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Wen Shi,1 Juan Wu,1 Qi Tan,1 Chun-Mei Hu,2 Xia Zhang,2 Hong-Qiu Pan,3 Zhen Yang,4 Meng-Yu He,1 Min Yu,1 Bo Zhang,5 Wei-Ping Xie,1 Hong Wang11Department of Respiratory and Critical Care Medicine, Jiangsu Province Hospital. The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China; 2Department of Tuberculosis, The Second Hospital of Nanjing, Nanjing, Jiangsu Province, People’s Republic of China; 3Department of Tuberculosis, The Third Hospital of Zhenjiang City, Zhenjiang, Jiangsu Province, People’s Republic of China; 4Department of Respiratory Medicine, Jiangbei Hospital, Nanjing, Jiangsu Province, People’s Republic of China; 5Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA, USAPurpose: Multidrug-resistant tuberculosis (MDR-TB) remains a challenge of global TB control, with difficulty in early detection of drug-sensitive tuberculosis (DS-TB). We investigate the diagnostic significance of IDO as a potential biomarker to discriminate MDR patients among the TB patients.Patients and methods: Plasma indoleamine 2,3-dioxygenase (IDO) was measured by the ratio of kynurenine (Kyn) to tryptophan (Trp) concentrations, using high performance liquid chromatography-mass spectrometry (LC-MS/MS). Chest computed tomography (CT) imaging signs from TB patients were collected and analyzed in 18 DS-TB patients, 16 MDR-TB patients, 6 lung cancer (LC) patients, and 11 healthy individuals. Lung imaging signs from TB patients were collected and analyzed.Results: We found that plasma IDO activity was significantly higher in the MDR-TB patients than in the DS-TB patients (p=0.012) and in the LC patients (p=0.003). We evaluated the diagnostic significance of plasma IDO activity in discriminating the MDR-TB group from the DS-TB group using a receiver operating characteristic (ROC) curve. With a cutoff level of 46.58 uM/mM, the diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for IDO activity were 87.50%, 72.22%, 73.68%, and 86.67%, respectively. Plasma IDO activity was higher in cavity cases than in non-cavity cases (p=0.042), proving a positive correlation between lung cavity number and cavity size (p

Background: Chronic stress-induced neuroinflammation plays a pivotal role in the development and exacerbation of mental disorders, such as anxiety and depression. Dimethyl Fumarate (DMF), an effective therapeutic agent approved for the treatment of multiple sclerosis, has been widely reported to display anti-inflammatory and anti-oxidative effects. However, the impact of DMF on chronic stress-induced anxiety disorders and the exact underlying mechanisms remain largely unknown., Methods: We established a mouse model of chronic social defeat stress (CSDS). DMF was administered orally 1 h before daily stress session for 10 days in CSDS + DMF group. qRT-PCR and western blotting were used to analyze mRNA and protein expression of NLRP3, Caspase-1 and IL-1β. Immunofluorescence staining was carried out to detect the expression of Iba 1 and c-fos positive cells as well as morphological change of Iba 1 + microglia. Whole-cell patch-clamp recording was applied to evaluate synaptic transmission and intrinsic excitability of neurons., Results: DMF treatment significantly alleviated CSDS-induced anxiety-like behaviors in mice. Mechanistically, DMF treatment prevented CSDS-induced neuroinflammation by inhibiting the activation of microglia and NLRP3/Caspase-1/IL-1β signaling pathway in basolateral amygdala (BLA), a brain region important for emotional processing. Furthermore, DMF treatment effectively reversed the CSDS-caused disruption of excitatory and inhibitory synaptic transmission balance, as well as the increased intrinsic excitability of BLA neurons., Conclusions: Our findings provide new evidence that DMF may exert anxiolytic effect by preventing CSDS-induced activation of NLRP3/Caspase-1/IL-1β signaling pathway and alleviating hyperactivity of BLA neurons., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The MeltPro TB assay (MeltPro) is a molecular rapid diagnostic test designed for detecting resistance to antituberculosis drugs. However, the performance of MeltPro as an initial diagnostic test for simultaneously detecting the presence of Mycobacterium tuberculosis (MTB) and drug resistance has not been evaluated. This study aims to assess the performance of MeltPro as initial diagnostic test for simultaneous detection of MTB and drug resistance in clinical samples from patients with presumptive pulmonary tuberculosis (PTB)., Methods: A retrospective analysis was conducted on 1283 patients with presumptive PTB from two clinical centers, out of which 875 were diagnosed with PTB. The diagnostic accuracy of MeltPro, Xpert MTB/RIF (Xpert), and MGIT 960 for PTB detection was evaluated. Rifampicin (RIF), isoniazid (INH), ethambutol (EMB), streptomycin (STR), and fluoroquinolone (FQ) resistance were detected using MeltPro, with Xpert and/or the broth microdilution plate method (MYCOTB) results as references., Results: For the diagnosis of PTB, MeltPro showed a sensitivity of 69.0%, which was similar to Xpert (72.7%; P > 0.05) and higher than MGIT (58.1%; P < 0.001). The specificity of MeltPro was 97.1%, similar to Xpert (98.0%; P > 0.05). In smear-negative patients, MeltPro's sensitivity was 50.9%, similar to Xpert (56.5%; P > 0.05), and higher than MGIT (33.1%; P < 0.001). Based on Xpert and/or MYCOTB results, MeltPro exhibited a sensitivity and specificity of 98.3% and 99.2%, respectively, for detecting RIF resistance. Based on MYCOTB results, MeltPro's sensitivity for detecting resistance to INH, EMB, STR, and FQ was 96.4%, 89.1%, 97.5%, and 90.3%, respectively, with specificities of 96.0%, 96.0%, 95.2%, and 99.4%, respectively., Conclusion: The MeltPro TB assay could potentially be an effective alternative as the initial test for rapid diagnosis of PTB with drug-resistance detection in clinical practice., (© 2023. The Author(s).)

Background: Lymph node metastasis (LNM) is a critical prognostic factor in resectable pancreatic cancer (PC) patients, determining treatment strategies. This study aimed to develop a clinical model to adequately and accurately predict the risk of LNM in PC patients., Methods: 13,200 resectable PC patients were enrolled from the SEER (Surveillance, Epidemiology, and End Results) database, and randomly divided into a training group and an internal validation group at a ratio of 7:3. An independent group (n = 62) obtained from The First Affiliated Hospital of Xinxiang Medical University was enrolled as the external validation group. The univariate and multivariate logistic regression analyses were used to screen independent risk factors for LNM. The minimum Akaike's information criterion (AIC) was performed to select the optimal model parameters and construct a nomogram for assessing the risk of LNM. The performance of the nomogram was assessed by the receiver operating characteristics (ROC) curve, calibration plot, and decision curve analysis (DCA). In addition, an online web calculator was designed to assess the risk of LNM., Result: A total of six risk predictors (including age at diagnosis, race, primary site, grade, histology, and T-stage) were identified and included in the nomogram. The areas under the curves (AUCs) [95% confidential interval (CI)] were 0.711 (95%CI: 0.700-0.722), 0.700 (95%CI: 0.683-0.717), and 0.845 (95%CI: 0.749-0.942) in the training, internal validation and external validation groups, respectively. The calibration curves showed satisfied consistency between nomogram-predicted LNM and actual observed LNM. The concordance indexes (C-indexes) in the training, internal, and external validation sets were 0.689, 0.686, and 0.752, respectively. The DCA curves of the nomogram demonstrated good clinical utility., Conclusion: We constructed a nomogram model for predicting LNM in pancreatic cancer patients, which may help oncologists and surgeons to choose more individualized clinical treatment strategies and make better clinical decisions., (© 2023. The Author(s).)

