Combination of retagliptin and henagliflozin as add-on therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin: A multicentre, randomized, double-blind, active-controlled, phase 3 trial.

AIM: This study assessed the efficacy and safety of co-administering retagliptin and henagliflozin versus individual agents at corresponding doses in patients with type 2 diabetes mellitus who were inadequately controlled with metformin. METHODS: This multicentre, phase 3 trial consisted of a 24-week, randomized, double-blind, active-controlled period. Patients with glycated haemoglobin (HbA1c) levels between 7.5% and 10.5% were randomized to receive once-daily retagliptin 100 mg (R100; n = 155), henagliflozin 5 mg (H5; n = 156), henagliflozin 10 mg (H10; n = 156), co-administered R100/H5 (n = 155), or R100/H10 (n = 156). The primary endpoint was the change in HbA1c from baseline to week 24. RESULTS: Based on the primary estimand, the least squares mean reductions in HbA1c at week 24 were significantly greater in the R100/H5 (-1.51%) and R100/H10 (-1.54%) groups compared with those receiving the corresponding doses of individual agents (-0.98% for R100, -0.86% for H5 and -0.95% for H10, respectively; p < .0001 for all pairwise comparisons). Achievement of HbA1c <7.0% at week 24 was observed in 27.1% of patients in the R100 group, 21.2% in the H5 group, 24.4% in the H10 group, 57.4% in the R100/H5 group and 56.4% in the R100/H10 group. Reductions in fasting plasma glucose and 2-h postprandial glucose were also more pronounced in the co-administration groups compared with the individual agents at corresponding doses. Decreases in body weight and systolic blood pressure were greater in the groups containing henagliflozin than in the R100 group. The incidence rates of adverse events were similar across all treatment groups, with no reported episodes of severe hypoglycaemia. CONCLUSIONS: For patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapy, the co-administration of retagliptin and henagliflozin yielded more effective glycaemic control through 24 weeks compared with the individual agents at their corresponding doses.

A type VI secretion system effector TseG of Pantoea ananatis is involved in virulence and antibacterial activity.

The type VI secretion system (T6SS) of many gram-negative bacteria injects toxic effectors into adjacent cells to manipulate host cells during pathogenesis or to kill competing bacteria. However, the identification and function of the T6SS effectors remains only partly known. Pantoea ananatis, a gram-negative bacterium, is commonly found in various plants and natural environments, including water and soil. In the current study, genomic analysis of P. ananatis DZ-12 causing brown stalk rot on maize demonstrated that it carries three T6SS gene clusters, namely, T6SS-1, T6SS-2, and T6SS-3. Interestingly, only T6SS-1 secretion systems are involved in pathogenicity and bacterial competition. The study also investigated the T6SS-1 system in detail and identified an unknown T6SS-1-secreted effector TseG by using the upstream T6SS effector chaperone TecG containing a conserved domain of DUF2169. TseG can directly interact with the chaperone TecG for delivery and with a downstream immunity protein TsiG for protection from its toxicity. TseG, highly conserved in the Pantoea genus, is involved in virulence in maize, potato, and onion. Additionally, P. ananatis uses TseG to target Escherichia coli, gaining a competitive advantage. This study provides the first report on the T6SS-1-secreted effector from P. ananatis, thereby enriching our understanding of the various types and functions of type VI effector proteins.

Clozapine-Induced Severe Toxicity: Exploring the Pharmacokinetic Profile of Clozapine and Its Significance in Hemodynamic Instability - A Case Report.

Hemodynamic instability in patients with clozapine intoxication can indirectly reflect the serum concentration of clozapine.We have described a case of a 32-year-old pregnant woman who developed life-threatening clozapine toxicity at 28 weeks of gestation. The levels of clozapine and norclozapine in the serum were high. We initiated hemoperfusion(HP) and other detoxification therapies to remove the drug. The patient had severely dilated peripheral blood vessels, which led to cardiac symptoms such as fatal hypotension and uncontrollable tachycardia, resulting in very high cardiac output and elevated Central venous oxygen saturation (ScvO2). Pharmacological intervention significantly improved the hemodynamics.In light of our observations in the ongoing case, we posit that evaluating hemodynamic parameters before and after blood detoxification could serve as a valuable means to gauge effectiveness and provide guidance for treatment.

