized controlled trials were included. A total of 499 cases were included, with 251 in the observation group and 248 in the control group. Meta-analysis results showed that the efficacy of imipenem combined with glutamine in the treatment of severe acute pancreatitis with abdominal infection was significantly better than that of imipenem alone (odds ratio=0.78, 95%CI 0.71–0.86, p=0.040). CONCLUSION: Imipenem combined with glutamine can significantly improve the efficacy in the treatment of severe acute pancreatitis with abdominal cavity infection.

Plants monitor seasonal cues to optimize reproductive success by tuning onset of reproduction and inflorescence architecture. TERMINAL FLOWER 1 (TFL1) and FLOWERING LOCUS T (FT) and their orthologs antagonistically regulate these life history traits, yet their mechanism of action, antagonism and targets remain poorly understood. Here, we show that TFL1 is recruited to thousands of loci by the bZIP transcription factor FD. We identify the master regulator of floral fate, LEAFY (LFY) as a target under dual opposite regulation by TFL1 and FT and uncover a pivotal role of FT in promoting flower fate via LFY upregulation. We provide evidence that the antagonism between FT and TFL1 relies on competition for chromatin-bound FD at shared target loci. Direct TFL1-FD regulated target genes identify this complex as a hub for repressing both master regulators of reproductive development and endogenous signalling pathways. Our data provide mechanistic insight into how TFL1-FD sculpt inflorescence architecture, a trait important for reproductive success, plant architecture and yield., The flowering regulators TFL1 and FT act antagonistically to synchronize reproductive transition in flowering plants. Here Zhu et al. show that TFL1 is recruited by the bZIP transcription factor FD to thousands of target loci and reveal that FT competes with TFL1 for chromatin bound-FD at shared targets including LFY, upregulation of which by FT promotes floral fate.

Context.— We implemented multiple nucleic acid amplification test platforms because of the limited availability of test kits for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the early stages of the pandemic. Interpretation of results generated by different platforms and prioritization for testing algorithms required cross-comparison. Objective.— To compare the analytical sensitivity of 3 commercial SARS-CoV-2 molecular assays, selected samples were studied in parallel with Cobas SARS-CoV-2 test, NxTAG CoV Extended Panel, and ID NOW COVID-19 assays. Design.— A total of 8043 SARS-CoV-2 tests performed from March 22 to April 19, 2020, were included in this study. For all 1794 positive specimens detected by the cobas SARS-CoV-2 assay, the cycle threshold (Ct) values were manually tracked and plotted to demonstrate the distribution of sample viral levels. Additionally, 50 and 63 low-positive specimens (Ct values >32) as well as 50 and 61 consecutive positive specimens by the cobas assay were tested with NxTAG and ID NOW, respectively, to estimate their relative sensitivities. Results.— The Ct values of cobas SARS-CoV-2–positive samples were evenly distributed throughout ranges of 13.32 to 39.50 (mean, 25.06) and 13.60 to 42.49 (mean, 26.45) for ORF1 and E gene targets, respectively. NxTAG reliably detected only specimens with E gene Ct values lower than 33, and is estimated to detect 89.4% of positive specimens detected by cobas assay. ID NOW had performance variation independent of Ct value and is estimated to detect 83.5% of cobas positives. Conclusions.— Clinical specimens exhibit a wide range of viral burden, with a significant portion at low levels. Analytical sensitivity of testing platforms is critical for reliable detection of SARS-CoV-2 and uniform care to patients.

