Rotavirus-mediated DGAT1 degradation: A pathophysiological mechanism of viral-induced malabsorptive diarrhea.

Gastroenteritis is among the leading causes of mortality globally in infants and young children, with rotavirus (RV) causing ~258 million episodes of diarrhea and ~128,000 deaths annually in infants and children. RV-induced mechanisms that result in diarrhea are not completely understood, but malabsorption is a contributing factor. RV alters cellular lipid metabolism by inducing lipid droplet (LD) formation as a platform for replication factories named viroplasms. A link between LD formation and gastroenteritis has not been identified. We found that diacylglycerol O-acyltransferase 1 (DGAT1), the terminal step in triacylglycerol synthesis required for LD biogenesis, is degraded in RV-infected cells by a proteasome-mediated mechanism. RV-infected DGAT1-silenced cells show earlier and increased numbers of LD-associated viroplasms per cell that translate into a fourfold-to-fivefold increase in viral yield (P < 0.05). Interestingly, DGAT1 deficiency in children is associated with diarrhea due to altered trafficking of key ion transporters to the apical brush border of enterocytes. Confocal microscopy and immunoblot analyses of RV-infected cells and DGAT1-/- human intestinal enteroids (HIEs) show a decrease in expression of nutrient transporters, ion transporters, tight junctional proteins, and cytoskeletal proteins. Increased phospho-eIF2α (eukaryotic initiation factor 2 alpha) in DGAT1-/- HIEs, and RV-infected cells, indicates a mechanism for malabsorptive diarrhea, namely inhibition of translation of cellular proteins critical for nutrient digestion and intestinal absorption. Our study elucidates a pathophysiological mechanism of RV-induced DGAT1 deficiency by protein degradation that mediates malabsorptive diarrhea, as well as a role for lipid metabolism, in the pathogenesis of gastroenteritis.

GLK transcription factors accompany ELONGATED HYPOCOTYL5 to orchestrate light-induced seedling development in Arabidopsis.

Light-induced de-etiolation is an important aspect of seedling photomorphogenesis. GOLDEN2 LIKE (GLK) transcriptional regulators are involved in chloroplast development, but to what extent they participate in photomorphogenesis is not clear. Here, we show that ELONGATED HYPOCOTYL5 (HY5) binds to GLK promoters to activate their expression, and also interacts with GLK proteins in Arabidopsis (Arabidopsis thaliana). The chlorophyll content in the de-etiolating Arabidopsis seedlings of the hy5 glk2 double mutants was lower than that in the hy5 single mutant. GLKs inhibited hypocotyl elongation, and the phenotype could superimpose on the hy5 phenotype. Correspondingly, GLK2 regulated the expression of photosynthesis and cell elongation genes partially independent of HY5. Before exposure to light, DE-ETIOLATED 1 (DET1) affected accumulation of GLK proteins. The enhanced etioplast development and photosystem gene expression observed in the det1 mutant were attenuated in the det1 glk2 double mutant. Our study reveals that GLKs act downstream of HY5, or additive to HY5, and are likely quantitatively adjusted by DET1, to orchestrate multiple developmental traits during the light-induced skotomorphogenesis-to-photomorphogenesis transition in Arabidopsis.

Photolithography-Free, Solution-Processable Perovskite Electrodes for High-Performance Organic Transistors.

Solution-processable electrodes are promising for next-generation electronics due to their simplicity, cost-effectiveness, and potential for large-area fabrication. However, current solution-processable electrodes based on conductive polymers, carbon-based compounds, and metal nanowires face challenges related to stability, patterning, and production scalability. Here we introduce a novel approach using 3D tin halide perovskites (THPs) combined with a photolithography-free solution patterning technique to fabricate solution-processed electrodes. We demonstrate the preparation of highly conductive CsSnI3 films (234.9 S cm-1) and the fabrication of patterned 35 × 35 perovskite electrode arrays on a 4-in. silicon wafer. These electrodes, used as source/drain electrodes in organic transistors, resulted in devices showing high uniformity and stability. This electrode fabrication strategy is also applicable to other 3D THPs like FASnI3 and MASnI3, showcasing versatility for diverse applications. The results highlight the feasibility and advantages of using 3D THPs as solution-processable electrodes, providing a new material system for the advancement of solution-processed electronics.