The pharmacokinetics/pharmacodynamics of ceftazidime/avibactam for central nervous system infections caused by carbapenem-resistant Gram-negatives: a prospective study.

OBJECTIVES: To describe the pharmacokinetics/pharmacodynamics (PK/PD) of ceftazidime/avibactam in critically ill patients with CNS infections. METHODS: A prospective study of critically ill patients with CNS infections who were treated with ceftazidime/avibactam and the steady-state concentration (Css) of ceftazidime/avibactam in serum and/or CSF was conducted between August 2020 and May 2023. The relationship between PK/PD goal achievement, microbial eradication and the clinical efficacy of ceftazidime/avibactam was evaluated. RESULTS: Seven patients were finally included. The ceftazidime/avibactam target attainment in plasma was optimal for three, quasi-optimal for one and suboptimal for three. In three patients with CSF drug concentrations measured, ceftazidime/avibactam target attainment in CSF was 100% (3/3), which was optimal. The AUCCSF/serum values were 0.59, 0.44 and 0.35 for ceftazidime and 0.57, 0.53 and 0.51 for avibactam. Of the seven patients, 100% (7/7) were treated effectively, 71.4% (5/7) achieved microbiological eradication, 85.7% (6/7) survived and 14.3% (1/7) did not survive. CONCLUSIONS: The limited clinical data suggest that ceftazidime/avibactam is effective in the treatment of CNS infections caused by MDR Gram-negative bacilli (MDR-GNB), can achieve the ideal drug concentration of CSF, and has good blood-brain barrier penetration.

Ambient Electrochemical Ammonia Synthesis: From Theoretical Guidance to Catalyst Design.

Ammonia, a vital component in the synthesis of fertilizers, plastics, and explosives, is traditionally produced via the energy-intensive and environmentally detrimental Haber-Bosch process. Given its considerable energy consumption and significant greenhouse gas emissions, there is a growing shift toward electrocatalytic ammonia synthesis as an eco-friendly alternative. However, developing efficient electrocatalysts capable of achieving high selectivity, Faraday efficiency, and yield under ambient conditions remains a significant challenge. This review delves into the decades-long research into electrocatalytic ammonia synthesis, highlighting the evolution of fundamental principles, theoretical descriptors, and reaction mechanisms. An in-depth analysis of the nitrogen reduction reaction (NRR) and nitrate reduction reaction (NitRR) is provided, with a focus on their electrocatalysts. Additionally, the theories behind electrocatalyst design for ammonia synthesis are examined, including the Gibbs free energy approach, Sabatier principle, d-band center theory, and orbital spin states. The review culminates in a comprehensive overview of the current challenges and prospective future directions in electrocatalyst development for NRR and NitRR, paving the way for more sustainable methods of ammonia production.

Fusarium graminearum rapid alkalinization factor peptide negatively regulates plant immunity and cell growth via the FERONIA receptor kinase.

The plant rapid alkalinization factor (RALF) peptides function as key regulators in cell growth and immune responses through the receptor kinase FERONIA (FER). In this study, we report that the transcription factor FgPacC binds directly to the promoter of FgRALF gene, which encodes a functional homologue of the plant RALF peptides from the wheat head blight fungus Fusarium graminearum (FgRALF). More importantly, FgPacC promotes fungal infection via host immune suppression by activating the expression of FgRALF. The FgRALF peptide also exhibited typical activities of plant RALF functions, such as inducing plant alkalinization and inhibiting cell growth, including wheat (Triticum aestivum), tomato (Solanum lycopersicum) and Arabidopsis thaliana. We further identified the wheat receptor kinase FERONIA (TaFER), which is capable of restoring the defects of the A. thaliana FER mutant. In addition, we found that FgRALF peptide binds to the extracellular malectin-like domain (ECD) of TaFER (TaFERECD ) to suppress the PAMP-triggered immunity (PTI) and cell growth. Overexpression of TaFERECD in A. thaliana confers plant resistance to F. graminearum and protects from FgRALF-induced cell growth inhibition. Collectively, our results demonstrate that the fungal pathogen-secreted RALF mimic suppresses host immunity and inhibits cell growth via plant FER receptor. This establishes a novel pathway for the development of disease-resistant crops in the future without compromising their yield potential.