Recently, more and more attention has been paid to the strong oxidation ability of newly prepared potassium ferrate (NAPF) in sludge reduction process, but less attention has been paid to the change of phosphorus in this process. The feasibility of phosphorus migration and transformation during excess sludge reduction pretreatment using NAPF pre-oxidation combined with anaerobic digestion was investigated. After 70 mg/g suspended solids NAPF pretreatment and 16 days anaerobic digestion, the solid-phase volatile suspended solids decreased by 44.2%, and much organic matter had been released into the liquid-phase and then degraded during digestion by indigenous microorganisms. As the sludge pre-oxidation process was performed, solid-phase organic phosphorus and chemically combined phosphorus also released into the liquid-phase as PO43−, peaking at 100 mg/L. During anaerobic digestion, the Fe3+ in the liquid-phase was gradually reduced to Fe2+, and then formed Fe2+-PO43− compound crystals and re-migrated to the solid-phase. The concentration of PO43− decreased to 17.08±1.1 mg/L in the liquid-phase after anaerobic digestion. Finally, the phosphorus in the Fe2+-PO43− compound accounts for 80% of the total phosphorus in the solid-phase. A large number of vivianite crystals in sludge were observed. Therefore, this technology not only effectively reduces sludge, but also increases the proportion of PO43− in the sludge in the form of Vivianite.

To observe the effect of acupoint catgut embedment(ACE) on expression of p38 mitogen activated protein kinase (p38MAPK), intercellular adhesion molecule-1(ICAM-1), interleukin-4 (IL-4) and eosinophils (EOS) in lung tissue of asthmatic rats, so as to explore its mechanism underlying improvement of asthma.Forty male Wistar rats were randomly divided into control, model, ACE and dexamethasone (DEX) groups, with 10 rats in each group. The asthmatic model was established by intraperitoneal injection of mixture suspension (1 mL) of ovalbumin (OVA,10%) and 10% Al (OH)Findings of optical microscope and TEM showed obvious bronchial deformation and inflammatory cell infiltration, rupture of EOS cell membrane, uneven cytoplasm with swelling and uneven density of eosinophilic granules in EOS of the model group, which was relatively milder in the ACE and DEX groups. Compared with the control group, the EOS number in BALF and the expressions of p38MAPK, ICAM-1 and IL-4 mRNAs in the lung tissue were significantly increased (Catgut embedding at acupoints may alleviate the airway inflammatory response in asthma rats, which may be related with its effects in down-regulating p38MAPK signaling, ICAM-1 and IL-4 mRNA expression, reducing the aggregation of EOS, and promoting the apoptosis of EOS.

Male diabetic individuals present a marked impairment in fertility; however, knowledge regarding the pathogenic mechanisms and therapeutic strategies is unsatisfactory. The new hypoglycemic drug dapagliflozin has shown certain benefits, such as decreasing the risk of cardiovascular and renal events in patients with diabetes. Even so, until now, the effects and underlying mechanisms of dapagliflozin on diabetic male infertility have awaited clarification. Here, we found that dapagliflozin lowered blood glucose levels, alleviated seminiferous tubule destruction, and increased sperm concentrations and motility in leptin receptor-deficient diabetic db/db mice. Moreover, the glucagon-like peptide-1 receptor (GLP-1R) antagonist exendin (9-39) had no effect on glucose levels but reversed the protective effects of dapagliflozin on testicular structure and sperm quality in db/db mice. We also found that dapagliflozin inhibited the testicular apoptotic process by upregulating the expression of the antiapoptotic protein B-cell lymphoma 2 (BCL2) and X-linked inhibitor of apoptosis protein (XIAP) and inhibiting oxidative stress by enhancing the antioxidant status, including total antioxidant capacity, total superoxide dismutase (SOD) activity, and glutathione peroxidase (GPx) activity, as well as decreasing the level of 4-hydroxynonenal (4-HNE). Exendin (9-39) administration partially reversed these effects. Furthermore, dapagliflozin upregulated the glucagon-like peptide-1 (GLP-1) level in plasma and GLP-1R expression by promoting AKT8 virus oncogene cellular homolog (Akt) phosphorylation in testicular tissue. Exendin (9-39) partially inhibited Akt phosphorylation. These results suggest that dapagliflozin protects against diabetes-induced spermatogenic dysfunction via activation of the GLP-1R/phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Our results indicate the potential effects of dapagliflozin against diabetes-induced spermatogenic dysfunction.