Effect of Intermittent Oro-Esophageal Tube Feeding in Bulbar Palsy After Ischemic Stroke: A Randomized Controlled Study.

BACKGROUND: Nasogastric tube feeding (NG) has been widely used in patients with bulbar palsy after ischemic stroke but is associated with a significant risk of complications including malnutrition and pneumonia. Intermittent oro-esophageal tube feeding (IOE) can help alleviate these concerns. This study explored the clinical effect of IOE versus NG on nutritional status, swallowing function, stroke-associated pneumonia, and depression in patients with bulbar palsy after ischemic stroke. METHODS: This randomized controlled study included 148 patients with bulbar palsy after ischemic stroke who underwent routine treatment and swallowing rehabilitation training in the Department of Rehabilitation Medicine between July 2017 and July 2019 in China. The participants were randomly divided into the IOE group (n=74) and NG group (n=74) with IOE and NG as nutritional supports, respectively. The primary outcome was nutritional status including (1) body mass index (kg/m2), (2) serum ALB (albumin, g/L), and (3) PA (prealbumin, mg/L). The secondary outcomes were (1) swallowing function including (i) Functional Oral Intake Scale (FOIS) and (ii) Penetration-Aspiration Scale, (2) pneumonia, (3) depression, and (4) adverse events. Statistical analyses for continuous outcomes were performed using t test, Mann-Whitney U test and Wilcoxon signed-rank test and categorical variables using χ2 test. SPSS 21.0 was used for all analysis. RESULTS: There were no significant baseline differences between the 2 groups. After the treatment, the IOE group demonstrated significantly better results compared with the NG group in ALB ([32.71±0.94] versus [32.28±0.81] g/L; P=0.003), PA ([278.15±13.81] versus [270.31±15.08] mg/L; P=0.001], body mass index ([19.77±1.03] versus [19.41±0.98] kg/m2; P=0.002], FOIS (P<0.001), Penetration-Aspiration Scale (P<0.001), stroke-associated pneumonia ([1, 4.05%] versus [26, 35.14%]; P<0.001), depression ([1, 1.35%] versus [44, 59.46%]; P<0.001) and overall less adverse events (reflux, fever, discomfort in the throat; P<0.001). CONCLUSIONS: In patients with dysphagia with bulbar palsy after ischemic stroke who received routine treatment and swallowing rehabilitation training, IOE is safer and more conducive to the improvement of nutritional status, swallowing function, stroke-associated pneumonia, and depression than NG. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR-INC-17011741.

Identification of novel single nucleotide variants in the drug resistance mechanism of Mycobacterium tuberculosis isolates by whole-genome analysis.

BACKGROUND: Tuberculosis (TB) represents a major global health challenge. Drug resistance in Mycobacterium tuberculosis (MTB) poses a substantial obstacle to effective TB treatment. Identifying genomic mutations in MTB isolates holds promise for unraveling the underlying mechanisms of drug resistance in this bacterium. METHODS: In this study, we investigated the roles of single nucleotide variants (SNVs) in MTB isolates resistant to four antibiotics (moxifloxacin, ofloxacin, amikacin, and capreomycin) through whole-genome analysis. We identified the drug-resistance-associated SNVs by comparing the genomes of MTB isolates with reference genomes using the MuMmer4 tool. RESULTS: We observed a strikingly high proportion (94.2%) of MTB isolates resistant to ofloxacin, underscoring the current prevalence of drug resistance in MTB. An average of 3529 SNVs were detected in a single ofloxacin-resistant isolate, indicating a mutation rate of approximately 0.08% under the selective pressure of ofloxacin exposure. We identified a set of 60 SNVs associated with extensively drug-resistant tuberculosis (XDR-TB), among which 42 SNVs were non-synonymous mutations located in the coding regions of nine key genes (ctpI, desA3, mce1R, moeB1, ndhA, PE_PGRS4, PPE18, rpsA, secF). Protein structure modeling revealed that SNVs of three genes (PE_PGRS4, desA3, secF) are close to the critical catalytic active sites in the three-dimensional structure of the coding proteins. CONCLUSION: This comprehensive study elucidates novel resistance mechanisms in MTB against antibiotics, paving the way for future design and development of anti-tuberculosis drugs.