Objectives: Fecal microbiota transplantation (FMT) has been recommended for the treatment of recurrent Clostridioides difficile infection (CDI). We aimed to evaluate the therapeutic efficacy and safety of washed microbiota transplantation (WMT), a new method of FMT, for CDI across various medical settings., Methods: This multicenter real-world cohort study included CDI patients undergoing WMT. The primary outcome was the clinical cure rate of CDI within 8 weeks after WMT. Secondary outcomes included the CDI recurrence rate and reduction in total abdominal symptom score (TASS) during the follow-up period. Adverse events related to WMT were recorded., Results: Altogether 90.7% (49/54) of CDI patients achieved clinical cure after treated with WMT. The cure rate was 83.3% for cases with severe and complicated CDI (ScCDI) (n = 30) and 100% for non-ScCDI cases (n = 24) (P = 0.059). No difference was observed in the clinical cure rate between patients with first and recurrent CDI (91.9% vs 88.2%, P = 0.645). One week post-WMT, TASS showed a remarkable decrease compared to that at baseline (P < 0.001). Totally, 8.2% (4/49) of patients suffered CDI recurrence during the follow-up period. A WHO performance score of 4, age ≥65 years, higher TASS score, and higher Charlson comorbidity index score were potential risk factors for efficacy (P = 0.018, 0.03, 0.01, 0.034, respectively). Four (3.8%) transient adverse events related to WMT were observed., Conclusions: This study emphasizes the attractive value of WMT for CDI. Early WMT may be recommended for CDI, especially for those in serious condition or with complex comorbidities., Trial Registration: ClinicalTrials.gov, no. NCT03895593 (registered on 27 March 2019)., (© 2023 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

One of the most sought-after topics in neuroscience is to understand how the environment regulates the activity and function of neural circuitry and subsequently influences relevant behaviors. In response to alterations in the environment, the neural circuits undergo adaptive changes ranging from gene expression changes to altered cellular function. Performing sequencing of the transcriptome involved in these behavior-related circuits will provide clues to accurately dissect the detailed mechanisms of related behavior. Here, we describe methods for marking and collecting the ventral hippocampus-projecting basolateral amygdala neurons, which have been repeatedly implicated in regulation of anxiety-like behavior, and subsequently constructing a library ready for sequencing. Specifically, the reported approaches include adeno-associated virus injection, acute brain slice isolation, cell suspension preparation, cell extraction, and cDNA library construction. By utilizing the techniques described here, researchers can comprehensively investigate the transcriptional levels of neural clusters embedded in particular circuits and discover potential pathogenic and therapeutic targets for behavior-relevant disorders. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Tagging of behavior-related neural circuits Basic Protocol 2: Isolation and capture of fluorescent-positive cells Basic Protocol 3: Foundation of sequencing library., (© 2023 Wiley Periodicals LLC.)

Background: Chronic stress exposure increases the risk of mental health problems such as anxiety and depression. The medial prefrontal cortex (mPFC) is a hub for controlling stress responses through communicating with multiple limbic structures, including the basolateral amygdala (BLA) and nucleus accumbens (NAc). However, considering the complex topographical organization of the mPFC neurons in different subregions (dmPFC vs. vmPFC) and across multiple layers (Layer II/III vs. Layer V), the exact effects of chronic stress on these distinct mPFC output neurons remain largely unknown., Results: We first characterized the topographical organization of mPFC neurons projecting to BLA and NAc. Then, by using a typical mouse model of chronic restraint stress (CRS), we investigated the effects of chronic stress on the synaptic activity and intrinsic properties of the two mPFC neuronal populations. Our results showed that there was limited collateralization of the BLA- and NAc-projecting pyramidal neurons, regardless of the subregion or layer they were situated in. CRS significantly reduced the inhibitory synaptic transmission onto the BLA-projecting neurons in dmPFC layer V without any effect on the excitatory synaptic transmission, thus leading to a shift of the excitation-inhibition (E-I) balance toward excitation. However, CRS did not affect the E-I balance in NAc-projecting neurons in any subregions or layers of mPFC. Moreover, CRS also preferentially increased the intrinsic excitability of the BLA-projecting neurons in dmPFC layer V. By contrast, it even caused a decreasing tendency in the excitability of NAc-projecting neurons in vmPFC layer II/III., Conclusion: Our findings indicate that chronic stress exposure preferentially modulates the activity of the mPFC-BLA circuit in a subregion (dmPFC) and laminar (layer V) -dependent manner., (© 2023. The Author(s).)

Anxiety is a normal and transitory emotional state that allows the organisms to cope well with the real or perceived threats, while excessive or prolonged anxiety is a key characteristic of anxiety disorders. We have recently revealed that prolonged anxiety induced by chronic stress is associated with the circuit-varying dysfunction of basolateral amygdala projection neurons (BLA PNs). However, it is not yet known whether similar mechanisms also emerge for acute stress-induced, short-lasting increase of anxiety. Here, using a mouse model of acute restraint stress (ARS), we found that ARS mice showed increased anxiety-like behavior at 2 h but not 24 h after stress, and this effect was accompanied by a transient increase of the activity of BLA PNs. Specifically, ex vivo patch-clamp recordings revealed that the increased BLA neuronal activity did not differ among the distinct BLA neuronal populations, regardless of their projection targets being the dorsomedial prefrontal cortex (dmPFC) or elsewhere. We further demonstrated that such effects were mainly mediated by the enhanced presynaptic glutamate release in dmPFC-to-BLA synapses but not lateral amygdala-to-BLA ones. Furthermore, while optogenetically weakening the presynaptic glutamate release in dmPFC-to-BLA synapses ameliorated ARS-induced anxiety-like behavior, strengthening the release increased in unstressed mice. Together, these findings suggest that acute stress causes short-lasting increase in anxiety-like behavior by facilitating synaptic transmission from the prefrontal cortex to the amygdala in a circuit-independent fashion., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Aims/introduction: Diet therapy is a vital approach to manage type 2 diabetes and prediabetes. However, the comparative efficacy of different eating patterns is not clear enough. We aimed to compare the efficacy of various eating patterns for glycemic control, anthropometrics, and serum lipid profiles in the management of type 2 diabetes and prediabetes., Materials and Methods: We conducted a network meta-analysis using arm-based Bayesian methods and random effect models, and drew the conclusions using the partially contextualized framework. We searched twelve databases and yielded 9,534 related references, where 107 studies were eligible, comprising 8,909 participants., Results: Eleven diets were evaluated for 14 outcomes. Caloric restriction was ranked as the best pattern for weight loss (SUCRA 86.8%) and waist circumference (82.2%), low-carbohydrate diets for body mass index (81.6%), and high-density lipoprotein (84.0%), and low-glycemic-index diets for total cholesterol (87.5%) and low-density lipoprotein (86.6%). Other interventions showed some superiorities, but were imprecise due to insufficient participants and needed further investigation. The attrition rates of interventions were similar. Meta-regression suggested that macronutrients, energy intake, and weight may modify outcomes differently. The evidence was of moderate-to-low quality, and 38.2% of the evidence items met the minimal clinically important differences., Conclusions: The selection and development of dietary strategies for diabetic/prediabetic patients should depend on their holistic conditions, i.e., serum lipid profiles, glucometabolic patterns, weight, and blood pressure. It is recommended to identify the most critical and urgent metabolic indicator to control for one specific patient, and then choose the most appropriate eating pattern accordingly., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Extinguishing the previously acquired fear is critical for the adaptation of an organism to the ever-changing environment, a process requiring the engagement of GABA A receptors (GABA A Rs). GABA A Rs consist of tens of structurally, pharmacologically, and functionally heterogeneous subtypes. However, the specific roles of these subtypes in fear extinction remain largely unexplored. Here, we observed that in the medial prefrontal cortex (mPFC), a core region for mood regulation, the extrasynaptically situated, δ-subunit-containing GABA A Rs [GABA A (δ)Rs], had a permissive role in tuning fear extinction in male mice, an effect sharply contrasting to the established but suppressive role by the whole GABA A R family. First, the fear extinction in individual mice was positively correlated with the level of GABA A (δ)R expression and function in their mPFC. Second, knockdown of GABA A (δ)R in mPFC, specifically in its infralimbic (IL) subregion, sufficed to impair the fear extinction in mice. Third, GABA A (δ)R-deficient mice also showed fear extinction deficits, and re-expressing GABA A (δ)Rs in the IL of these mice rescued the impaired extinction. Further mechanistic studies demonstrated that the permissive effect of GABA A (δ)R was associated with its role in enabling the extinction-evoked plastic regulation of neuronal excitability in IL projection neurons. By contrast, GABA A (δ)R had little influence on the extinction-evoked plasticity of glutamatergic transmission in these cells. Altogether, our findings revealed an unconventional and permissive role of extrasynaptic GABA A receptors in fear extinction through a route relying on nonsynaptic plasticity. SIGNIFICANCE STATEMENT The medial prefrontal cortex (mPFC) is one of the kernel brain regions engaged in fear extinction. Previous studies have repetitively shown that the GABA A receptor (GABA A R) family in this region act to suppress fear extinction. However, the roles of specific GABA A R subtypes in mPFC are largely unknown. We observed that the GABA A R-containing δ-subunit [GABA A (δ)R], a subtype of GABA A Rs exclusively situated in the extrasynaptic membrane and mediating the tonic neuronal inhibition, works oppositely to the whole GABA A R family and promotes (but does not suppress) fear extinction. More interestingly, in striking contrast to the synaptic GABA A Rs that suppress fear extinction by breaking the extinction-evoked plasticity of glutamatergic transmission, the GABA A (δ)R promotes fear extinction through enabling the plastic regulation of neuronal excitability in the infralimbic subregion of mPFC. Our findings thus reveal an unconventional role of GABA A (δ)R in promoting fear extinction through a route relying on nonsynaptic plasticity., (Copyright © 2022 the authors.)