Glutamine transporters play an important role in supporting increased tumor nutritional demands, often through overexpression of the solute carrier (SLC) family of membrane transporters. We aimed to understand the relationship of SLC transporter expression with pediatric brain tumor subtypes, lipid metabolism and their potential prognostic significance using data from the Pediatric Brain Tumor Atlas (PBTA). Using the expression of amino acid transporter genes, we found that elevated expression of glutamine transporters (SLC1A5, SLC7A5, SLC7A11, SLC38A5, SLC38A3) predicted shorter progression-free survival (PFS) in low-grade gliomas (LGGs) and poorer overall survival in pediatric ependymomas, high-grade gliomas (HGGs), and medulloblastomas. We focused specifically on SLC1A5 given the availability of imaging probes (18 F-Fluoroglutamine and 18F-Fluciclovine) for the corresponding amino acid transporter (ASCT2). Kaplan-Meier analysis found that higher expression of SLC1A5 was associated with shorter OS in ependymoma and medulloblastoma (p = 0.032 and p = 9.8e-4) and shorter PFS in LGG (p = 0.022). We found a universally higher expression of ATP citrate lyase (ACLY) and Acetyl-CoA carboxylase 1 (ACC) relative to normal brain tissue across all histologies. BRAF driven low grade gliomas and SHH-driven medulloblastomas showed differential expression of ACLY compared to other histologies. In addition, Acyl-CoA synthetase short chain family member 1 and 2 (ACSS1 and 2) were universally downregulated in pediatric gliomas, indicating that pediatric CNS tumors seem to rely on ACLY over ACSS for lipid synthesis. Gene set analysis showed higher expression and network rewiring of amino acid, lipid, and immune pathways in SLC1A5-high expressing clusters. SLC1A5 correlated negatively with pathways associated with lipid metabolic breakdown/degradation and correlated positively with pathways associated with lipid biosynthesis. In conclusion, our work demonstrates that glutamine transporters, particularly SLC1A5, represent compelling targets in pediatric brain tumors and can be exploited with theranostic approaches and amino-acid PET imaging.

Cancer-associated pain is debilitating. However, the mechanism underlying cancer-induced spontaneous pain and evoked pain remains unclear. Here, using behavioral tests with immunofluorescent staining, overexpression, and knockdown of TRESK methods, we found an extensive distribution of TRESK potassium channel on both CGRP+ and IB4+ nerve fibers in the hindpaw skin, on CGRP+ nerve fibers in the tibial periosteum which lacks IB4+ fibers innervation, and on CGRP+ and IB4+ dorsal root ganglion (DRG) neurons in rats. Moreover, we found a decreased expression of TRESK in the corresponding nerve fibers within the hindpaw skin, the tibial periosteum and the DRG neurons in bone cancer rats. Overexpression of TRESK in DRG neurons attenuated both cancer-induced spontaneous pain (partly reflect skeletal pain) and evoked pain (reflect cutaneous pain) in tumor-bearing rats, in which the relief of evoked pain is time delayed than spontaneous pain. In contrast, knockdown of TRESK in DRG neurons produced both spontaneous pain and evoked pain in naïve rats. These results suggested that the differential distribution and decreased expression of TRESK in the periosteum and skin, which is attributed to the lack of IB4+ fibers innervation within the periosteum of the tibia, probably contribute to the behavioral divergence of cancer-induced spontaneous pain and evoked pain in bone cancer rats. Thus, the assessment of spontaneous pain and evoked pain should be accomplished simultaneously when evaluating the effect of some novel analgesics in animal models. Also, this study provides solid evidence for the role of peripheral TRESK in both cancer-induced spontaneous pain and evoked cutaneous pain.

The aims of this study were to evaluate the situation of sleep quality among Chinese medical staff during the coronavirus disease 2019 (COVID-19) pandemic. We used the Pittsburgh Sleep Quality Index (PSQI) to assess sleep quality among medical staff from 8 May 2020 to 22 May 2020 in People's Republic of China. A total of 101 (25%) participants were poor sleepers, while 303 (75%) were good sleepers, as defined by PSQI. The PSQI scores were higher in high age, married, master/doctor, nurse, and frequent night shifts groups when compared with those in middle and low age, unmarried and divorced/widowed, bachelor or below, clinician and other job, low frequency night shifts, respectively (all p

