Integrated rice-yellow catfish farming resulting in variations in the agricultural environment, rice growth performance, and soil bacterial communities.

Different rice production patterns exert varying comprehensive impacts on the agricultural environment. Integrated rice-fish farming, an advanced and rapidly developing agricultural production pattern, aims to improve resource utilization efficiency and enhance food productivity. To unravel the responses and internal interactions of the agricultural ecological environment to integrated rice-fish farming, we assessed and compared environmental factor, rice growth performance, and soil microbiome in both integrated rice-yellow catfish farming (IRYF) and rice monoculture (RM) systems. Our results revealed significant increases in the total nitrogen and ammonia concentrations in the paddy water and soil induced by the IRYF. Rice growth performance in the IRYF group surpassed that in the RM group. IRYF obviously impacted almost all dominant bacterial phyla, genera, and functional groups (top ten most abundant), enhancing the ability of bacteria to degrade and utilize organic matter. Additionally, IRYF led to noticeable reductions in the Shannon, Simpson, Chao 1, and Pielou_J indices. IRYF strengthened the interconnections between various taxonomic units in bacterial co-occurrence network, resulting in increased complexity, stability, and disturbance resistance in the soil bacterial community. IRYF notably facilitated the transition from a community assembly dominated by stochastic processes to one dominated by deterministic processes for the soil bacterial community. The deterministic process driving this transition was variable selection. All the environmental factors, except for soil nitrate, demonstrated relatively high contributions to alterations in soil bacterial communities, with environmental variables significantly positively correlated with the soil bacterial community in the IRYF group. Alterations in functionality, composition, and diversity of the soil bacterial community were clearly associated with most environmental variables and rice growth performance indices. Our research contributed to understanding the comprehensive impacts of integrated rice-fish farming on agricultural ecosystems and provide theoretical support for achieving the sustainable agricultural production and optimizing the rice production patterns.

Influences of the Integrated Rice-Crayfish Farming System with Different Stocking Densities on the Paddy Soil Microbiomes.

Integrated rice-fish farming has emerged as a novel agricultural production pattern to address global food security challenges. Aiming to determine the optimal, scientifically sound, and sustainable stocking density of red claw crayfish (Cherax quadricarinatus) in an integrated rice-crayfish farming system, we employed Illumina high-throughput 16S rRNA gene sequencing to evaluate the impact of different stocking densities of red claw crayfish on the composition, diversity, function, and co-occurrence network patterns of soil bacterial communities. The high stocking density of red claw crayfish reduced the diversity and evenness of the soil bacterial community during the mid-culture stage. Proteobacteria, Actinobacteria, and Chloroflexi emerged as the most prevalent phyla throughout the experimental period. Low stocking densities initially boosted the relative abundance of Actinobacteria in the paddy soil, while high densities did so during the middle and final stages. There were 90 distinct functional groups identified across all the paddy soil samples, with chemoheterotrophy and aerobic chemoheterotrophy being the most abundant. Low stocking densities initially favored these functional groups, whereas high densities enhanced their relative abundances in the later stages of cultivation. Medium stocking density of red claw crayfish led to a more complex bacterial community during the mid- and final culture stages. The experimental period showed significant correlations with soil bacterial communities, with total nitrogen (TN) and total phosphorus (TP) concentrations emerging as primary factors contributing to the alterations in soil bacterial communities. In summary, our findings demonstrated that integrated rice-crayfish farming significantly impacted the soil microbiomes and environmental factors at varying stocking densities. Our study contributed to theoretical insights into the profound impact of integrated rice-crayfish farming with various stocking densities on bacterial communities in paddy soils.

A safety and efficacy study of allogeneic haematopoietic stem cell transplantation for refractory and relapsed T-cell acute lymphoblastic leukaemia/lymphoblastic lymphoma patients who achieved complete remission after autologous CD7 chimeric antigen receptor T-cell therapy.