Dysregulated GABAergic inhibition in the amygdala has long been implicated in stress-related neuropsychiatric disorders. However, the molecular and circuit mechanisms underlying the dysregulation remain elusive. Here, by using a mouse model of chronic social defeat stress (CSDS), we observed that the dysregulation varied drastically across individual projection neurons (PNs) in the basolateral amygdala (BLA), one of the kernel amygdala subregions critical for stress coping. While persistently reducing the extrasynaptic GABA A receptor (GABA A R)-mediated tonic current in the BLA PNs projecting to the ventral hippocampus (BLA → vHPC PNs), CSDS increased the current in those projecting to the anterodorsal bed nucleus of stria terminalis (BLA → adBNST PNs), suggesting projection-based dysregulation of tonic inhibition in BLA PNs by CSDS. Transcriptional and electrophysiological analysis revealed that the opposite CSDS influences were mediated by loss- and gain-of-function of δ-containing GABA A Rs (GABA A (δ)Rs) in BLA → vHPC and BLA → adBNST PNs, respectively. Importantly, it was the lost inhibition in the former population but not the augmentation in the latter population that correlated with the increased anxiety-like behavior in CSDS mice. Virally mediated maintenance of GABA A (δ)R currents in BLA → vHPC PNs occluded CSDS-induced anxiety-like behavior. These findings clarify the molecular substrate for the dysregulated GABAergic inhibition in amygdala circuits for stress-associated psychopathology., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2021 Science China Press. Published by Elsevier B.V. All rights reserved.)

Aims: Early life stress (ELS) increases the risk of psychiatric diseases such as anxiety disorders and depression in later life. Hyperactivation of the basolateral amygdala (BLA) neurons plays a pivotal role in the pathogenesis of stress-related diseases. However, the functional roles of BLA neurons in ELS-induced anxiety disorders are not completely understood., Main Methods: Mice were subjected to maternal separation (MS) during postnatal days 3 to 21 to mimic ELS. Anxiety-like behavior was tested by open field test (OFT), elevated plus maze (EPM), and novelty suppressed feeding (NSF). Then, c-fos expression, a proxy for neuronal activity, was evaluated by immunofluorescence. Finally, synaptic transmission and intrinsic excitability were measured by whole-cell patch-clamp recordings., Key Findings: MS significantly increased anxiety-like behavior in adulthood, as indicated by less time spent in the center area of the OFT, less time spent in and fewer entries to the open arms of the EPM, and increased latency to feed in NSF. Mechanistically, MS increased the expression of c-fos in BLA. MS enhanced the excitatory, but not inhibitory, synaptic transmission onto BLA projection neurons (PNs), which was caused by enhanced presynaptic glutamate release. Moreover, MS also markedly increased the intrinsic neuronal excitability of BLA PNs, probably due to the reduced medium afterhyperpolarization (mAHP) in BLA PNs., Significance: Our results suggest that the changes of neuronal activity and synaptic transmission in the BLA PNs may play a crucial role in ELS-induced anxiety-like behavior, and these findings provide new insights into the pathological mechanisms of stress-related anxiety disorders., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Coronavirus disease 2019 (COVID-19) is caused by infection of the coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with typical respiratory symptoms. SARS-CoV-2 invades not only the respiratory system, but also other organs expressing the cell surface receptor angiotensin converting enzyme 2. In particular, the digestive system is a susceptible target of SARS-CoV-2. Gastrointestinal symptoms of COVID-19 include anorexia, nausea, vomiting, diarrhea, abdominal pain, and liver damage. Patients with digestive damage have a greater chance of progressing to severe or critical illness, a poorer prognosis, and a higher risk of death. This paper aims to summarize the digestive system symptoms of COVID-19 and discuss fecal-oral contagion of SARS-CoV-2. It also describes the characteristics of inflammatory bowel disease patients with SARS-CoV-2 infection and discusses precautions for preventing SARS-CoV-2 infection during gastrointestinal endoscopy procedures. Improved attention to digestive system abnormalities and gastrointestinal symptoms of COVID-19 patients may aid health care providers in the process of clinical diagnosis, treatment, and epidemic prevention and control., Competing Interests: Conflict-of-interest statement: All authors who have affiliations with Zhongnan Hospital of Wuhan University declare that they do not have any competing interests. All authors who have affiliations listed with Dascena (Houston, TX, United States) are employees or contractors of Dascena., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Due to the high price and limited supply of Panax notoginseng , a large number of samples adulterated with the leaves appear in the market. A group of new malonyl ginsenosides were exclusively detected in the P. notoginseng leaves (PNL). Targeted isolation of the malonyl ginsenosides was guided by UPLC-QDa MS. HRMS, 1D/2D NMR, and chemical methods were used for structural identification. A selected ion monitoring method was developed based on UPLC-QDa MS to detect the adulterations. In addition, the anti-inflammatory activities and the collision-induced dissociation features of the isolated saponins were studied. As a result, eight new 3-OH malonylated dammarane-type triterpene oligoglycosides (notoginsenosides L3-L10) were obtained from PNL. Adulteration with PNL can be easily detected with limit of detection as low as 0.06%. To sum up, the isolated ginsenosides can be used as quality markers for fraud detection, which will promote the quality control of the notoginseng products.