Highly accurate testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the point of care (POC) is an unmet diagnostic need in emergency care and time-sensitive outpatient care settings. Reverse transcription-PCR (RT-PCR) technology is the gold standard for SARS-CoV-2 diagnostics., Highly accurate testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the point of care (POC) is an unmet diagnostic need in emergency care and time-sensitive outpatient care settings. Reverse transcription-PCR (RT-PCR) technology is the gold standard for SARS-CoV-2 diagnostics. We performed a multisite U.S. study comparing the clinical performance of the first U.S. Food and Drug Administration (FDA)-authorized POC RT-PCR for detection of SARS-CoV-2 in 20 min, the cobas Liat SARS-CoV-2 and influenza A/B nucleic acid test, to the most widely used RT-PCR laboratory test, the cobas 68/8800 SARS-CoV-2 test. Clinical nasopharyngeal swab specimens from 444 patients with 357 evaluable specimens at five U.S. clinical laboratories were enrolled from 21 September 2020 to 23 October 2020. The overall agreement between the Liat and 68/8800 systems for SARS-CoV-2 diagnostics was 98.6% (352/357). Using Liat, positive percent agreement for SARS-CoV-2 was 100% (162/162) and the negative percent agreement was 97.4% (190/195). The Liat is an RT-PCR POC test that provides highly accurate SARS-CoV-2 results in 20 min with performance equivalent to that of high-throughput laboratory molecular testing. Rapid RT-PCR testing at the POC can enable more timely infection control and individual care decisions for coronavirus disease 2019.

Glutamine transporters play an important role in supporting increased tumor nutritional demands relative to non-cancerous cells, often through overexpression of the solute carrier (SLC) family of membrane transporters. Preclinical studies in adult cancers demonstrate that targeting glutamine addiction via SLC1A5 inhibition results in growth-inhibitory and tumoricidal effects. Given their relatively higher expression in cancer versus normal brain tissue, SLC transporters represent compelling targets for molecularly-targeted radiation and application of available prognostic amino-acid PET imaging probes. However, the role of SLC transporters in pediatric brain cancers has yet to be investigated. We aimed to understand the relationship of SLC transporter expression with pediatric brain tumor subtypes and their potential prognostic significance using data from the Pediatric Brain Tumor Atlas (PBTA). Using the expression of amino acid transporter genes in ensemble survival models (Reactome: R-HSA-352230), we found that elevated expression of glutamine transporters (SLC1A5, SLC7A5, SLC7A11, SLC38A5, SLC38A3) predicted shorter progression-free survival (PFS) in low-grade gliomas (LGGs) and poorer overall survival in pediatric ependymomas, high-grade gliomas (HGGs), and medulloblastomas. We focused specifically on SLC1A5 given the availability of imaging probes (18 F-Fluoroglutamine and 18F-Fluciclovine) for the corresponding amino acid transporter (ASCT2). Through transcriptome-based consensus clustering, we found that supratentorial, RELA fusion-positive ependymomas and sonic hedgehog-activated medulloblastomas were over-represented among clusters expressing higher levels of SLC1A5 (p = 3.38e-7 and p = 2.18-26, respectively). Kaplan-Meier analysis found that higher expression of SLC1A5 was associated with shorter OS in ependymoma and medulloblastoma (p = 9.8e-4 and p = 0.032) and shorter PFS in LGG (p = 0.022). Gene set analysis showed higher expression and network rewiring of amino acid, lipid, and immune pathways in SLC1A5-high expressing clusters. Our work demonstrates that glutamine transporters, particularly SLC1A5, represent compelling targets in pediatric brain cancers that warrant further investigation for molecularly-targeted treatment and amino-acid PET imaging.