CD7-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown promising initial complete remission (CR) rates in patients with refractory or relapsed (r/r) T-cell acute lymphoblastic leukaemia and lymphoblastic lymphoma (T-ALL/LBL). To enhance the remission duration, consolidation with allogeneic haematopoietic stem cell transplantation (allo-HSCT) is considered. Our study delved into the outcomes of 34 patients with r/r T-ALL/LBL who underwent allo-HSCT after achieving CR with autologous CD7 CAR-T therapy. These were compared with 124 consecutive T-ALL/LBL patients who received allo-HSCT in CR following chemotherapy. The study revealed that both the CAR-T and chemotherapy cohorts exhibited comparable 2-year overall survival (OS) (61.9% [95% CI, 44.1-78.1] vs. 67.6% [95% CI, 57.5-76.9], p = 0.210), leukaemia-free survival (LFS) (62.3% [95% CI, 44.6-78.4] vs. 62.0% [95% CI, 51.8-71.7], p = 0.548), non-relapse mortality (NRM) rates (32.0% [95% CI, 19.0-54.0] vs. 25.3% [95% CI, 17.9-35.8], p = 0.288) and relapse incidence rates (8.8% [95% CI, 3.0-26.0] vs. 15.8% [95% CI, 9.8-25.2], p = 0.557). Patients aged ≤14 in the CD7 CAR-T group achieved high 2-year OS and LFS rates of 87.5%. Our study indicates that CD7 CAR-T therapy followed by allo-HSCT is not only effective and safe for r/r T-ALL/LBL patients but also on par with the outcomes of those achieving CR through chemotherapy, without increasing NRM.

Preoperative glucose-to-lymphocyte ratio predicts survival in cancer.

Background: Systemic inflammation and glucose metabolism have been closely related to the survival of cancer patients. Therefore, we aimed to evaluate whether preoperative glucose-to-lymphocyte ratio (GLR) can be used to predict the survival of cancer patients. Methods: We retrospectively examined 2172 cancer patients who underwent surgery from January 1, 2014, to December 31, 2016. There were 240 patients with non-small cell lung cancer (NSCLC), 378 patients with colorectal cancer (CRC), 221 patients with breast cancer (BC), 335 patients with gastric cancer (GC), 270 patients with liver cancer, 233 patients with esophageal cancer (EC), 295 patients with renal cancer, and 200 patients with melanoma. The formula for preoperative GLR calculation was as follows: GLR=glucose/lymphocyte count. The overall survival (OS) was estimated using the Kaplan-Meier method. The predictive factors for OS were determined using multivariate analysis. Results: The Kaplan-Meier analysis showed that the median survival time in the high-GLR group was much shorter than that of those in the low-GLR group for different cancers. Cox multivariate regression analysis reveals that preoperative GLR was an independent factor for predicting overall survival in different tumor types. Conclusion: Elevated preoperative GLR was remarkably associated with a poorer prognosis in patients with NSCLC, CRC, breast cancer, gastric cancer, kidney cancer, liver cancer, esophageal cancer, and melanoma. Preoperative GLR promises to be an essential predictor of survival for cancer patients.

Crosstalk between ubiquitin ligases and ncRNAs drives cardiovascular disease progression.

Cardiovascular diseases (CVDs) are multifactorial chronic diseases and have the highest rates of morbidity and mortality worldwide. The ubiquitin-proteasome system (UPS) plays a crucial role in posttranslational modification and quality control of proteins, maintaining intracellular homeostasis via degradation of misfolded, short-lived, or nonfunctional regulatory proteins. Noncoding RNAs (ncRNAs, such as microRNAs, long noncoding RNAs, circular RNAs and small interfering RNAs) serve as epigenetic factors and directly or indirectly participate in various physiological and pathological processes. NcRNAs that regulate ubiquitination or are regulated by the UPS are involved in the execution of target protein stability. The cross-linked relationship between the UPS, ncRNAs and CVDs has drawn researchers' attention. Herein, we provide an update on recent developments and perspectives on how the crosstalk of the UPS and ncRNAs affects the pathological mechanisms of CVDs, particularly myocardial ischemia/reperfusion injury, myocardial infarction, cardiomyopathy, heart failure, atherosclerosis, hypertension, and ischemic stroke. In addition, we further envision that RNA interference or ncRNA mimics or inhibitors targeting the UPS can potentially be used as therapeutic tools and strategies.