A glycoside hydrolase 30 protein BpXynC of Bacillus paralicheniformis NMSW12 recognized as A MAMP triggers plant immunity response.

Bacillus spp. has been widely used as a biocontrol agent to control plant diseases. However, little is known about mechanisms of the protein MAMP secreted by Bacillus spp. Herein, our study reported a glycoside hydrolase family 30 (GH30) protein, BpXynC, produced by the biocontrol bacteria Bacillus paralicheniformis NMSW12, that can induce cell death in several plant species. The results revealed that the recombinant protein triggers cell death in Nicotiana benthamiana in a BAK1-dependent manner and elicits an early defense response, including ROS burst, activation of MAPK cascades, and upregulation of plant immunity marker genes. BpXynC was also found to be a glucuronoxylanase that exhibits hydrolysis activity on xlyan. Two mutants of BpXynC which lost the glucuronoxylanase activity still retained the elicitor activity. The qRT-PCR results of defense-related genes showed that BpXynC induces plant immunity responses via an SA-mediated pathway. BpXynC and its mutants could induce resistance in N. benthamiana against infection by Sclerotinia sclerotiorum and tobacco mosaic virus (TMV). Furthermore, BpXynC-treated tomato fruits exhibited strong resistance to the infection of Phytophthora capsica. Overall, our study revealed that GH30 protein BpXynC can induce plant immunity response as MAMP, which can be further applied as a biopesticide to control plant diseases.

P407 hydrogel loaded with nitric oxide microbubbles promotes angiogenesis and functional improvement in testicular transplantation.

Prepubertal male patients with cancer have decreased fertility after treatment, but there are currently no suitable means for fertility rescue. Testicular transplantation seems to be a promising treatment. The short-term insufficiency of blood supply after transplantation is the key problem that needs to be solved. In this research, nitric oxide (NO), a gas and small molecule transmitter with the effect of promoting angiogenesis, acted at the site of testicular transplantation. Herein, poloxamer-407 (P407) and lipid microbubble materials served as transport carriers for NO and helped NO to function at the transplant site. P407 hydrogel loaded with NO microbubbles (PNO) slowly released NO in vitro. The three-dimensional space of the hydrogel provided a stable environment for NO microbubbles, which is conducive to the continuous release of NO. In this study, 25% PNO (w/v) was selected, and the gelling temperature was 19.47 °C. The gelling efficiency was relatively high at body temperature. Rheological experiments showed that PNO, at this concentration, had stable mechanical properties. The results from in vivo experiments demonstrated that testicular grafts in the PNO group exhibited a notably accelerated blood flow recovery compared to the other groups. Additionally, the PNO group displayed a significant improvement in reproductive function recovery. In conclusion, PNO exhibited slow release of NO, and a small amount of NO promoted angiogenesis in testicular grafts and restored reproductive function.

Temporally-coordinated bivalent histone modifications of BCG1 enable fungal invasion and immune evasion.

Bivalent histone modifications, including functionally opposite H3K4me3 and H3K27me3 marks simultaneously on the same nucleosome, control various cellular processes by fine-tuning the gene expression in eukaryotes. However, the role of bivalent histone modifications in fungal virulence remains elusive. By mapping the genome-wide landscape of H3K4me3 and H3K27me3 dynamic modifications in Fusarium graminearum (Fg) during invasion, we identify the infection-related bivalent chromatin-marked genes (BCGs). BCG1 gene, which encodes a secreted Fusarium-specific xylanase containing a G/Q-rich motif, displays the highest increase of bivalent modification during Fg infection. We report that the G/Q-rich motif of BCG1 is a stimulator of its xylanase activity and is essential for the full virulence of Fg. Intriguingly, this G/Q-rich motif is recognized by pattern-recognition receptors to trigger plant immunity. We discover that Fg employs H3K4me3 modification to induce BCG1 expression required for host cell wall degradation. After breaching the cell wall barrier, this active chromatin state is reset to bivalency by co-modifying with H3K27me3, which enables epigenetic silencing of BCG1 to escape from host immune surveillance. Collectively, our study highlights how fungal pathogens deploy bivalent epigenetic modification to achieve temporally-coordinated activation and suppression of a critical fungal gene, thereby facilitating successful infection and host immune evasion.