While much of the somatic coding variation underlying the oncogenic transformation of pediatric high-grade gliomas (HGGs) has been profiled, transcriptional splicing programs of these tumors remain under-explored. Here, we characterize aberrant alternative splicing in pediatric midline HGGs (n = 84). We identified 19,275 recurrent and significant (20% change from control, P < 0.05, FDR < 0.05) aberrant splicing events in 8,587 genes compared to non-diseased brainstem controls. Of those, 27% (n = 5,157) resulted in either a gain or loss of a known protein functional site within 3,294 genes. We prioritized splice variants affecting targetable kinases and found that mRNAs encoding CDC-like kinase 1 (CLK1), a known modulator of master splicing regulators, exhibit significantly increased exon 4 inclusion in midline HGGs. This leads to a gain of two known phosphorylation sites in CLK1, increased CLK1 protein expression and hyper-phosphorylation of Serine-rich splicing factors. To assess the impact of this event, we performed differential splicing and expression analyses, comparing tumors with the highest (n= 5) and lowest (n = 5) exon 4 inclusion. We discovered 3,037 genes to be differentially up-regulated in high exon 4 inclusion tumors with an enrichment of cancer-related pathways, including DNA repair, mitotic spindle, myogenesis and EMT. We next integrated these gene signatures with protein-protein interaction networks of kinase and transcription factors and show that increased CLK1 exon 4 inclusion disrupts critical regulatory networks, such as those involving FOXM1, which is implicated in cell cycle and proliferation processes. In summary, we describe aberrant splicing in pediatric HGGs as an additional mechanism that could drive tumorigenesis. Future work will focus on molecular validation and therapeutic targeting of CLK1 in available HGG models. Characterizing tumor-specific splicing variation has the potential to open new therapeutic strategies and understand mechanisms of treatment resistance in children with central nervous system tumors.

Background and Objective: Prevention and control of metabolic syndrome is the key to improving the development of systemic lupus erythematosus. The aim of this study was to analyze the relevant factors regarding metabolic syndrome (MS) in systemic lupus erythematosus (SLE). Methods: A total number of 1238 SLE patients in Yijishan Hospital of Wannan Medical College, Anhui province, from February 2012 to July 2017, were analyzed retrospectively. SLE patients with MS were grouped to group SLE-MS, the others without MS was grouped to group SLE-nMS. The two groups were compared with respect to general characteristics, clinical signs, and laboratory parameters. Random forest approach and multivariate logistic regression were conducted to analyze the related factors regarding MS in SLE. Results: The constituent ratio of metabolic syndrome was 27.14% (336/1238). More SLE patients with MS presented with more farmers, more married people, lower education level, and more lupus nephritis, proteinuria, oral ulcers, tubular urine, hematuria than SLE patients without MS (P

Rationale: Idiopathic asthenozoospermia (iAZS) is one of the major causes of male infertility and has no effective therapeutic treatment. Understanding the potential mechanisms that cause it may be helpful in seeking novel targets and treatment strategies for overcoming the problem of low sperm motility in iAZS individuals. Methods: Computer-assisted semen analysis (CASA) was utilized to assess the sperm motility. RT-qPCR, Western blot, immunofluorescence staining, and calcium imaging analysis were performed to examine the expression and function of CatSper channels. Hyperactivation and acrosome reaction were used to evaluate the functional characteristics of epididymal sperm. In vivo fertility assay was applied to determine the fertility of rats. CatSper1 knockdown and overexpression experiments were performed to confirm the roles of CatSper channels in the pathogenesis of iAZS and the therapeutic effects of electroacupuncture (EA) treatment on AZS model rats. Results: Here, we reported a functional down-regulation of CatSper channel from CatSper1 to CatSper 4 in the sperm of both iAZS patients and ornidazole (ORN)-induced AZS model rats, and an impaired sperm function characterized by a reduction of protein tyrosine phosphorylation, hyperactivation, and acrosome reaction in the epididymal sperm of AZS rats. Knockdown of CatSper1 in the testis tissues is sufficient to induce AZS in normal rats, and this action was validated by the reversal effects of CatSper1 overexpression. Transcutaneous electrical acupoint stimulation (TEAS) and electroacupuncture (EA) at 2 Hz frequency improve the sperm motility via enhancing the functional expression of CatSper channels in the sperm. Gene silencing CatSper1 in the sperm abolishes the therapeutic effects of 2 Hz-EA treatment on AZS rats. Conclusions: We conclude that a functional down-regulation of CatSper channel in the sperm may be a contributor or a downstream indicator for a portion of AZS, especially iAZS, while 2 Hz-TEAS or EA treatment has a therapeutic effect on iAZS through inducing the functional up-regulation of CatSper channels in the sperm. This study provides a novel mechanism for the pathogenesis of some AZS especially iAZS, and presents a potential therapeutic target of CatSper for iAZS treatment. Acupuncture treatment like TEAS may be used as a promising complementary and alternative medicine (CAM) therapy for male infertility caused by iAZS in clinical practice.