AMAR-seq: Automated Multimodal Sequencing of DNA Methylation, Chromatin Accessibility, and RNA Expression with Single-Cell Resolution.

Parallel single-cell multimodal sequencing is the most intuitive and precise tool for cellular status research. In this study, we propose AMAR-seq to automate methylation, chromatin accessibility, and RNA expression coanalysis with single-cell precision. We validated the accuracy and robustness of AMAR-seq in comparison with standard single-omics methods. The high gene detection rate and genome coverage of AMAR-seq enabled us to establish a genome-wide gene expression regulatory atlas and triple-omics landscape with single base resolution and implement single-cell copy number variation analysis. Applying AMAR-seq to investigate the process of mouse embryonic stem cell differentiation, we revealed the dynamic coupling of the epigenome and transcriptome, which may contribute to unraveling the molecular mechanisms of early embryonic development. Collectively, we propose AMAR-seq for the in-depth and accurate establishment of single-cell multiomics regulatory patterns in a cost-effective, efficient, and automated manner, paving the way for insightful dissection of complex life processes.

Apigenin suppresses epithelial-mesenchymal transition in high glucose-induced retinal pigment epithelial cell by inhibiting CBP/p300-mediated histone acetylation.

Epithelial mesenchymal transition (EMT) is a critical process implicated in the pathogenesis of retinal fibrosis and the exacerbation of diabetic retinopathy (DR) within retinal pigment epithelium (RPE) cells. Apigenin (AP), a potential dietary supplement for managing diabetes and its associated complications, has demonstrated inhibitory effects on EMT in various diseases. However, the specific impact and underlying mechanisms of AP on EMT in RPE cells remain poorly understood. In this study, we have successfully validated the inhibitory effects of AP on high glucose-induced EMT in ARPE-19 cells and diabetic db/db mice. Notably, our findings have identified CBP/p300 as a potential therapeutic target for EMT in RPE cells and have further substantiated that AP effectively downregulates the expression of EMT-related genes by attenuating the activity of CBP/p300, consequently reducing histone acetylation alterations within the promoter region of these genes. Taken together, our results provide novel evidence supporting the inhibitory effect of AP on EMT in RPE cells, and highlight the potential of specifically targeting CBP/p300 as a strategy for inhibiting retinal fibrosis in the context of DR.

Genome-wide identification, expression analysis of WRKY transcription factors in Citrus ichangensis and functional validation of CiWRKY31 in response to cold stress.