Pesticides' overuse and misuse have been reported to induce ingredient variations in herbal medicine, which is now gaining attention in the medicinal field as a form of alternative medicine. To date, available studies on pesticide-induced ingredient variations of herbal medicine are limited only on a few compounds and remain most others unexamined. In this study, a plant metabolomics-based strategy was performed to systematically explore the effects of two frequently used insecticides on the comprehensive constituents of Lonicerae Japonicae Flos (LJF), the flower buds of Lonicera japonica Thunb. Field trials were designed on a cultivating plot of L. japonica with controls and treatments of imidacloprid (IMI) and compound flonicamid and acetamiprid (CFA). Unbiased metabolite profiling was conducted by ultra-high performance liquid chromatography/quadrupole-Orbitrap mass spectrometer. After data pretreatment by automatic extraction and screening, a data matrix of metabolite features was submitted for statistical analyses. Consequently, 29 metabolic markers, including chlorogenic acids, iridoids and organic acid-glucosides were obtained and characterized. The relative quantitative assay was subsequently performed to monitor their variations across flowering developments. This is the first study that systematically explored the insecticide-induced metabolite variations of LJF while taking into account the inherent variability of flowering development. The results were beneficial for holistic quality assessment of LJF and significant for guiding scientific use of pesticides in the large-scale cultivation., (Copyright © 2021 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Background: Accurate and reliable self-report measurement tools examining depressive symptoms are scant in child psychiatry. This study assessed the psychometric properties of the Chinese Version of the Quick Inventory of Depressive Symptomatology-Self-Report (C-QIDS-SR) in depressed adolescents in China. Methods: Adolescents with major depressive episodes or bipolar depressive episodes were assessed using the C-QIDS-SR. The structure validity of the C-QIDS-SR was estimated using principal component analysis with varimax rotation. Results: A total of 246 depressed adolescents were included in the study. Cronbach's alpha was 0.77. The correlation coefficient between the baseline and endpoint assessments was 0.49 ( p < 0.001), whereas, the correlation coefficient between the C-QIDS-SR and the Hamilton Rating Scale for Depression-17 items (HAMD-17) was 0.63 ( p < 0.001). Principal component analysis with varimax rotation demonstrated the unidimensional structure of the C-QIDS-SR. Conclusion: The C-QIDS-SR is a reliable and valid instrument with acceptable psychometric properties to measure depressive symptoms in adolescents., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Zhang, Zhao, Zhang, He, Pan, Cheung, Ungvari, Li and Xiang.)

Background: Many studies have compared the performance of time series models in predicting pulmonary tuberculosis (PTB), but few have considered the role of meteorological factors in their prediction models. This study aims to explore whether incorporating meteorological factors can improve the performance of time series models in predicting PTB., Methods: We collected the monthly reported number of PTB cases and records of six meteorological factors in three cities of China from 2005 to 2018. Based on this data, we constructed three time series models, including an autoregressive integrated moving average (ARIMA) model, the ARIMA with exogenous variables (ARIMAX) model, and a recurrent neural network (RNN) model. The ARIMAX and RNN models incorporated meteorological factors, while the ARIMA model did not. The mean absolute percentage error (MAPE) and root mean square error (RMSE) were used to evaluate the performance of the models in predicting PTB cases in 2018., Results: Both the cross-correlation analysis and Spearman rank correlation test showed that PTB cases reported in the study areas were related to meteorological factors. The predictive performance of both the ARIMA and RNN models was improved after incorporating meteorological factors. The MAPEs of the ARIMA, ARIMAX, and RNN models were 12.54%, 11.96%, and 12.36% in Xuzhou, 15.57%, 11.16%, and 14.09% in Nantong, and 9.70%, 9.66%, and 12.50% in Wuxi, respectively. The RMSEs of the three models were 36.194, 33.956, and 34.785 in Xuzhou, 34.073, 25.884, and 31.828 in Nantong, and 19.545, 19.026, and 26.019 in Wuxi, respectively., Conclusions: Our study revealed a possible link between PTB and meteorological factors. Taking meteorological factors into consideration increased the accuracy of time series models in predicting PTB, and the ARIMAX model was superior to the ARIMA and RNN models in study settings.

Background: Fear is an adaptive response across species in the face of threatening cues. It can be either innate or learned through postnatal experience. We have previously shown that genetic deletion of both Rap1a and Rap1b, two isoforms of small GTPase Rap1 in forebrain, causes impairment in auditory fear conditioning. However, the specific roles of these two isoforms are not yet known., Results: In the present study, employing mice with forebrain-restricted deletion of Rap1a or Rap1b, we found that they are both dispensable for normal acquisition of fear learning. However, Rap1b but not Rap1a knockout (KO) mice displayed impairment in the retrieval of learned fear. Subsequently, we found that the expression of c-Fos, a marker of neuronal activity, is specifically decreased in prelimbic cortex (PL) of Rap1b KO mice after auditory fear conditioning, while remained unaltered in the amygdala and infralimbic cortex (IL). On the other hand, neither Rap1a nor Rap1b knockout altered the innate fear of mice in response to their predator odor, 2,5-Dihydro-2,4,5-Trimethylthiazoline (TMT)., Conclusion: Thus, our results indicate that it is Rap1b but not Rap1a involved in the retrieval process of fear learning, and the learned but not innate fear requires Rap1 signaling in forebrain., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

From December 25, 2019 to January 31, 2020, 33 cases of the coronavirus disease 2019 (COVID-19) were identified in the Department of Respiratory and Critical Care Medicine of Zhongnan Hospital of Wuhan University, China, yet none of the affiliated HCWs was infected. Here we analyzed the infection control measures used in three different departments in the Zhongnan Hospital of Wuhan University and correlated the measures with the corresponding infection data of HCWs affiliated with these departments. We found that three infection control measures, namely the isolation of the presumed positive patients, the use of facemasks and intensified hand hygiene play important roles in preventing nosocomial transmission of COVID-19.

Methyl-CpG-binding protein 2 (MeCP2) encoded by the MECP2 gene is a transcriptional regulator whose mutations cause Rett syndrome (RTT). Mecp2 -deficient mice show fear regulation impairment; however, the cellular and molecular mechanisms underlying this abnormal behavior are largely uncharacterized. Here, we showed that Mecp2 gene deficiency in cholinergic interneurons of the nucleus accumbens (NAc) dramatically impaired fear learning. We further found that spontaneous activity of cholinergic interneurons in Mecp2 -deficient mice decreased, mediated by enhanced inhibitory transmission via α2-containing GABA A receptors. With MeCP2 restoration, opto- and chemo-genetic activation, and RNA interference in ChAT-expressing interneurons of the NAc, impaired fear retrieval was rescued. Taken together, these results reveal a previously unknown role of MeCP2 in NAc cholinergic interneurons in fear regulation, suggesting that modulation of neurons in the NAc may ameliorate fear-related disorders., Competing Interests: YZ, YZ, SC, PS, JY, YX, SX, XY, JF, CS, HH, HP, XC, HW, XL No competing interests declared, (© 2020, Zhang et al.)

Chronic or prolonged exposure to stress ranks among the most important socioenvironmental factors contributing to the development of neuropsychiatric diseases, a process generally associated with loss of inhibitory tone in amygdala. Recent studies have identified distinct neuronal circuits within the basolateral amygdala (BLA) engaged in different emotional processes. However, the potential circuit involved in stress-induced dysregulation of inhibitory tones in BLA remains elusive. Here, a transgenic mouse model expressing yellow fluorescent protein under control of the Thy1 promoter was used to differentiate subpopulations of projection neurons (PNs) within the BLA. We observed that the tonic inhibition in amygdala neurons expressing and not expressing Thy1 (Thy1+/-) was oppositely regulated by chronic social defeat stress (CSDS). In unstressed control mice, the tonic inhibitory currents were significantly stronger in Thy1- PNs than their Thy1+ counterparts. CSDS markedly reduced the currents in Thy1- projection neurons (PNs), but increased that in Thy1+ ones. By contrast, CSDS failed to affect both the phasic A-type γ-aminobutyric acid receptor (GABA A R) currents and GABA B R currents in these two PN populations. Moreover, chronic corticosterone administration was sufficient to mimic the effect of CSDS on the tonic inhibition of Thy1+ and Thy1- PNs. As a consequence, the suppression of tonic GABA A R currents on the excitability of Thy1- PNs was weakened by CSDS, but enhanced in Thy1+ PNs. The differential regulation of chronic stress on the tonic inhibition in Thy1+ and Thy1- neurons may orchestrate cell-specific adaptation of amygdala neurons to chronic stress., (Copyright © 2020 Pan, Zhang, Liao, He, Xiao, Qin, Liu, Wang, Zou, Liu and Pan.)