Master transcription factors reprogram cell fate in multicellular eukaryotes. Pioneer transcription factors have prominent roles in this process because of their ability to contact their cognate binding motifs in closed chromatin. Reprogramming is pervasive in plants, whose development is plastic and tuned by the environment, yet little is known about pioneer transcription factors in this kingdom. Here, we show that the master transcription factor LEAFY (LFY), which promotes floral fate through upregulation of the floral commitment factor APETALA1 (AP1), is a pioneer transcription factor. In vitro, LFY binds to the endogenous AP1 target locus DNA assembled into a nucleosome. In vivo, LFY associates with nucleosome occupied binding sites at the majority of its target loci, including AP1. Upon binding, LFY ‘unlocks’ chromatin locally by displacing the H1 linker histone and by recruiting SWI/SNF chromatin remodelers, but broad changes in chromatin accessibility occur later. Our study provides a mechanistic framework for patterning of inflorescence architecture and uncovers striking similarities between LFY and animal pioneer transcription factor., Pioneer transcription factors access their DNA binding motifs in closed chromatin and often act in cell fate reprogramming. Here, Jin et al. present biochemical evidence for a pioneer factor in plants and show that LFY promotes floral cell fate and locally unlocks chromatin by displacing histone H1 and recruiting SWI/SNF chromatin remodelers.

Plants monitor seasonal cues, such as day-length, to optimize life history traits including onset of reproduction and inflorescence architecture1–3. Florigen family transcriptional co-regulators TERMINAL FLOWER 1 (TFL1) and FLOWERING LOCUS T (FT) antagonistically regulate these vital processes4–6yet how TFL1 and FT execute their roles and what the mechanism is for their antagonism remains poorly understood. We show genome-wide, that TFL1 is recruited to the chromatin by the bZIP transcription factor FLOWERING LOCUS D (FD) inArabidopsis. We find that seasonal cue-mediated upregulation of FT competes TFL1 from chromatin-bound FD at key target loci. We identify the master regulator of floral fate,LEAFY(LFY) as a target under dual opposite regulation by TFL1 and FT. Exonic bZIP motifs inLFYare critical for repression by TFL1, upregulation by FT and adoption of floral fate. Transcriptomic identification of target genes directly repressed by the TFL1-FD complex not only identifies key regulators of onset of reproduction and floral fate, but reveals that TFL1-FD repress sugar and hormone signalling pathways and chromatin regulators. Our data provide mechanistic insight into how florigen family member sculpt inflorescence architecture, a trait important for reproductive success and yield.

Background Previous studies have shown that T cell immunoglobulin domain and mucin-3 (Tim-3) and interleukin-17 (IL-17) are implicated in the development of several autoimmune diseases. However, it is unclear whether these proteins contribute to the pathogenesis of systemic lupus erythematosus (SLE). The purpose of this study was to evaluate SLE patient serum Tim-3 and IL-17 levels, and to assess correlations between these proteins and major clinical parameters of SLE. Material/Methods Overall, 55 SLE patients and 55 healthy controls were recruited in a case-control study. Serum Tim-3 and IL-17 levels were quantified using an enzyme-linked immunosorbent assay (ELISA) kit. Results Serum Tim-3 and IL-17 levels in SLE patients were significantly elevated relative to healthy controls (all P0.05). Serum Tim-3 with IL-17 levels were positively correlated in SLE patients (rs=0.817, P0.05). In addition, serum Tim-3 was associated with central lesions in SLE patients, while there were no significant correlations between serum Tim-3 or IL-17 levels and other SLE clinical parameters. Conclusions Increased serum Tim-3 and IL-17 levels and their clinical associations in SLE patients suggest their possible role in this disease.