UBD participates in neutrophilic asthma by promoting the activation of IL-17 signaling.

Neutrophilic asthma is a persistent and severe inflammatory lung disease characterized by neutrophil activation and the mechanisms of which are not completely elucidated. Ubiquitin D (UBD) is a ubiquitin-like modifier participating in infections, immune responses, and tumorigenesis, while whether UBD involves in neutrophilic asthma needs further study. In this study, we initially found that UBD expression was significantly elevated and interleukin 17 (IL-17) signaling was enriched in the endobronchial biopsies of severe asthma along with neutrophils increasing by bioinformatics analysis. We further confirmed that UBD was upregulated in the lung tissues of neutrophilic asthma mouse model. UBD overexpression promoted IL-17 signaling activation. Knockdown of UBD suppressed the activation of IL-17 signaling. UBD interacted with TRAF2 and reduced the total and the K48-linked ubiquitination of TRAF2. However, IL-17 A stimulation increased both the total and the K48-linked ubiquitination of TRAF2. Together, these findings indicated that UBD was upregulated and played a critical role in IL-17 signaling which contributed to a better understanding of the complex mechanisms in neutrophilic asthma.

Variations in antibiotic resistomes associated with archaeal, bacterial, and viral communities affected by integrated rice-fish farming in the paddy field ecosystem.

Antibiotic resistance genes (ARGs) serving as a newly recognized pollutant that poses potential risks to global human health, which in the paddy soil can be potentially altered by different agricultural production patterns. To elucidate the impacts and mechanisms of the widely used and sustainable agricultural production pattern, namely integrated rice-fish farming, on the antibiotic resistomes, we applied metagenomic sequencing to assess ARGs, mobile genetic elements (MGEs), bacteria, archaea, and viruses in paddy soil. There were 20 types and 359 subtypes of ARGs identified in paddy soil. The integrated rice-fish farming reduced the ARG and MGE diversities and the abundances of dominant ARGs and MGEs. Significantly decreased ARGs were mainly antibiotic deactivation and regulator types and primarily ranked level IV based on their potential threat to human health. The integrated rice-fish farming decreased the alpha diversities and altered microbial community compositions. MGEs, bacteria, archaea, and virus exhibited significant correlations with ARGs, while integrated rice-fish farming effectively changed their interrelationships. Viruses, bacteria, and MGEs played crucial roles in affecting the ARGs by the integrated rice-fish farming. The most crucial pathway by which integrated rice-fish farming affected ARGs was through the modulation of viral communities, thereby directly or indirectly influencing ARG abundance. Our research contributed to the control and restoration of ARGs pollution from a new perspective and providing theoretical support for the development of clean and sustainable agricultural production.

Astragaloside IV inhibits idiopathic pulmonary fibrosis through activation of autophagy by miR-21-mediated PTEN/PI3K/AKT/mTOR pathway.

As the main active ingredient of Astragalus, Astragaloside IV (AS-IV) can ameliorate pulmonary fibrosis. In this experiment, we studied how AS-IV reduces idiopathic pulmonary fibrosis (IPF). Bleomycin (BLM) or TGF-ß1 was treated in mice or alveolar epithelial cells to mimic IPF in vivo as well as in vitro. ASV-IV alleviated levels of inflammatory cytokines and fibrosis markers in IPF model. Through detection of autophagy-related genes, ASV-IV was observed to induce autophagy in IPF. Besides, ASV-IV inhibited miR-21 expression in IPF models, and overexpression of miR-21 could reverse the protective potential of ASV-IV on IPF. PTEN was targeted by miR-21 and was up-regulated by ASV-IV in IPF models. In addition, levels of inflammatory cytokines and fibrosis markers, autophagy, as well as the PI3K/AKT/mTOR pathway regulated by ASV-IV could be neutralized after treatment with autophagy inhibitors, miR-21 mimics, or si-PTEN. Our study demonstrates that ASV-IV inhibits IPF through activation of autophagy by miR-21-mediated PTEN/PI3K/AKT/mTOR pathway, suggesting that ASV-IV could be acted to be a promising therapeutic method for IPF.