Objective: To analyze the clinical characteristics of cases of novel coronavirus pneumonia and a preliminary study to explore the relationship between different clinical classification and liver damage. Methods: Consecutively confirmed novel coronavirus infection cases admitted to seven designated hospitals during January 23, 2020 to February 8, 2020 were included. Clinical classification (mild, moderate, severe, and critical) was carried out according to the diagnosis and treatment program of novel coronavirus pneumonia (Trial Fifth Edition) issued by the National Health Commission. The research data were analyzed using SPSS19.0 statistical software. Quantitative data were expressed as median (interquartile range), and qualitative data were expressed as frequency and rate. Results: 32 confirmed cases that met the inclusion criteria were included. 28 cases were of mild or moderate type (87.50%), and four cases (12.50%) of severe or critical type. Four cases (12.5%) were combined with one underlying disease (bronchial asthma, coronary heart disease, malignant tumor, chronic kidney disease), and one case (3.13%) was simultaneously combined with high blood pressure and malignant tumor. The results of laboratory examination showed that the alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), and total bilirubin (TBil) for entire cohort were 26.98 (16.88 ~ 46.09) U/L and 24.75 (18.71 ~ 31.79) U/L, 39.00 (36.20 ~ 44.20) g/L and 16.40 (11.34 ~ 21.15) μmol/L, respectively. ALT, AST, ALB and TBil of the mild or moderate subgroups were 22.75 (16.31 ~ 37.25) U/L, 23.63 (18.71 ~ 26.50) U/L, 39.70 (36.50 ~ 46.10) g/L, and 15.95 (11.34 ~ 20.83) μmol/L, respectively. ALT, AST, ALB and TBil of the severe or critical subgroups were 60.25 (40.88 ~ 68.90) U/L, 37.00 (20.88 ~ 64.45) U/L, 35.75 (28.68 ~ 42.00) g/L, and 20.50 (11.28 ~ 25.00) μmol/L, respectively. Conclusion: The results of this multicenter retrospective study suggests that novel coronavirus pneumonia combined with liver damage is more likely to be caused by adverse drug reactions and systemic inflammation in severe patients receiving medical treatment. Therefore, liver function monitoring and evaluation should be strengthened during the treatment of such patients.

Two novel heptanornemoralisin-type diterpenoids nornemoralisins A (1) and B (2), together with two known compounds nemoralisin (3) and nemoralisin A (4), were isolated from the stem bark and leaves of Aphanamixis polystachya (Wall.) R. Parker. Their structures were established through comprehensive analyses of NMR spectroscopic data and high resolution mass spectrometric (HR-ESI-MS) data. The absolute configurations of carbon stereocenters were elucidated by circular dichroism (CD) analyses. The four compounds were tested for their potential cytotoxic effects against ACHN, HeLa, SMMC-7721, and MCF-7 cell lines. Nornemoralisins A (1) and B (2) exhibited significant cytotoxicity on ACHN with an IC 50 value of 13.9 ± 0.8 and 10.3 ± 0.4 μM, respectively, and other compounds failed to reveal obvious cytotoxicity on the tested cell lines, compared to positive control vinblastine (IC 50 , 28.0 ± 0.9 μM)., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The δ subunit-containing GABAA receptor [GABAA(δ)R], which is exclusively situated in the extrasynaptic space, has considerable influence on emotion and behavior. Although the expression of this receptor experiences dramatic fluctuation during postnatal development, it remains unknown whether it regulates emotion in a development-dependent manner. Here, by using mice with genetic deletion of GABAA(δ)R (knockout) and their wild-type littermates, we examined the role of GABAA(δ)R in regulating anxiety-like behavior, as measured with open field test (OFT) and elevated plus maze during the transition from puberty to adulthood. We observed that for female mice, the knockout ones at puberty but not adulthood showed increased anxiety-like behavior in the OFT relative to their wild-type littermates. However, such increase was not observed in elevated plus maze. For male mice, no between-genotype differences were observed in both tests at the above two developmental stages. Our results suggest that GABAA(δ)R preferentially affects the anxiety-like behavior in OFT in a development-dependent manner, but only in female mice.

Major depressive disorder is a devastating psychiatric disease that afflicts up to 17% of the world's population. Postmortem brain analyses and imaging studies of patients with depression have implicated basal lateral amygdala (BLA) dysfunction in the pathophysiology of depression. However, the circuit and molecular mechanisms through which BLA neurons modulate depressive behavior are largely uncharacterized. Here, in mice, we identified that BLA cholecystokinin (CCK) glutamatergic neurons mediated negative reinforcement via D2 medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and that chronic social defeat selectively potentiated excitatory transmission of the CCK BLA -D2 NAc circuit in susceptible mice via reduction of presynaptic cannabinoid type-1 receptor (CB 1 R). Knockdown of CB 1 R in the CCK BLA -D2 NAc circuit elevated synaptic activity and promoted stress susceptibility. Notably, selective inhibition of the CCK BLA -D2 NAc circuit or administration of synthetic cannabinoids in the NAc was sufficient to produce antidepressant-like effects. Overall, our studies reveal the circuit and molecular mechanisms of depression.

Background: Chronic stress exposure increases the risk of developing various neuropsychiatric illnesses. The behavioral sequelae of stress correlate with dendritic hypertrophy and glutamate-related synaptic remodeling at basolateral amygdala projection neurons (BLA PNs). Yet, though BLA PNs are functionally heterogeneous with diverse corticolimbic targets, it remains unclear whether stress differentially impacts specific output circuits., Methods: Confocal imaging was used to reconstruct the morphology of mouse BLA PNs with the aid of retrograde tracing and biocytin staining. The synaptic activity in these neurons was measured with in vitro electrophysiology, and anxiety-like behavior of the mice was assessed with the elevated plus maze and open field test., Results: Chronic restraint stress (CRS) produced dendritic hypertrophy across mouse BLA PNs, regardless of whether they did (BLA→dorsomedial prefrontal cortex [dmPFC]) or did not (BLA↛dmPFC) target dmPFC. However, CRS increased the size of dendritic spine heads and the number of mature, mushroom-shaped spines only in BLA↛dmPFC PNs, sparing neighboring BLA→dmPFC PNs. Moreover, the excitatory glutamatergic transmission was also selectively increased in BLA↛dmPFC PNs, and this effect correlated with CRS-induced increases in anxiety-like behavior. Segregating BLA↛dmPFC PNs based on their targeting of ventral hippocampus (BLA→ventral hippocampus) or nucleus accumbens (BLA→nucleus accumbens) revealed that CRS increased spine density and glutamatergic signaling in BLA→ventral hippocampus PNs in a manner that correlated with anxiety-like behavior., Conclusions: Chronic stress caused BLA PN neuronal remodeling with a previously unrecognized degree of circuit specificity, offering new insight into the pathophysiological basis of depression, anxiety disorders, and other stress-related conditions., (Copyright © 2018 Society of Biological Psychiatry. All rights reserved.)

Background: Tuberculosis patients often experience hospitalization. Inpatient services may result in high medical expenditures. It is important to explore the hospitalization rates of tuberculosis patients and the potential factors that are associated with admission rates and inpatient service expenditures., Methods: Data from patients diagnosed and treated at the No.3 hospital of Zhenjiang City from Apr. 2014 to Mar. 2015 were obtained. Univariate and multivariate statistical analyses were applied for the analysis of potential factors associated with admission rates, average length of stay and cost., Results: A total of 356 tuberculosis patients were treated at the No.3 hospital of Zhenjiang City. A total of 221 of the 356 patients were hospitalized. Sputum smear test results and type of health insurance were the potential factors associated with hospitalization rates. The average admission was (1.26 ± 0.64) per patient. The average length of stay of inpatients was 29.99 ± 25.83 days. Age, occupation, and sputum smear test were related to the average length of stay. The average total cost to inpatients was 13007.91 ± 5205.58 CNY. The sputum smear test results, type of health insurance, occupation and age were the main potential factors associated with TB inpatient expenditures., Conclusions: The admission rate of tuberculosis patients was high. Despite advances in TB insurance policies, there were substantial costs associated with TB diagnosis and treatment. TB patients still face a heavy financial burden. Health care providers should revise the service package and reform the health insurance regulations to ensure that TB patients receive appropriate care.