BACKGROUND: Ichang papeda (Citrus ichangensis), a wild perennial plant of the Rutaceae family, is a cold-hardy plant. WRKY transcription factors are crucial regulators of plant growth and development as well as abiotic stress responses. However, the WRKY genes in C. ichangensis (CiWRKY) and their expression patterns under cold stress have not been thoroughly investigated, hindering our understanding of their role in cold tolerance. RESULTS: In this study, a total of 52 CiWRKY genes identified in the genome of C. ichangensis were classified into three main groups and five subgroups based on phylogenetic analysis. Comprehensive analyses of motif features, conserved domains, and gene structures were performed. Segmental duplication plays a significant role in the CiWRKY gene family expansion. Cis-acting element analysis revealed the presence of various stress-responsive elements in the promoters of the majority of CiWRKYs. Gene ontology (GO) analysis and protein-protein interaction predictions indicate that the CiWRKYs exhibit crucial roles in regulation of both development and stress response. Expression profiling analysis demonstrates that 14 CiWRKYs were substantially induced under cold stress. Virus-induced gene silencing (VIGS) assay confirmed that CiWRKY31, one of the cold-induced WRKYs, functions positively in regulation of cold tolerance. CONCLUSION: Sequence and protein properties of CiWRKYs were systematically analyzed. Among the 52 CiWRKY genes 14 members exhibited cold-responsive expression patterns, and CiWRKY31 was verified to be a positive regulator of cold tolerance. These findings pave way for future investigations to understand the molecular functions of CiWRKYs in cold tolerance and contribute to unravelling WRKYs that may be used for engineering cold tolerance in citrus.

Human Sapovirus Replication in Human Intestinal Enteroids.

Human sapoviruses (HuSaVs), like human noroviruses (HuNoV), belong to the Caliciviridae family and cause acute gastroenteritis in humans. Since their discovery in 1976, numerous attempts to grow HuSaVs in vitro were unsuccessful until 2020, when these viruses were reported to replicate in a duodenal cancer cell-derived line. Physiological cellular models allowing viral replication are essential to investigate HuSaV biology and replication mechanisms such as genetic susceptibility, restriction factors, and immune responses to infection. In this study, we demonstrate replication of two HuSaV strains in human intestinal enteroids (HIEs) known to support the replication of HuNoV and other human enteric viruses. HuSaVs replicated in differentiated HIEs originating from jejunum, duodenum and ileum, but not from the colon, and bile acids were required. Between 2h and 3 to 6 days postinfection, viral RNA levels increased up from 0.5 to 1.8 log10-fold. Importantly, HuSaVs were able to replicate in HIEs independent of their secretor status and histo-blood group antigen expression. The HIE model supports HuSaV replication and allows a better understanding of host-pathogen mechanisms such as cellular tropism and mechanisms of viral replication. IMPORTANCE Human sapoviruses (HuSaVs) are a frequent but overlooked cause of acute gastroenteritis, especially in children. Little is known about this pathogen, whose successful in vitro cultivation was reported only recently, in a cancer cell-derived line. Here, we assessed the replication of HuSaV in human intestinal enteroids (HIEs), which are nontransformed cultures originally derived from human intestinal stem cells that can be grown in vitro and are known to allow the replication of other enteric viruses. Successful infection of HIEs with two strains belonging to different genotypes of the virus allowed discovery that the tropism of these HuSaVs is restricted to the small intestine, does not occur in the colon, and replication requires bile acid but is independent of the expression of histo-blood group antigens. Thus, HIEs represent a physiologically relevant model to further investigate HuSaV biology and a suitable platform for the future development of vaccines and antivirals.

DFinder: a novel end-to-end graph embedding-based method to identify drug-food interactions.

MOTIVATION: Drug-food interactions (DFIs) occur when some constituents of food affect the bioaccessibility or efficacy of the drug by involving in drug pharmacodynamic and/or pharmacokinetic processes. Many computational methods have achieved remarkable results in link prediction tasks between biological entities, which show the potential of computational methods in discovering novel DFIs. However, there are few computational approaches that pay attention to DFI identification. This is mainly due to the lack of DFI data. In addition, food is generally made up of a variety of chemical substances. The complexity of food makes it difficult to generate accurate feature representations for food. Therefore, it is urgent to develop effective computational approaches for learning the food feature representation and predicting DFIs. RESULTS: In this article, we first collect DFI data from DrugBank and PubMed, respectively, to construct two datasets, named DrugBank-DFI and PubMed-DFI. Based on these two datasets, two DFI networks are constructed. Then, we propose a novel end-to-end graph embedding-based method named DFinder to identify DFIs. DFinder combines node attribute features and topological structure features to learn the representations of drugs and food constituents. In topology space, we adopt a simplified graph convolution network-based method to learn the topological structure features. In feature space, we use a deep neural network to extract attribute features from the original node attributes. The evaluation results indicate that DFinder performs better than other baseline methods. AVAILABILITY AND IMPLEMENTATION: The source code is available at https://github.com/23AIBox/23AIBox-DFinder. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Role of AKR1B10 in inflammatory diseases.