A descriptive pharmacokinetic/pharmacodynamic analysis of ceftazidime-avibactam in a case series of critically ill patients with augmented renal clearance.

To describe the pharmacokinetics/pharmacodynamics (PK/PD) of a 2 h infusion of ceftazidime-avibactam (CAZ-AVI) in critically ill patients with augmented renal clearance (ARC). A retrospective review of all critically ill patients with ARC who were treated with CAZ-AVI between August 2020 and May 2023 was conducted. Patients whose 12-h creatinine clearance prior to CAZ-AVI treatment and steady-state concentration (Css) of CAZ-AVI were both monitored were enrolled. The free fraction (fCss) of CAZ-AVI was calculated from Css. The joint PK/PD targets of CAZ-AVI were considered optimal when a Css/minimum inhibitory concentration (MIC) ratio for CAZ ≥4 (equivalent to 100% fT > 4 MIC) and a Css/CT ratio of AVI >1 (equivalent to 100% fT > CT 4.0 mg/L) were reached simultaneously, quasioptimal when only one of the two targets was reached, and suboptimal when neither target was reached. The relationship between PK/PD goal achievement, microbial eradication and the clinical efficacy of CAZ-AVI was evaluated. Four patients were included. Only one patient achieved optimal joint PK/PD targets, while the other three reached suboptimal targets. The patient with optimal PK/PD targets achieved microbiological eradication, while the other three patients did not, but all four patients achieved good clinical efficacy. Standard dosages may not enable most critically ill patients with ARC to reach the optimal joint PK/PD targets of CAZ-AVI. Optimal drug dose adjustment of CAZ-AVI in ARC patients requires dynamic drug concentration monitoring.

Broad-spectrum antagonistic potential of Bacillus spp. volatiles against Rhizoctonia solani and Xanthomonas oryzae pv. oryzae.

Rhizoctonia solani and Xanthomonas oryzae pv. oryzae (Xoo) are the two major diseases affecting the quality and quantity of rice production. In the current study, volatile organic compounds (VOCs) of Bacillus spp. were used as green biocontrol agents for plant diseases. In in vitro experiments, Bacillus spp. FZB42, NMTD17, and LLTC93-VOCs displayed strong antimicrobial volatile activity with inhibition rates of 76, 66, and 78% for R. solani and 78, 81, and 76% for Xoo, respectively, compared to control. The synthetic VOCs, namely Pentadecane (PDC), Benzaldehyde (BDH), 1,2-Benz isothiazol-3(2H)-one (1,2-BIT), and mixture (MIX) of VOCs showed high volatile activity with inhibition rates of 86, 86, 89, and 92% against R. solani and 81, 81, 82, and 86%, respectively, against Xoo as compared to control. In addition, the scanning and transmission electron microscopes (SEM and TEM) analyses were performed to examine the effect of Bacillus and synthetic VOC treatments on R. solani and Xoo morphology. The analysis revealed the deformed and irregularized morphology of R. solani mycelia and Xoo cells after VOC treatments. The microscopic analysis showed that the rapid inhibition was due to severe oxidative productions inside the R. solani mycelia and Xoo cells. By using molecular docking, it was determined that the synthetic VOCs entered the active binding site of trehalase and NADH dehydrogenase proteins, causing R. solani and Xoo cells to die prematurely and an accumulation of ROS. In the greenhouse experiment, FZB42, NMTD17, and LLTC93-VOCs significantly reduced the lesions of R. solani 8, 7, and 6 cm, and Xoo 7, 6, and 6 cm, respectively, then control. The synthetic VOCs demonstrated that the PDC, BDH, 1,2-BIT, and MIX-VOCs significantly reduced R. solani lesions on leaves 6, 6, 6, and 5 cm and Xoo 6, 5, 5, and 4 cm, respectively, as compared to control. Furthermore, plant defence-related genes and antioxidant enzymes were upregulated in rice plants. These findings provide novel mechanisms by which Bacillus antimicrobial VOCs control plant diseases.

Combination of NK and Other Immune Markers at Early Phase Stratify the Risk of Sepsis Patients: A Retrospective Study.