Liquid chromatography-mass spectrometry (LC-MS) guided isolation is a favored strategy to quickly and efficiently explore the chemical diversity of herbal medicines. In this study, two methods were adopted to improve the performance of the strategy, including offline two-dimensional (2D) LC to extend the peak capacities and predicted metabolites screening (PMS) to automatically screen the targets with expanded databases. Ginsenosides in the leaves of Panax notoginseng (PNL) were taken as a case. An offline 2D LC system was constructed with an orthogonality of 0.69 and peak capacity of 8925. Quadrupole time-of-flight mass spectrometry-fast data directed analysis (QTOF-Fast DDA) was employed for detection of the ginsenosides in the fractioned samples. Four modified groups, including glucose, xylose, rhamnose and malonyl, were adopted and markedly extended the screening coverage. The combined strategy showed about 7.5 times improvement in the screening capability. PMS is conveniently and automatically implemented in UNIFI. Using this strategy, 945 ginsenosides were discovered from PNL, including 662 potentially novel ginsenosides. Furthermore, two new ginsenosides were purified, and unambiguously identified by NMR analysis, partially demonstrating the LC-MS guided isolation. The combined strategy can also be applied in characterizing and discovering new bioactive constituents from other herbal medicines., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The role of δ subunit-containing GABA A receptor (GABA A (δ)R) in fear generalization is uncertain. Here, by using mice with or without genetic deletion of GABA A (δ)R and using protocols in which the conditioned tone stimuli were cross presented with different nonconditioned stimuli, we observed that when the two tone stimuli were largely similar, both genotypes froze similarly to either of them. However, when they differed markedly, the knockout mice froze much more than their wild-type littermates to the nonconditioned but not conditioned stimuli. Thus, GABA A (δ)R may prevent inappropriate fear generalization when the incoming stimuli differ clearly from the learned threat., (© 2017 Zhang et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Maintaining gamma-aminobutyric acidergic (GABAergic) inhibition in the amygdala within a physiological range is critical for the appropriate expression of emotions such as fear and anxiety. The synaptic GABA type A receptor (GABA A R) is generally known to mediate the primary component of amygdala inhibition and prevent inappropriate expression of fear. However, little is known about the contribution of the extrasynaptic GABA A R to amygdala inhibition and fear., Methods: By using mice expressing green fluorescent protein in interneurons (INs) and lacking the δ subunit-containing GABA A R (GABA A (δ)R), which is exclusively situated in the extrasynaptic membrane, we systematically investigated the role of GABA A (δ)R in regulating inhibition in the lateral amygdala (LA) and fear learning using the combined approaches of immunohistochemistry, electrophysiology, and behavior., Results: In sharp contrast to the established role of synaptic GABA A R in mediating LA inhibition, we found that either pharmacological or physiological recruitment of GABA A (δ)R resulted in the weakening of GABAergic transmission onto projection neurons in LA while leaving the glutamatergic transmission unaltered, suggesting disinhibition by GABA A (δ)R. The disinhibition arose from IN-specific expression of GABA A (δ)R with its activation decreasing the input resistance of local INs and suppressing their activation. Genetic deletion of GABA A (δ)R attenuated its role in suppressing LA INs and disinhibiting LA. Importantly, the GABA A (δ)R facilitated long-term potentiation in sensory afferents to LA and permitted the expression of learned fear., Conclusions: Our findings suggest that GABA A (δ)R serves as a brake rather than a mediator of GABAergic inhibition in LA. The disinhibition by GABA A (δ)R may help to prevent excessive suppression of amygdala activity and thus ensure the expression of emotion., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

A Bacillus sp. 9912 mutant, 9912D, was approved as a new biological fungicide agent by the Ministry of Agriculture of the People's Republic of China in 2016 owing to its excellent inhibitory effect on various plant pathogens and being environment-friendly. Here, we present the genome of 9912D with a circular chromosome having 4436 coding DNA sequences (CDSs), and a circular plasmid encoding 59 CDSs. This strain was finally designated as Bacillus velezensis based on phylogenomic analyses. Genome analysis revealed a total of 19 candidate gene clusters involved in secondary metabolite biosynthesis, including potential new type II lantibiotics. The absence of fengycin biosynthetic gene cluster is noteworthy. Our data offer insights into the genetic, biological and physiological characteristics of this strain and aid in deeper understanding of its biocontrol mechanism., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Targeted identification of potentially bioactive molecules from herbal medicines is often stymied by the insufficient chromatographic separation, ubiquitous matrix interference, and pervasive isomerism. An enhanced targeted identification strategy is presented and validated by the selective identification of flavonoid O-glycosides (FOGs) from Carthamus tinctorius. It consists of four steps: (i) enhanced separation and detection by offline two-dimensional liquid chromatography/LTQ-Orbitrap MS (offline 2D-LC/LTQ-Orbitrap MS) using collision-induced dissociation (CID) and high-energy C-trap dissociation (HCD); (ii) improved identification of the major aglycones by acid hydrolysis and LC-SPE-NMR; (iii) simplified spectral elucidation by high-resolution diagnostic product ions/neutral loss filtering; and (iv) more convincing structural identification by matching an in-house library. An offline 2D-LC system configuring an Acchrom XAmide column and a BEH Shield RP-18 UPLC ® column enabled much better separation of the easily co-eluting components. Combined use of CID and HCD could produce complementary fragmentation information. The intensity ratios of the aglycone ion species ([Y 0 -H] - /Y 0 - and [Y 0 -2H] - /Y 0 - ) in the HCD-MS 2 spectra were found diagnostic for discriminating the aglycone subtypes and characterizing the glycosylation patterns. Five aglycone structures (kaempferol, 6-hydroxykaempferol, 6-methoxykaempferol, carthamidin, and isocarthamidin) were identified based on the 1 H-NMR data recorded by LC-SPE-NMR. Of the 107 characterized flavonoids, 80 FOGs were first reported from C. tinctorius. Unknown aglycones, pentose, and novel acyl substituents were discovered. A new compound thereof was isolated and fully identified, which could partially validate the MS-oriented identification. This integral strategy can improve the potency, efficiency, and accuracy in the detection of new compounds from medicinal herbs and other natural sources., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The simultaneous identification and quantification of target metabolites from herbal medicines are difficult to implement by the full-scan MS based nontargeted metabolomics approaches. Here an in-source multiple collision-neutral loss filtering (IMC-NLF) based nontargeted metabolomics approach is developed and applied to identify and quantify the variations of malonyl-ginsenosides, a common group of acyl saponins with potential anti-diabetic activity, among Panax ginseng, P. quinquefolius, and P. notoginseng. The key steps of the IMC-NLF strategy are the acquisition of specific high-resolution neutral loss data and the efficient filtering of target precursor ions from the full-scan spectra. Using a hybrid LTQ-Orbitrap mass spectrometer after UHPLC separation, abundant in-source product ions, [M-H-CO 2 ] - (due to the vulnerability of the carboxyl group) and [M-H-Mal.] - , were generated at the energies of 70 V and 90 V, respectively. After spectral deconvolution, the generated peak list was screened by dual NLF using a Neutral Loss MS Finder software (NL of 43.9898 Da for CO 2 and 86.0004 Da for the malonyl substituent). By combining the precursor ions list-triggered HCD-MS/MS and basic hydrolysis, a total of 101 malonyl-ginsenosides (including 69 from P. ginseng, 52 from P. quinquefolius, and 44 from P. notoginseng) were identified or tentatively characterized. The variations of 81 characterized malonyl-ginsenosides among 45 batches of Ginseng samples were statistically analyzed disclosing ten potential markers. It is the first systematic analysis of malonyl-ginsenosides. The IMC-NLF approach by a single analytical platform is promising in targeted analyses of modification-specific metabolites in metabolomics and drug metabolism., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Four new alkaloids, comprising three 3-oxo-3,7-seco-oxindole alkaloids (hirsutanine D-F, 1-3) and one oxindole alkaloid N-oxide (uncarine B N-oxide, 4), together with four known heteroyohimbine-type oxindole alkaloids, were isolated from the stems of Uncaria hirsuta Havil. Structures of 1-4 were elucidated by extensive NMR and HR-ESIMS data analyses. Compound 3 is the first 3-oxo-3,7-seco-oxindole alkaloid with ring B opened and degraded isolated from the Uncaria genus. Compounds 1-3 exhibited slight inhibition effect on the proliferation of the breast cancer cell MDA-MB-231. The positive mode collision-induced dissociation of the 3-oxo-3,7-seco-oxindole alkaloids (1-3) was featured by the β-cleavage and α-cleavage of the amido bond, while the N-oxide (4) showed characteristic neutral eliminations of ·OH and H 2 O., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: Based on the medical records and follow-up records of hospitalized patients who received anti-tuberculosis therapy in the Third People's Hospital of Zhenjiang in Jiangsu province from 2006 to 2012, we investigated the incidence and outcome of anti-tuberculosis drug induced hepatotoxicity(ATDH)and provided evidence for the prevention of ATDH., Methods: According to tuberculosis patients' medical information and liver function test records, ATDH patients were diagnosed according to the criteria of International Consensus Meeting and American Thoracic Society respectively, then the related factors and outcomes were analyzed., Results: A total of 1 967 hospitalized tuberculosis patients were reviewed retrospectively, in which 1 403(71.3%)were men, 1 790(91.0%)were pulmonary tuberculosis patients, 1 528(77.8%)were patients receiving initiative treatment, 979(49.8%)were sputum smear-positive patients, and 1 297(65.9%)had other complicated diseases. According to the criterion of International Consensus Meeting, the incidence of ATDH was 16.5%, the median time of onset was 25 days. According to the criterion of American Thoracic Society, the incidence of ATDH was 8.3%, the median time of onset was 23 days. The incidence of ATDH was significantly higher in males and HRZE therapy group(P<0.05). Under the two liver criteria, 69.5% and 70.1% of the patients changed primary therapy respectively after ATDH occurred. 89.8% and 88.4% patients' liver function returned to normal range after changing or stopping therapy., Conclusion: According to two liver injury criteria, the incidences of ATDH were 16.5% and 8.3% in hospitalized tuberculosis patients respectively, and ATDH mainly occurred in the first month of anti-tuberculosis treatment. The monitoring of liver function should be strengthened in males and HRZE therapy group to reduce the incidence of ATDH.