Inflammation is an important pathophysiological process in many diseases; it has beneficial and harmful effects. When exposed to various stimuli, the body triggers an inflammatory response to eliminate invaded pathogens and damaged tissues to maintain homeostasis. However, uncontrollable persistent or excessive inflammatory responses may damage tissues and induce various diseases, such as metabolic diseases (e.g. diabetes), autoimmune diseases, nervous system-related diseases, digestive system-related diseases, and even tumours. Aldo-keto reductase 1B10 (AKR1B10) is an important player in the development and progression of multiple diseases, such as tumours and inflammatory diseases. AKR1B10 is upregulated in solid tumours, such as hepatocellular carcinoma (HCC), non-small cell lung carcinoma, and breast cancer, and is a reliable serum marker. However, information on the role of AKR1B10 in inflammation is limited. In this study, we summarized the role of AKR1B10 in inflammatory diseases, including its expression, functional contribution to inflammatory responses, and regulation of signalling pathways related to inflammation. We also discussed the role of AKR1B10 in glucose and lipid metabolism and oxidative stress. This study provides novel information and increases the understanding of clinical inflammatory diseases.

Diallyl disulfide synergizes with melphalan to increase apoptosis and DNA damage through elevation of reactive oxygen species in multiple myeloma cells.

Diallyl disulfide (DADS), one of the main components of garlic, is well known to have anticancer effects on multiple cancers. However, its efficacy in treating multiple myeloma (MM) is yet to be determined. We explored the effects of DADS on MM cells and investigated the synergistic effects of DADS when combined with five anti-MM drugs, including melphalan, bortezomib, carfilzomib, doxorubicin, and lenalidomide. We analyzed cell viability, cell apoptosis, and DNA damage to determine the efficacy of DADS and the drug combinations. Our findings revealed that DADS induces apoptosis in MM cells through the mitochondria-dependent pathway and increases the levels of γ-H2AX, a DNA damage marker. Combination index (CI) measurements indicated that the combination of DADS with melphalan has a significant synergistic effect on MM cells. This was further confirmed by the increases in apoptotic cells and DNA damage in MM cells treated with the two drug combinations compared with those cells treated with a single drug alone. The synergy between DADS and melphalan was also observed in primary MM cells. Furthermore, mechanistic investigations showed that DADS decreases reduced glutathione (GSH) levels and increases reactive oxygen species (ROS) production in MM cells. The addition of GSH is effective in neutralizing DADS cytotoxicity and inhibiting the synergy between DADS and melphalan in MM cells. Taken together, our study highlights the effectiveness of DADS in treating MM cells and the promising therapeutic potential of combining DADS and melphalan for MM treatment.

The nonradiative decay mechanism of dinuclear iridium complexes: a density functional theory study.

Dinuclear metal complexes are a promising class of compounds applicable to photoluminescence and catalysis. However, an understanding of the mechanism of the nonradiative decay process of dinuclear metal complexes remains very limited. Herein, the mechanism of the nonradiative decay process of dinuclear iridium(III) complexes (D1 and D2) and their mononuclear iridium(III) complex (M1) is elucidated by using density functional theory (DFT). Our results reveal that the nonradiative decay process occurs on a weak Ir-N bond and therefore results in metal-centered triplet excited (3MC) states. The deactivation pathways connecting the Franck-Condon region and the minimum energy seam of crossing (MESX) were further identified to be the determining step, which is the thermal deactivation pathways of 3MLCT → TS → 3MC→ MESX. The smaller energy barrier from the T1 minimum to the MESX state for D1 (9.48 kcal mol-1) and D2 (8.64 kcal mol-1) relative to that for M1 (10.95 kcal mol-1) plays a key role in observed weak emissions of D1 and D2 in the red region compared to that of M1. Moreover, by introducing the electron-withdrawing Cl atom at the para- or meta-position of the 2-phenylpyrimidine (ppd) moiety, a large energy barrier between the 3MC state and the T1 minimum is obtained. Our work not only provides the possibility of the nonradiative decay process of dinuclear iridium(III) materials, but also paves a promising way for reducing the nonradiative process and developing saturated efficient red dinuclear iridium(III) materials for broader potential application.