Purpose: Immune dysfunction plays a pivotal role in sepsis pathogenesis. Previous studies have revealed the crucial role of T cells and human leukocyte antigen-DR (HLA-DR) in sepsis. However, the function of natural killer (NK) cells remains unclear. This study aimed to investigate whether NK cells are associated with sepsis prognosis. In addition, we aimed to explore the interrelation and influence between NK and other immunological features in patients with sepsis. Patients and Methods: This retrospective, observational study included patients with sepsis from two hospitals in mainland China. The clinical characteristics and immune results during the early phase were collected. Patients were classified according to the level of immune cells to analyze the relationship between immunological features and 28-day mortality. Results: A total of 984 patients were included in this study. Non-survivors were older and had lower levels of lymphocytes, monocytes, NK cells, HLA-DR, and T cells. Patients were classified into eight groups according to their levels of NK cells, HLA-DR, and T cells. Only patients with decreased NK and T cell counts showed a significant increase in 28-day mortality. An increase in CD8+ T cells was correlated with the alleviation of 28-day mortality only among patients with high NK cell levels. Conclusion: This study provides novel insights into the association between NK cells and 28-day mortality as well as the interrelation between NK cells and other immune cells in sepsis. The relationship between CD8+ T cells and 28-day mortality in sepsis is dependent on NK cell count.

Transcriptomic analysis of Ralstonia solanacearum in response to antibacterial volatiles of Bacillus velezensis FZB42.

Volatile organic compounds (VOCs), produced by a variety of microbial species and used as biological agents, have been demonstrated to play a significant role in controlling phytopathogens. In continuation of our previous studies, we aim to elucidate the underlying mechanisms and pathways involved in interactions between pathogens and microbial VOCs. In the current study, we tested how VOCs produced by Bacillus velezensis FZB42 affect the growth of Ralstonia solanacearum TBBS1 in vitro.Query The result showed that the colony growth of R. solanacearum was reduced with an inhibition rate of 0.83 ± 0.043 as compared to the control 1.7 ± 0.076, respectively. The number of viable cells of R. solanacearum was significantly decreased to 7.68 CFU/mL as compared to the control (9.02 CFU/mL). In addition, transcriptomic analysis of R. solanacearum in response to VOCs produced by FZB42 was performed to better understand the effect of VOCs on R. solanacearum. The transcriptional response of R. solanacearum to FZB42-VOCs was determined using an Illumina RNA-seq approach. The results revealed significant changes in the expression of 2094 R. solanacearum genes, including 593 upregulated and 1501 downregulated genes. To validate the RNA-seq results, the expression of 10 genes was quantified using RT-qPCR. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were used to functionally annotate differentially expressed genes. Significant changes were observed in genes directly or indirectly related to virulence, including those related to bacterial invasion, motility, chemotaxis, and secretion systems. Overall, RNA-seq profiling provides new insights into the possible fundamental molecular mechanisms that are responsible for the reduction in growth and virulence of R. solanacearum upon application of FZB42-VOC.

Indocyanine green clearance test as a predictor of linezolid overexposure in septic patients.

OBJECTIVES: Hepatic impairment increases the risk of drug overexposure in septic patients. However, there is a lack of effective indicators to predict overexposure risk. The indocyanine green (ICG) clearance test is a helpful method for dynamically assessing hepatic function and perfusion. This study aimed to investigate whether the ICG test could serve as a potential predictor of linezolid trough concentration (Cmin) and to compare its efficacy with that of conventional liver function markers. METHODS: A total of 35 consecutive septic patients treated with linezolid were grouped into either linezolid Cmin of ≤7 µg/mL or >7 µg/mL. Correlations between linezolid Cmin and ICG-PDR (plasma disappearance rate), ICG-R15 (retention ratio after 15 min) and other traditional indicators were analysed by Spearman's rank test. A multivariable regression model was employed to discern factors contributing independently to overexposure. RESULTS: Statistical differences were observed between groups for APACHE II score (P = 0.031), SOFA score (P = 0.018), creatinine clearance (CLCr) (P = 0.003), thrombocytes (P = 0.039), lactate (P = 0.003), ICG-PDR (P < 0.001) and ICG-R15 (P < 0.001). Moreover, linezolid Cmin was correlated with ICG-PDR (ρ = -0.628, P < 0.001), ICG-R15 (ρ = 0.676, P < 0.001) and CLCr (ρ = -0.503, P = 0.002). ICG-PDR was identified as an independent predictor of linezolid overexposure, with an optimal cut-off value of 17.70%/min (93.3% sensitivity, 85.0% specificity; P < 0.001). CONCLUSIONS: This pilot clinical trial represents the first investigation of potential of the ICG test to predict linezolid overexposure in septic patients.