Background: To investigate the prevalence of and risk factors for leukopenia in tuberculosis patients and the impact of anti-tuberculosis regimens on the occurrence of leukopenia in newly treated tuberculosis patients., Methods: A total of 1,904 tuberculosis patients were included in the study. A cross-sectional survey of the prevalence of leukopenia was initially conducted, and then factors influencing leukopenia were identified using Logistic regression analysis. Non-treatment factors influencing peripheral blood leukocyte counts were analyzed using univariate COX proportional hazards models. Covariate analysis was used to assess the independent effect of different anti-tuberculosis regimens on peripheral blood leukocyte counts., Results: Being female, advanced age and longer duration of previous anti-tuberculosis treatment (>6 month) were risk factors for leukopenia in tuberculosis patients, while secondary pulmonary tuberculosis, higher body mass index (BMI: 24-27.9 kg/m(2)), and higher degree of education (senior high school or above) were protective factors. Gender, vegetable consumption, drinking, pulmonary infection, other chronic diseases, and use of antibiotics were significantly associated with the development of leukopenia in patients on anti-tuberculosis treatment. In tuberculosis patients treated with anti-tuberculosis regimens not containing antibiotics, peripheral blood leukocyte levels gradually declined with the prolongation of treatment duration. In tuberculosis patients treated with anti-tuberculosis regimens containing antibiotics, peripheral blood leukocyte levels showed a declining trend., Conclusions: Female patients, patients at advanced age and recurrent tuberculosis patients having longer previous anti-tuberculosis treatment are high-risk populations for leukopenia. Attention should be paid to the influence of vegetable consumption and drinking, co-morbidities and use of antibiotics during anti-tuberculosis treatment.

Pseudomonas sp. 10B238 was a putatively novel species of Pseudomonas, isolated from a deep-sea sediment of the South China Sea, which had the genetic potential to produce secondary metabolites related to nonribosomal peptides (NRPs), as well as showed moderate antimicrobial activities. Here we report a high quality draft genome of Pseudomonas sp. 10B238, which comprises 4,933,052bp with the G+C content of 60.23%. A total of 11 potential secondary metabolite biosynthetic gene clusters were predicted, including a NRP for new peptide siderophore. And many anaerobic respiratory terminal enzymes were found for life in deep-sea environments. Our results may provide insights into biosynthetic pathway for antimicrobial bioactive compounds and be helpful to understand the physiological characteristic of this species., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Two actinomycete strains, designated 10A08AT and 10A08BT, were isolated from marine sediment samples of the South China Sea and their taxonomic positions were determined by a polyphasic approach. The two Gram-stain-positive, aerobic strains produced branched substrate mycelium and aerial hyphae, and no diffusible pigment was produced in the media tested. At maturity, spore chains were formed on aerial hyphae and all mycelium fragmented with age. Whole-cell hydrolysates of both strains contained meso-diaminopimelic acid and no diagnostic sugars. Their predominant menaquinones (>10 %) were MK-9(H4), MK-9(H6) and MK-10(H6) for strain 10A08AT and MK-9(H4), MK-9(H6), MK-10(H4) and MK-10(H6) for strain 10A08BT. The polar lipids detected from the two strains were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine and unknown phosphoglycolipids and phospholipids. The major fatty acids (>10 %) of both strains were iso-C16 : 0 and summed feature 4 (iso-C17 : 1 I and/or anteiso-C17 : 1 B). The genomic DNA G+C contents of strains 10A08AT and 10A08BT were 70.9 and 71.6 mol%, respectively. On the basis of 16S rRNA gene sequence similarities, the two strains were shown to be most closely related to species of the genus Nocardiopsis. DNA–DNA hybridization relatedness values of < 70 % between these two isolates and their closest neighbour, Nocardiopsis terrae YIM 90022T, and between the two strains supported the conclusion that they represent two novel species. Based on phylogenetic analysis and phenotypic and genotypic data, it is concluded that the two isolates belong to the genus Nocardiopsis, and the names Nocardiopsis oceani sp. nov. (type strain 10A08AT = DSM 45931T = BCRC 16951T) and Nocardiopsis nanhaiensis sp. nov. (type strain 10A08BT = CGMCC 47227T = BCRC 16952T) are proposed.