How enteral nutrition modes influence nasopharyngeal carcinoma survivors with late dysphagia after radiotherapy: a randomized controlled study.

BACKGROUND: Palliation to late dysphagia after radiotherapy for nasopharyngeal carcinoma (NPC) continues to be a challenge. Intermittent oro-esophageal tube feeding (IOE) is an emerging enteral nutrition mode that can address nutrition and quality of life issues related to nasogastric tube feeding (NGT). OBJECTIVES: This study aims to investigate the effect of IOE versus NGT in late dysphagia after radiotherapy for NPC. METHODS: This randomized controlled study included 82 NPC survivors with late dysphagia after radiotherapy. The subjects were randomized divided into the IOE and NGT groups (n1 = n2 = 41). Both groups received standard-of-care rehabilitation. Enteral nutrition supports were administered through IOE or NGT accordingly. This study lasted 2 weeks for each participant. The primary outcome was nutritional status including albumin, hemoglobin, total serum protein, and body mass index. The secondary outcomes were (i) the functional oral intake scale (FOIS), (ii) the penetration-aspiration scale (PAS), (iii) oral transit time (OTT), (iv) hyoid pause time (HPT), (v) pharyngeal transport time (PTT), and (vi) swallowing-quality of life (SWAL-QoL). RESULTS: Three cases quitted the study halfway and there were no significant baseline differences between the IOE (n = 40) and NGT (n = 39) groups. Both time and group effects were significant in all nutritional indicators. The time effect was significant in the FOIS levels, OTT and PTT, while the group effect was not. Either time or group effect were insignificant in the PAS levels and HPT. Both group and time effects were significant in the SWAL-QoL total scores (zGroup = 5.080, P < 0.001; zTime = 18.005, P < 0.001). The significance of time and group effects varied across different dimensions of the SWAL-QoL. CONCLUSIONS: Rehabilitation interventions can improve swallowing function among NPC survivors with late dysphagia after radiotherapy. In this population who received standard-of-care rehabilitation, IOE is more conducive to the improvement of nutritional status, and swallowing-related quality of life. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06301763.

A Novel lncRNA lncRNA-4045 Promotes the Progression of Hepatocellular Carcinoma by Affecting the Expression of AKR1B10.