Effect of vitamin D3 supplementation in winter on physical performance of university students: a one-month randomized controlled trial.

BACKGROUND: There is epidemiological evidence which suggests an association between 25-hydroxyvitamin D [25(OH)D] levels and bone and muscle function; however, it is unclear whether vitamin D supplementation has an added benefit beyond bone health. Here, we investigated the effects of vitamin D3 supplementation (1 month) on physical performance in Chinese university students in winter. METHODS: One hundred and seventeen eligible subjects with 25(OH)D (19.2 ± 7.8 ng/mL) were randomly assigned to either vitamin D3 supplement (N = 56; 1000 IU/day) or the control (N = 61) group for 1 month. Pre- and post-measurements included: 1) serum levels of 25(OH)D; 2) musculoskeletal and pulmonary function [vertical jump height (VJH) and right handgrip strength (RHS), forced vital capacity (FVC), and forced expiratory volume at 1s (FEV1)]; 3) bone turnover markers [parathyroid hormone (PTH), n-terminal osteocalcin (N-MID), and calcium]; 4) hemoglobin-related parameters [hemoglobin (Hb), hematocrit (HCT), red blood cells (RBC), and red cell distribution width (RDW)]; 5) lipid parameters [total triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C)]; 6) Fatigue-related indicators [serum creatine kinase (CK), lactate dehydrogenase (LDH), and total testosterone (T)]. In addition, aerobic capacity was assessed by measuring maximal oxygen uptake (VO2max) at baseline. RESULTS: During wintertime, supplementation with 1000 IU/d of vitamin D3 significantly increased serum 25(OH)D levels (from 18.85 ± 7.04 to 26.98 ± 5.88 ng/mL, p < 0.05), accompanied by a decrease of PTH (p < 0.05). However, vitamin D3 supplementation did not significantly impact the physical performance, serum lipid parameters, and bone turnover markers of students. Furthermore, 25(OH)D was found to be positively correlated with VJH and negatively correlated with PTH and TC at the beginning and end of the study (p < 0.05). In addition, the multiple linear regression analysis showed that 25(OH)D combined with athletic, gender, height, weight, Hb, and FVC could account for 84.0% of the VO2max value. CONCLUSIONS: The study demonstrated that one-month of 1000 IU/d of vitamin D3 supplementation during the winter had beneficial effects on 25(OH)D status and PTH. However, vitamin D3 intervention was not sufficient to improve physical performance. Furthermore, 25(OH)D levels combined with athletic, Hb and FVC could be a predictor of VO2max.

degQ associated with the degS/degU two-component system regulates biofilm formation, antimicrobial metabolite production, and biocontrol activity in Bacillus velezensis DMW1.

The gram-positive bacterium Bacillus velezensis strain DMW1 produces a high level of antimicrobial metabolites that can suppress the growth of phytopathogens. We investigated the mechanism used by degQ and the degS/degU two-component system to regulate the biocontrol characteristics of DMW1. When degQ and degU were deleted, the biofilm formation, cell motility, colonization activities, and antifungal abilities of ΔdegQ and ΔdegU were significantly reduced compared to wild-type DMW1. The expression levels of biofilm-related genes (epsA, epsB, epsC, and tasA) and swarming-related genes (swrA and swrB) were all down-regulated. We also evaluated the impact on secondary metabolites of these two genes. The degQ and degU genes reduced surfactin and macrolactin production and up-regulated the production of fengycin, iturin, bacillaene, and difficidin metabolites. The reverse transcription-quantitative PCR results were consistent with these observations. Electrophoretic mobility shift assay and microscale thermophoresis revealed that DegU can bind to the promoter regions of these six antimicrobial metabolite genes and regulate their synthesis. In conclusion, we provided systematic evidence to demonstrate that the degQ and degU genes are important regulators of multicellular behaviour and antimicrobial metabolic processes in B. velezensis DMW1 and suggested novel amenable strains to be used for the industrial production of antimicrobial metabolites.