An efficient and target-oriented sample enrichment method was established to increase the content of the minor alkaloids in crude extract by using the corresponding two-phase solvent system applied in pH-zone-refining counter-current chromatography. The enrichment and separation of seven minor indole alkaloids from Uncaria rhynchophylla (Miq.) Miq. ex Havil(UR) were selected as an example to show the advantage of this method. An optimized two-phase solvent system composed of n-hexane-ethyl acetate-methanol-water (3:7:1:9, v/v) was used in this study, where triethylamine (TEA) as the retainer and hydrochloric acid (HCl) as the eluter were added at the equimolar of 10mM. Crude alkaloids of UR dissolved in the corresponding upper phase (containing 10mM TEA) were extracted twice with lower phase (containing 10mM TEA) and lower phase (containing 10mM HCl), respectively, the second lower phase extract was subjected to pH-zone-refining CCC separation after alkalization and desalination. Finally, from 10g of crude alkaloids, 4g of refined alkaloids was obtained and the total content of seven target indole alkaloids was increased from 4.64% to 15.78%. Seven indole alkaloids, including 54mg isocorynoxeine, 21mg corynoxeine, 46mg isorhynchophylline, 35mg rhynchophylline, 65mg hirsutine, 51mg hirsuteine and 27mg geissoschizine methylether were all simultaneously separated from 2.5g of refined alkaloids, with the purity of 86.4%, 97.5%, 90.3%, 92.1%, 98.5%, 92.3%, and 92.8%, respectively. The total content and purities of the seven minor indole alkaloids were tested by HPLC and their chemical structures were elucidated by ESI-HRMS and (1)H NMR., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A novel actinomycete strain, designated 11A07(T), was isolated from young Scomberomorus niphonius in the Bohai Sea. Basic local alignment search tool analyses showed that this isolate had the highest 16S rRNA gene sequence similarity of 97.41% with Streptomyces rimosus subsp. paromomycinus DSM 41429(T). Phylogenetic tree revealed that strain 11A07(T) formed a distinct lineage clustered with Streptomyces panacagri Gsoil 519(T), Streptomyces sodiiphilus YIM 80305(T) and Streptomyces albus subsp. albus NRRL B-2365(T) having similarities of 97.30%, 97.10% and 96.83%, respectively. Multilocus sequence analysis further demonstrated that the new isolate was different from the selected representatives of Streptomyces as a separate phylogenetic line. Strain 11A07(T) produced straight or rectiflexibile spore chains with smooth surface, white aerial mycelia and brown diffusible pigments on international streptomyces project 2 medium. Maximum tolerated NaCl concentration for growth was 11.0%. Whole-cell sugars were mannose, ribose, glucose, galactose and xylose. The predominant menaquinones were MK-9(H2), MK-9(H4) and MK-9 (H6). The fatty-acid profile contained iso-C16:0, C18:0 10-methyl (tuberculostearic acid) and anteiso-C17:0 as the major compositions. The polar lipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol mannoside and an unknown phospholipid. The G+C content of the genomic DNA was 71.4 mol%. These morphological, phenotypic and chemotaxonomic properties showed that strain 11A07(T) could be readily distinguished from the most closely related members of the genus Streptomyces. Thus, based on the polyphasic taxonomic data, strain 11A07(T) (=JCM 19630(T)=CCTCC AA 2013020(T)=KCTC 29263(T)) represents a novel species within the genus Streptomyces, for which the name Streptomyces bohaiensis sp. nov. is proposed.

A new actinomycete strain NA4 was isolated from a deep-sea sediment collected from the South China Sea and showed promising antifungal activities against soilborne fungal pathogens. It was identified as Streptomyces cavourensis by morphological, physiological, and phylogenetic analyses based on its 16S rRNA gene sequence. The main antifungal components were isolated and identified from the fermentation culture as bafilomycins B1 and C1. These compounds exhibited significant antifungal activities and a broad antifungal spectrum. The results suggest that the Streptomyces cavourensis NA4 and bafilomycins B1 and C1 could be used as potential biocontrol agents for soilborne fungal diseases of plants.

MicroRNAs are increasingly important in the study of cancer because of their ability to down regulate the expression of tumor suppressors and promote tumorigenesis. Here, miR-221, which is dysregulated in various tumors, was investigated for its expression in colon cancer tissues and its correlation with patient prognosis. Colon cancer tissue samples were obtained from 182 individuals who underwent surgical resection in our hospital from June 2008 to September 2009. Real-time PCR was used to detect the expression of miR-221 in these tissues. Patient survival was determined by telephone interview, and survival curves were plotted by using the Kaplan-Meier method and compared by the Log-rank test. Statistical methods also included X(2) test and Cox proportional hazard regression model. Differences in the expression of miR-221 by gender, pathology, and pathological staging were not statistically significant (P>0.05), but differences in the expression of miR-221 among age groups were statistically significant (P<0.05). A survival analysis indicated that high expression of miR-221 was closely associated with a shorter survival time (P<0.05). Further, later p-TNM (hazard ratio, HR=2.973, 95% confidence interval, CI: 1.329-6.519, P=0.003) and high expression of miR-211 (HR=2.394, 95% CI: 1.210-4.910, P=0.006) were identified as risk factors for colon cancer prognosis. Thus, high miRNA-221 expression might be a prognostic marker of colon cancer patients. The high expression of miRNA-221 was associated with poor prognosis of patients with colon cancer.

Capsaicin, one of the major pungent ingredients found in red peppers, has been shown to have anti-carcinogenic effect on various cancer cells through multiple mechanisms. In this study, we investigated the apoptotic effect of capsaicin on human hepatocellular cancer cell line SMMC-7721, as well as the possible mechanisms involved. Treatment of SMMC-7721 cells with capsaicin resulted in a dose-dependent inhibition of cell-viability and induction of apoptosis which was associated with the generation of ROS and persistent disruption of mitochondrial membrane potential. These effects were significantly blocked when cells were pretreated with a general antioxidant N-acetyl cysteine (NAC). We also found that capsaicin induced JNK and p38 MAPK phosphorylation. JNK and p38 MAPK inhibitor effectively blocked capsaicin-induced SMMC-7721 cell apoptosis. In addition, NAC completely blocked phosphorylation of JNK and p38 MAPK induced by capsaicin. Our results indicate that capsaicin induced in SMMC-7721 cell apoptosis through generation of intracellular ROS and activation of JNK and p38 MAPK pathways.

Two new indole-diterpenoids 4b-deoxy-1'-O-acetylpaxilline (1) and 4b-deoxypenijanthine A (2) were isolated from the fermentation broth and the mycelia of the soil fungus Penicillium sp. CM-7, along with three known structurally related compounds, 1'-O-acetylpaxilline (3), paspaline (4) and 3-deoxo-4b-deoxypaxilline (5). The structures of compounds 1 and 2 were elucidated by extensive spectroscopic methods, especially 2D NMR, and their absolute configurations were suggested on the basis of the circular dichroism spectral analysis and the NOESY data., (Copyright © 2014 John Wiley & Sons, Ltd.)

Background: Chronic stress is generally known to exacerbate the development of numerous neuropsychiatric diseases such as fear and anxiety disorders, which is at least partially due to the disinhibition of amygdala subsequent to the prolonged stress exposure. GABA receptor A (GABAAR) mediates the primary component of inhibition in brain and its activation produces two forms of inhibition: the phasic and tonic inhibition. While both of them are critically engaged in limiting the activity of amygdala, their roles in the amygdala disinhibition subsequent to chronic stress exposure are largely unknown., Results: We investigated the possible alterations of phasic and tonic GABAAR currents and their roles in the amygdala disinhibition subsequent to chronic stress. We found that both chronic immobilization and unpredictable stress led to long lasting loss of tonic GABAAR currents in the projection neurons of lateral amygdala. By contrast, the phasic GABAAR currents, as measured by the spontaneous inhibitory postsynaptic currents, were virtually unaltered. The loss of tonic inhibition varied with the duration of daily stress and the total days of stress exposure. It was prevented by pretreatment with metyrapone to block corticosterone synthesis or RU 38486, a glucocorticoid receptor antagonist, suggesting the critical involvement of glucocorticoid receptor activation. Moreover, chronic treatment with corticosterone mimicked the effect of chronic stress and reduced the tonic inhibition in lateral amygdala of control mice. The loss of tonic inhibition resulted in the impaired GABAergic gating on neuronal excitability in amygdala, which was prevented by metyrapone pretreatment., Conclusions: Our study suggests that enduring loss of tonic but not phasic GABAAR currents critically contributes to the prolonged amygdala disinhibition subsequent to chronic stress. We propose that the preferential loss of tonic inhibition may account for the development of stress-related neuropsychiatric diseases.