BACKGROUND: Long noncoding RNAs (lncRNAs) have been shown to be related to the occurrence and development of a variety of cancers including hepatocellular carcinoma (HCC). However, a large number of potential HCC-related lncRNAs remain undiscovered and are yet to be fully understood. METHODS: Differentially expressed lncRNAs were first obtained from the tumor tissues and adjacent normal tissues of five HCC patients using high-throughput microarray chips. Then the expression levels of 10 differentially expressed lncRNAs were verified in 50 pairs of tissue samples from patients with HCC by quantitative real-time PCR (qRT-PCR). The oncogenic effects of lncRNA-4045 (ENST00000524045.6) in HCC cell lines were verified through a series of in vitro experiments including CCK-8 assay, plate clone formation assay, transwell assay, scratch assay, and flow cytometry. Subsequently, the potential target genes of lncRNA-4045 were predicted by bioinformatics analysis, fluorescence in situ hybridization assay, and RNA sequencing. The mechanism of lncRNA-4045 in HCC was explored by WB assay as well as rescue and enhancement experiments. RESULTS: The results from microarray chips showed 1,708 lncRNAs to have been significantly upregulated and 2725 lncRNAs to have been significantly downregulated in HCC tissues. Via validation in 50 HCC patients, a novel lncRNA lncRNA-4045 was found significantly upregulated in HCC tissues. Additionally, a series of in vitro experiments showed that lncRNA-4045 promoted the proliferation, invasion, and migration of HCC cell lines, and inhibited the apoptosis of HCC cell lines. The results of qRT-PCR in HCC tissues showed that the expression levels of AKR1B10 were significantly positively correlated with lncRNA-4045. LncRNA-4045 knockdown significantly down-regulated AKR1B10 protein expression, and overexpression of lncRNA-4045 led to significant up-regulation of AKR1B10 protein in HCC cell lines. Lastly, down-regulation of AKR1B10 could partially eliminate the enhancement of cell proliferation induced by lncRNA-4045 overexpression, while up-regulation of AKR1B10 was shown to enhance those effects. CONCLUSION: LncRNA-4045 may promote HCC via enhancement of the expression of AKR1B10 protein.

Analysis of risk factors and development of predictive model for malnutrition in patients with traumatic brain injury.

Malnutrition is a highly prevalent complication in patients with traumatic brain injury (TBI), and it is closely related to the prognosis of patients. Accurate identification of patients at high risk of malnutrition is essential. Therefore, we analyzed the risk factors of malnutrition in patients with TBI and developed a model to predict the risk of malnutrition. A retrospective collection of 345 patients with TBI, and they were divided into malnutrition and comparison groups according to the occurrence of malnutrition. Univariate correlation and multifactor logistic regression analyses were performed to determine patients' malnutrition risk factors. We used univariate and logistic regression (forward stepwise method) analyses to identify significant predictors associated with malnutrition in patients with TBI and developed a predictive model for malnutrition prediction. The model's discrimination, calibration, and clinical utility were evaluated using the receiver operating characteristic (ROC) curve, calibration plots, and decision curve analysis (DCA). A total of 216 patients (62.6%) developed malnutrition. Multifactorial logistic regression analysis showed that pulmonary infection, urinary tract infection, dysphagia, application of NGT, GCS score ≤ 8, and low ADL score were independent risk factors for malnutrition in patients with TBI (P < 0.05). The area under the curve of the model was 0.947. Calibration plots showed good discrimination of model calibration. DCA showed that the column line plot models were all clinically meaningful when nutritional interventions were performed over a considerable range of threshold probabilities (0-0.98). Malnutrition is widespread in patients with TBI, and the nomogram is a good predictor of whether patients develop malnutrition.

Reliability and Validity of the Chinese Mandarin Version of the Dysphagia Handicap Index.

This study aimed to develop the Dysphagia Handicap Index-Chinese Mandarin (DHI-CM) and to assess its reliability and validity. This prospective study was conducted in China with individuals who speak Mandarin. The DHI-CM was developed according to a five-stage process. 264 patients with oropharyngeal dysphagia (OD) and 187 healthy individuals completed the study. Reliability was assessed using Cronbach's α and test-retest reliability. Differences between healthy participants and patients with OD were analyzed for instrument validity. Convergent and concurrent validity were assessed using the Swallowing Quality of Life Questionnaire (SWAL-QoL) and Functional Oral Intake Scale (FOIS), respectively. The Content Validity Index (CVI) was used to assess content validity. Exploratory and Confirmatory Factor Analyses (EFA and CFA, respectively) were used to assess structural validity. The Cronbach's alpha was > 0.9 for the total score and every individual subscale. The Pearson and intraclass correlation coefficients were both > 0.8. The patients with OD showed significantly higher scores in the DHI-CM and its subscales than the healthy individuals. Significant correlations were found between most subscales of the DHI-CM and both the SWAL-QoL and FOIS. The CVI of the DHI-CM was 0.892 and ranged between 0.878 and 1.000 for the subscales. The EFA identified three components that explained 24.33%, 23.99%, and 22.73% of the variance, respectively. The scale showed good structural validity through CFA. Conclusions. The DHI-CM demonstrated good reliability and validity among Mandarin-speaking Chinese adults.