GMMAD: a comprehensive database of human gut microbial metabolite associations with diseases.

BACKGROUND: The natural products, metabolites, of gut microbes are crucial effect factors on diseases. Comprehensive identification and annotation of relationships among disease, metabolites, and microbes can provide efficient and targeted solutions towards understanding the mechanism of complex disease and development of new markers and drugs. RESULTS: We developed Gut Microbial Metabolite Association with Disease (GMMAD), a manually curated database of associations among human diseases, gut microbes, and metabolites of gut microbes. Here, this initial release (i) contains 3,836 disease-microbe associations and 879,263 microbe-metabolite associations, which were extracted from literatures and available resources and then experienced our manual curation; (ii) defines an association strength score and a confidence score. With these two scores, GMMAD predicted 220,690 disease-metabolite associations, where the metabolites all belong to the gut microbes. We think that the positive effective (with both scores higher than suggested thresholds) associations will help identify disease marker and understand the pathogenic mechanism from the sense of gut microbes. The negative effective associations would be taken as biomarkers and have the potential as drug candidates. Literature proofs supported our proposal with experimental consistence; (iii) provides a user-friendly web interface that allows users to browse, search, and download information on associations among diseases, metabolites, and microbes. The resource is freely available at http://guolab.whu.edu.cn/GMMAD . CONCLUSIONS: As the online-available unique resource for gut microbial metabolite-disease associations, GMMAD is helpful for researchers to explore mechanisms of disease- metabolite-microbe and screen the drug and marker candidates for different diseases.

Whole Exome Sequencing Identified two Novel Truncation Mutations in the CTNNB1 Gene Associated with Neurodevelopmental Disorder, Language Dysfunction, and Microcephaly in Chinese Children.

Recently, the loss-of-function, heterozygous, and de novo mutations of the CTNNB1 gene have been proven to be partially responsible for intellectual disability in some patients. Herein, we report two unrelated children with neurodevelopmental disorder, abnormal facial features, speech impairments, microcephaly, and dystonia. Based on whole exome sequencing (WES), two new heterozygous and pathogenic mutations in exon 10 (c.1586dupA:p.Q530Afs*42) and exon 4 (c.257dup:p.Y86*) were identified in the CTNNB1 gene for the first time. These findings not only enrich the genetic spectrum of the CTNNB1 gene but also provide evidence for its role in neuronal development.

Plant-Microbes Interaction: Exploring the Impact of Cold-Tolerant Bacillus Strains RJGP41 and GBAC46 Volatiles on Tomato Growth Promotion through Different Mechanisms.

The interaction between plant and bacterial VOCs has been extensively studied, but the role of VOCs in growth promotion still needs to be explored. In the current study, we aim to explore the growth promotion mechanisms of cold-tolerant Bacillus strains GBAC46 and RJGP41 and the well-known PGPR strain FZB42 and their VOCs on tomato plants. The result showed that the activity of phytohormone (IAA) production was greatly improved in GBAC46 and RJGP41 as compared to FZB42 strains. The in vitro and in-pot experiment results showed that the Bacillus VOCs improved plant growth traits in terms of physiological parameters as compared to the CK. The VOCs identified through gas chromatography-mass spectrometry (GC-MS) analysis, namely 2 pentanone, 3-ethyl (2P3E) from GBAC46, 1,3-cyclobutanediol,2,2,4,4-tetramethyl (CBDO) from RJGP41, and benzaldehyde (BDH) from FZB42, were used for plant growth promotion. The results of the partition plate (I-plate) and in-pot experiments showed that all the selected VOCs (2P3E, CBDO, and BDH) promoted plant growth parameters as compared to CK. Furthermore, the root morphological factors also revealed that the selected VOCs improved the root physiological traits in tomato plants. The plant defense enzymes (POD, APX, SOD, and CAT) and total protein contents were studied, and the results showed that the antioxidant enzymes and protein contents significantly increased as compared to CK. Similarly, plant growth promotion expression genes (IAA4, ARF10A, GA2OX2, CKX2, and EXP1) were significantly upregulated and the ERF gene was downregulated as compared to CK. The overall findings suggest that both Bacillus isolates and their pure VOCs positively improved plant growth promotion activities by triggering the antioxidant enzyme activity, protein contents, and relative gene expressions in tomato plants.