Comparison of Intestinal Bacteria of Procambarus clarkii Farmed in Various Rice Paddy Regions.

The aim of this study was to assess the regional differences of Procambarus clarkii through analyzing gut microbiota in specimens from different areas in China. The P. clarkii were collected from ten integrated rice-crayfish farming systems locating across ten major producing areas as follows: Feixi (FX), Suqian (SQ), Yangzhou (YZ), Xuyi (XY), Qianjiang (QJ), Jianli (JL), Honghu (HH), Yueyang (YY), Changsha (CS), and Nanxian (NX). The composition of gut microbiota was assessed by analyzing 16S rRNA sequences. The PCoA results indicated significant differences in microbial community composition among the ten areas (R = 0.999, p = 0.001). The intestinal microbial diversity in P. clarkii cultured in rice fields from YY and CS exceeded that of other regions, with NX displaying the least diversity. At the phylum level, Proteobacteria were most abundant in HH, while Firmicutes showed increased relative abundances in FX and SQ, contrasted by lower relative abundances of Bacteroidetes in these areas. At the genus level, Ralstonia, Amedibacillus, Bacteroides, Anaerorhabdus, and Dysgonomonas were the dominant bacteria. The bacterial co-occurrence networks analysis revealed that the community structures in locations FX, SQ, XY, HH, and NX were comparatively simplistic, whereas those in the YZ, QJ, JL, YY, and CS regions displayed as more complex. In summary, the diversity and relative abundance of intestinal bacteria exhibits regional variability. These findings can offer theoretical data for evaluating the quality of P. clarkii aquaculture.

Unraveling the origins of the coexisting localized-interfacial mechanism in oxide-based memristors in CMOS-integrated synaptic device implementations.

The forefront of neuromorphic research strives to develop devices with specific properties, i.e., linear and symmetrical conductance changes under external stimuli. This is paramount for neural network accuracy when emulating a biological synapse. A parallel exploration of resistive memory as a replacement for conventional computing memory ensues. In search of a holistic solution, the proposed memristive device in this work is uniquely poised to address this elusive gap as a unified memory solution. Opposite biasing operations are leveraged to achieve stable abrupt and gradual switching characteristics within a single device, addressing the demands for lower latency and energy consumption for binary switching applications, and graduality for neuromorphic computing applications. We evaluated the underlying principles of both switching modes, attributing the anomalous gradual switching to the modulation of oxygen-deficient layers formed between the active electrode and oxide switching layer. The memristive cell (1R) was integrated with 40 nm transistor technology (1T) to form a 1T-1R memory cell, demonstrating a switching speed of 50 ns with a pulse amplitude of ±2.5 V in its forward-biased mode. Applying pulse trains of 20 ns to 490 ns in the reverse-biased mode exhibited synaptic weight properties, obtaining a nonlinearity (NL) factor of <0.5 for both potentiation and depression. The devices in both modes also demonstrated an endurance of >106 cycles, and their conductance states were also stable under temperature stress at 85 °C for 104 s. With the duality of the two switching modes, our device can be used for both memory and synaptic weight-storing applications.

Interfragmentary compression force and fixation stability of lateral tibial plateau fractures in normal and osteoporotic bones.