Lairun Jin,1 Jun Zhou,1 Hui Peng,2 Shushu Ding,1 Hui Yuan1 1School of Public Health, Wannan Medical College, Wuhu, Anhui, People’s Republic of China; 2Department of Hospital Infection Management, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, People’s Republic of China Objective: The aims of this study were to evaluate a subset of sleep-related cognitions and to examine whether dysfunctional beliefs and attitudes about sleep were associated with sleep quality in college students. Patients and methods: A total of 1,333 college students were enrolled in this study by randomized cluster sampling. A brief version of Dysfunctional Beliefs and Attitudes about Sleep Scale (DBAS-16) was administered to college students at several colleges. Sleep quality was also assessed using the Pittsburgh Sleep Quality Index (PSQI). The DBAS-16 scores were analyzed across different demographic variables, corresponding subscales of 7-item PSQI, and relevant sleep behavior variables. Results: A total of 343 participants were poor sleepers, while 990 were good sleepers, as defined by PSQI. The DBAS-16 scores were lower in poor sleepers than in good sleepers (46.32 ± 7.851 vs 49.87 ± 8.349, p < 0.001), and DBAS-16 scores were lower in females and nonmedical students when compared with those in males and medical students, respectively (48.20 ± 8.711 vs 49.73 ± 7.923, p = 0.001; 48.56 ± 8.406 vs 49.88 ± 8.208, p = 0.009, respectively). The total score for sleep quality, as measured by PSQI, was negatively correlated with the DBAS-16 total score (r = −0.197, p < 0.01). There were significant differences in PSQI scores between individuals with attitudes and those without attitudes about sleep with respect to good sleep habits (p < 0.001), self-relaxation (p = 0.001), physical exercise (p < 0.001), taking sleeping pills (p = 0.004), and taking no action (p < 0.001). Conclusion: Dysfunctional beliefs about sleep are associated with sleep quality and should be discouraged, especially for females and nonmedical college students. Keywords: sleep, dysfunctional beliefs, college students, sleep quality, cognition

Background: Postpartum subinvolution of the uterus is a more common condition after cesarean section. Auricular acupressure (AA) is widely used for the treatment of postpartum diseases. However, few studies have explored the effects of AA as a treatment of uterine involution following cesarean section to date. This study aimed to assess the efficacy and safety of AA for uterine involution after cesarean section. Methods: A total of 109 women who underwent cesarean section participated in this study. They were randomly allocated to either real AA or sham AA in a 1:1 ratio by a computer program. For 3 days, the real AA and sham AA groups received treatment 3 times daily. A series of assessments at 42 days after cesarean section, namely on the uterine size, the incidence of hydrometra, the first anal exsufflation time, bleeding volume at 6 hours, bleeding volume at 6–24 hours along with other general assessments were carried out. Results: A total of 89 women completed the study. The uterine size at 42 days after a cesarean section was 6.3 cm smaller in the real AA group than in the sham AA group (P

The tumor-stroma ratio (TSR) has been reported as a prognosis predictor in multiple cancers. The aim of this meta-analysis was to investigate the potential value of TSR as a prognostic predictor of cancer in the digestive system.We searched PubMed, Embase, Elsevier and Web of Science. All studies exploring the association of TSR with overall survival (OS) or disease-free survival (DFS), and lymph node metastasis (LNM) were identified.In total, eight studies were eligible for analysis, and they included 1959 patients. Meta-analysis showed that the low TSR in the tumor could predict poor overall survival (OS) in multiple cancers (pooled Hazard Ratio [HR]: 2.15, 95%CI: 1.80-2.57, P0.00001, fixed effects). For disease-free survival (DFS), low TSR was also a significant predictor (pooled Hazard Ratio [HR]: 2.31, 95%CI: 1.88-2.83, P0.00001, fixed effects). In addition, low TSR was correlated with tumor stage.The tumor-stroma ratio (TSR) may potentially serve as a poor prognostic predictor for the metastasis and prognosis of cancer.