Knockdown of TcGluCl leads to the premature pupation of Tribolium castaneum larvae possibly by influencing the calcium-mediating hormone homeostasis.

The glutamate-gated chloride channels (GluCls) are widely existed in the neural and nonneural tissues of invertebrate. In addition to play important roles in signal transduction, the GluCls also showed multiple physiological functions in insects such as participate in the juvenile hormone synthesis. In the present study, the potential roles of TcGluCl in growth and development of the red flour beetle Tribolium castaneum were explored. Knockdown of TcGluCl showed no effects on the survivability, weight growth, final pupation rate, eclosion and fecundity of T. castaneum, whereas resulted in the significant premature pupation of larvae. Inhibition of TcGluCl expression significantly changed the levels of juvenile hormone and ecdysone as well as the expressions of hormone biosynthetic genes. The increased ecdysone level and decreased juvenile hormone level were observed at the late stage of dsGluCl-treated larvae. Knockdown of TcGluCl significantly reduced the expressions of TcSTIM1 and TcOrai1, which were the primary proteins in store-operated calcium entry (SOCE) mediated Ca2+ influx mechanism. Whilst the L-glutamic acid treatment led to the increased TcOrai1 expression in T. castaneum. These findings suggested that knockdown of TcGluCl increased the ecdysone level and contributed to the premature pupation of larvae, which might be due to the reduced Ca2+ influx caused by the decreased expressions of TcSTIM1 and TcOrai1. These studies provide novel insights on the function of GluCls in insects.

Discovery and Structure-Activity Relationship of a Ryanodine Receptor 2 Inhibitor.

Ryanodine receptor 2 (RyR2) is a large Ca2+-release channel in the sarcoplasmic reticulum (SR) of cardiac muscle cells. It serves to release Ca2+ from the SR into the cytosol to initiate muscle contraction. RyR2 overactivation is associated with arrhythmogenic cardiac disease, but few specific inhibitors have been reported so far. Here, we identified an RyR2-selective inhibitor 1 from the chemical compound library and synthesized it from glycolic acid. Synthesis of various derivatives to investigate the structure-activity relationship of each substructure afforded another two RyR2-selective inhibitors 6 and 7, among which 6 was the most potent. Notably, compound 6 also inhibited Ca2+ release in cells expressing the RyR2 mutants R2474S, R4497C and K4750Q, which are associated with cardiac arrhythmias such as catecholaminergic polymorphic ventricular tachycardia (CPVT). This inhibitor is expected to be a useful tool for research on the structure and dynamics of RyR2, as well as a lead compound for the development of drug candidates to treat RyR2-related cardiac disease.

Peptidoglycan-associated lipoprotein contributes to the virulence of Acinetobacter baumannii and serves as a vaccine candidate.

The role of peptidoglycan-associated lipoprotein (Pal) in A. baumannii pathogenesis remains unclear. Here, we illustrated its role by constructing a pal deficient A. baumannii mutant and its complementary strain.Transcriptome analysis of the WT and pal mutant revealed a total of 596 differentially expressed genes. Gene Ontology analysis revealed that pal deficiency caused the downregulation of genes related to material transport and metabolic processes. The pal mutant showed a slower growth and was sensitive to detergent and serum killing compared to WT strain, whereas, the complemented pal mutant showed rescued phenotype. The pal mutant caused decreased mortality in mice pneumonia infection compared to WT strain, while the complemented pal mutant showed increased mortality. Mice immunized with recombinant Pal showed 40% protection against A. baumannii-mediated pneumonia. Collectively, these data indicate Pal is a virulence factor of A. baumannii and may serve as a potential target for preventive or therapeutic interventions.