Lateral platform collapse in fixations of lateral tibial plateau fractures (TPFs) using either double-lag screws fixation (DSF) or locking-plate fixation (LPF) is not rare. This study aimed to explore the effect of enhancing the interfragmentary compression force (IFCF) on fixation stability in lateral TPFs in normal and osteoporotic bones using finite element analysis. Finite element models of DSF in normal bone and LPF in normal and osteoporotic bones were established to simulate the fixations of lateral TPF. After model validation, axial compressive forces of 500, 1000, 1500, and 2500 N to the tibial plateau along with an IFCF of 0, 100, 200, and 300 N were applied. The maximum axial micromotion of the lateral fragment (MAM-LF), maximal translational micromotion of the lateral fragment (MTM-LF), peak von Mises stress (VMS), and peak equivalent elastic strain of the lateral fragment (EES-LF) were evaluated. The MAM-LF showed a decreasing trend as the IFCF increased in all models. For DSF models, the peak VMS of implants increased as the IFCF increased when the axial loads were 500 and 1000 N. The peak EES-LF decreased as the IFCF increased under axial loads of 1000, 1500, and 2500 N. For the normal and osteoporotic LPF models, the peak VMS of the implants decreased as the IFCF increased. Peak EES-LF decreased as IFCF increased. In conclusion, enhancing IFCF was beneficial in improving the fixation stability of lateral TPF. The optimal IFCF for DSF and LPF should be as high as reasonably feasible.

Correction: Luo et al. The Effects of Different Anode Positions on the Electrical Properties of Square-Silicon Drift Detector. Micromachines 2022, 13, 1496.

In the original publication [...].

Application of a combined cancellous lag screw enhances the stability of locking plate fixation of osteoporotic lateral tibial plateau fracture by providing interfragmentary compression force.

BACKGROUND: Insufficient interfragmentary compression force (IFCF) frequently leads to unstable fixation of osteoporotic lateral tibial plateau fractures (OLTPFs). A combined cancellous lag screw (CCLS) enhances IFCF; however, its effect on OLTPF fixation stability remains unclear. Therefore, we investigated the effect of CCLS on OLTPF stability using locking plate fixation (LPF). MATERIALS AND METHODS: Twelve synthetic osteoporotic tibial bones were used to simulate OLTPFs, which were fixed using LPF, LPF-AO cancellous lag screws (LPF-AOCLS), and LPF-CCLS. Subsequently, 10,000 cyclic loadings from 30 to 400 N were performed. The initial axial stiffness (IAS), maximal axial micromotion of the lateral fragment (MAM-LF) measured every 1000 cycles, and failure load after 10,000 cycles were tested. The same three fixations for OLTPF were simulated using finite element analysis (FEA). IFCFs of 0, 225, and 300 N were applied to the LPF, LPF-AOCLS, and LPF-CCLS, respectively, with a 1000-N axial compressive force. The MAM-LF, peak von Mises stress (VMS), peak equivalent elastic strain of the lateral fragment (EES-LF), and nodes of EES-LF > 2% (considered bone destruction) were calculated. RESULTS: Biomechanical tests revealed the LPF-AOCLS and LPF-CCLS groups to be superior to the LPF group in terms of the IAS, MAM-LF, and failure load (all p < 0.05). FEA revealed that the MAM-LF, peak VMS, peak EES-LF, and nodes with EES-LF > 2% in the LPF were higher than those in the LPF-AOCLS and LPF-CCLS. CONCLUSION: IFCF was shown to enhance the stability of OLTPFs using LPF. Considering overscrewing, CCLS is preferably recommended, although there were no significant differences between CCLS and AOCLS.

Effects of antimicrobial peptides from dietary Hermetia illucens larvae on the growth, immunity, gene expression, intestinal microbiota and resistance to Aeromonas hydrophila of juvenile red claw crayfish (Cherax quadricarinatus).