Previously we have demonstrated that brain-derived neurotrophic factor (BDNF) contributes to spinal long-term potentiation (LTP) and pain hypersensitivity through activation of GluN2B-containing N-methyl-d-aspartate (GluN2B-NMDA) receptors in rats following spinal nerve ligation (SNL). However, the molecular mechanisms by which BDNF impacts upon GluN2B-NMDA receptors and spinal LTP still remain unclear. In this study, we first documented that Fyn kinase-mediated phosphorylation of GluN2B subunit at tyrosine 1472 (pGluN2BY1472) was involved in BDNF-induced spinal LTP and pain hypersensitivity in intact rats. Second, we revealed a co-localization of Fyn and GluN2B-NMDA receptor in cultured dorsal horn neurons, implying that Fyn is a possible intermediate kinase linking BDNF/TrkB signaling with GluN2B-NMDA receptors in the spinal dorsal horn. Furthermore, we discovered that both SNL surgery and intrathecal active Fyn could induce an increased expression of dorsal horn pGluN2BY1472, as well as pain hypersensitivity in response to von Frey filaments stimuli; and more importantly, all these actions were effectively abrogated by pre-treatment with either PP2 or ifenprodil to respectively inhibit Fyn kinase and GluN2B-NMDA receptors activity. Moreover, we found that intrathecal administration of BDNF scavenger TrkB-Fc prior to SNL surgery, could prevent the nerve injury-induced increase of both pFynY420 and pGluN2BY1472 expression, and also inhibit the mechanical allodynia in neuropathic rats. Collectively, these results suggest that Fyn kinase-mediated pGluN2BY1472 is critical for BDNF-induced spinal LTP and pain hypersensitivity in SNL rats. Therefore, the BDNF-Fyn-GluN2B signaling cascade in the spinal dorsal horn may constitute a key mechanism underlying central sensitization and neuropathic pain development after peripheral nerve injury.

The denitrification (DN), partial nitrification (PN) and Anammox processes were coupled in an auto-recycling integration device to remove nitrogen from the supernatant of sludge reduction pretreatment. The nitrogen removal performance of the device and the effect of organic matter concentration on the nitrogen transformation were discussed. The results showed that DN, PN and Anammox are well coupled and total nitrogen (TN) removal rate reached 0.85 kg/(m3·d). The pre-DN process can achieve the removal of NO3−-N produced by the back-end PN-Anammox process without the need of reflux pump drive. When the influent NH4+-N concentration was approximately 400 mg/L, the effluent TN concentration was less than 20 mg/L. The fluctuation of organic matter led to changes of nitrogen transformation in the system, and the best ratio of influent CODbio/TN was 0.7–0.9. Nitrosomonas and Candidatus Brocadia played important roles in the nitrogen removal process as the main functional microorganisms of PN and Anammox, respectively.

Objective: Previous studies have shown that biologic agents out of the nine medicines might be beneficial for the treatment of SLE. The aim of this study was to evaluate the most effective medication of six biologic agents in treatment of SLE using network meta-analysis (NMA). The performance of these processes is ranked according to the results of this analysis. Methods: Multiple databases including PubMed, EMBASE and Cochrane Library was used to identify applicable articles and collect relevant data to analyzed by using STATA (13.0) software. The papers included in this study were divided into control group (placebo) and observation group (one of the six medicines). Results: A total of 21 eligible RCTs of biologic agents were identified, a total of 995 papers were included, and the results showed that the belimumab had the highest probability of being the most clinically efficacious intervention, with a surface under the cumulative ranking (SUCRA) curve of 75.0, was significantly superior (P < 0.05) to placebo alone. The blisibimod was the worst, with a SUCRA value of 29.4. The other biologic agents (atacicept, blisibimod, epratuzumab, rituximab, tabalumab) were insignificantly superior (P > 0.05) to placebo alone. Conclusions: Belimumab had the highest probability of being the best treatment for SLE compared with the other biologic agents (atacicept, blisibimod, epratuzumab, rituximab, tabalumab). The other biologic agents indicated an insignificant difference in efficacy for the treatment of SLE compared with placebo.