Antimicrobial peptides (AMPs), which are widely present in animals and plants, have a broad distribution, strong broad-spectrum antibacterial activity, low likelihood of developing drug resistance, high thermal stability and antiviral properties. The present study investigated the effects of adding AMPs from Hermetia illucens larvae on the growth performance, muscle composition, antioxidant capacity, immune response, gene expression, antibacterial ability and intestinal microbiota of Cherax quadricarinatus (red claw crayfish). Five experimental diets were prepared by adding 50 (M1), 100 (M2), 150 (M3) and 200 (M4) mg/kg of crude AMP extract from H. illucens larvae to the basal diet feed, which was also used as the control (M0). After an eight-week feeding experiment, it was discovered that the addition of 100-150 mg/kg of H. illucens larvae AMPs to the feed significantly improved the weight gain rate and specific growth rate of C. quadricarinatus. Furthermore, the addition of H. illucens larvae AMPs to the feed had no significant effect on the moisture content, crude protein, crude fat and ash content of the C. quadricarinatus muscle. The addition of 100-150 mg/kg of H. illucens larvae AMPs in the feed also increased the antioxidant capacity, nonspecific immune enzyme activity and related gene expression levels in C. quadricarinatus, thereby enhancing their antioxidant capacity and immune function. The H. illucens larvae AMPs improved the structure and composition of the intestinal microbiota of C. quadricarinatus, increasing the microbial community diversity of the crayfish gut. Finally, the addition of 100-150 mg/kg of H. illucens larvae AMPs in the feed enhanced the resistance of C. quadricarinatus against Aeromonas hydrophila, improving the survival rate of the crayfish. Based on the aforementioned findings, it is recommended that H. illucens larvae AMPs be incorporated into the C. quadricarinatus feed at a concentration of 100-150 mg/kg.

Robust links in photoactive covalent organic frameworks enable effective photocatalytic reactions under harsh conditions.

Developing heterogeneous photocatalysts for the applications in harsh conditions is of high importance but challenging. Herein, by converting the imine linkages into quinoline groups of triphenylamine incorporated covalent organic frameworks (COFs), two photosensitive COFs, namely TFPA-TAPT-COF-Q and TFPA-TPB-COF-Q, are successfully constructed. The obtained quinoline-linked COFs display improved stability and photocatalytic activity, making them suitable photocatalysts for photocatalytic reactions under harsh conditions, as verified by the recyclable photocatalytic reactions of organic acid involving oxidative decarboxylation and organic base involving benzylamine coupling. Under strong oxidative condition, the quinoline-linked COFs show a high efficiency up to 11831.6 µmol·g-1·h-1 and a long-term recyclable usability for photocatalytic production of H2O2, while the pristine imine-linked COFs are less catalytically active and easily decomposed in these harsh conditions. The results demonstrate that enhancing the linkage robustness of photoactive COFs is a promising strategy to construct heterogeneous catalysts for photocatalytic reactions under harsh conditions.

TBC1D23 mediates Golgi-specific LKB1 signaling.

Liver kinase B1 (LKB1), an evolutionarily conserved serine/threonine kinase, is a master regulator of the AMPK subfamily and controls cellular events such as polarity, proliferation, and energy homeostasis. Functions and mechanisms of the LKB1-AMPK axis at specific subcellular compartments, such as lysosome and mitochondria, have been established. AMPK is known to be activated at the Golgi; however, functions and regulatory mechanisms of the LKB1-AMPK axis at the Golgi apparatus remain elusive. Here, we show that TBC1D23, a Golgi-localized protein that is frequently mutated in the neurodevelopment disorder pontocerebellar hypoplasia (PCH), is specifically required for the LKB1 signaling at the Golgi. TBC1D23 directly interacts with LKB1 and recruits LKB1 to Golgi, promoting Golgi-specific activation of AMPK upon energy stress. Notably, Golgi-targeted expression of LKB1 rescues TBC1D23 deficiency in zebrafish models. Furthermore, the loss of LKB1 causes neurodevelopmental abnormalities in zebrafish, which partially recapitulates defects in TBC1D23-deficient zebrafish, and LKB1 sustains normal neuronal development via TBC1D23 interaction. Our study uncovers a regulatory mechanism of the LKB1 signaling, and reveals that a disrupted Golgi-LKB1 signaling underlies the pathogenesis of PCH.

Detection of kinematic abnormalities in persons with knee osteoarthritis using markerless motion capture during functional movement screen and daily activities.

Background: The functional movement screen (FMS) has been used to identify deficiencies in neuromuscular capabilities and balance among athletes. However, its effectiveness in detecting movement anomalies within the population afflicted by knee osteoarthritis (KOA), particularly through the application of a family-oriented objective assessment technique, remains unexplored. The objective of this study is to investigate the sensitivity of the FMS and daily activities in identifying kinematic abnormalities in KOA people employing a markerless motion capture system. Methods: A total of 45 persons, presenting various Kellgren-Lawrence grades of KOA, along with 15 healthy controls, completed five tasks of the FMS (deep squat, hurdle step, and in-line lunge) and daily activities (walking and sit-to-stand), which were recorded using the markerless motion capture system. The kinematic waveforms and discrete parameters were subjected to comparative analysis. Results: Notably, the FMS exhibited greater sensitivity compared to daily activities, with knee flexion, trunk sagittal, and trunk frontal angles during in-line lunge emerging as the most responsive indicators. Conclusion: The knee flexion, trunk sagittal, and trunk frontal angles during in-line lunge assessed via the markerless motion capture technique hold promise as potential indicators for the objective assessment of KOA.

The function of the gut microbiota-bile acid-TGR5 axis in diarrhea-predominant irritable bowel syndrome.

Imbalanced gut microbiota (GM) and abnormal fecal bile acid (BA) are thought to be the key factors for diarrhea-predominant irritable bowel syndrome (IBS-D), but the underlying mechanism remains unclear. Herein, we explore the influence of the GM-BA-Takeda G-protein-coupled receptor 5 (TGR5) axis on IBS-D. Twenty-five IBS-D patients and fifteen healthy controls were recruited to perform BA-related metabolic and metagenomic analyses. Further, the microbiota-humanized IBS-D rat model was established by fecal microbial transplantation (FMT) to investigate the GM-BA-TGR5 axis effects on the colonic barrier and visceral hypersensitivity (VH) in IBS-D. Finally, we used chenodeoxycholic acid (CDCA), an important BA screened out by metabolome, to evaluate whether it affected diarrhea and VH via the TGR5 pathway. Clinical research showed that GM associated with bile salt hydrolase (BSH) activity such as Bacteroides ovatus was markedly reduced in the GM of IBS-D, accompanied by elevated total and primary BA levels. Moreover, we found that CDCA not only was increased as the most important primary BA in IBS-D patients but also could induce VH through upregulating TGR5 in the colon and ileum of normal rats. TGR5 inhibitor could reverse the phenotype, depression-like behaviors, pathological change, and level of fecal BSH in a microbiota-humanized IBS-D rat model. Our findings proved that human-associated FMT could successfully induce the IBS-D rat model, and the imbalanced GM-BA-TGR5 axis may promote colonic mucosal barrier dysfunction and enhance VH in IBS-D. IMPORTANCE: Visceral hypersensitivity and intestinal mucosal barrier damage are important factors that cause abnormal brain-gut interaction in diarrhea-predominant irritable bowel syndrome (IBS-D). Recently, it was found that the imbalance of the gut microbiota-bile acid axis is closely related to them. Therefore, understanding the structure and function of the gut microbiota and bile acids and the underlying mechanisms by which they shape visceral hypersensitivity and mucosal barrier damage in IBS-D is critical. An examination of intestinal feces from IBS-D patients revealed that alterations in gut microbiota and bile acid metabolism underlie IBS-D and symptom onset. We also expanded beyond existing knowledge of well-studied gut microbiota and bile acid and found that Bacteroides ovatus and chenodeoxycholic acid may be potential bacteria and bile acid involved in the pathogenesis of IBS-D. Moreover, our data integration reveals the influence of the microbiota-bile acid-TGR5 axis on barrier function and visceral hypersensitivity.

Prusogliptin (DBPR108) monotherapy in treatment-naïve patients with type 2 diabetes: A randomized, double-blind, active and placebo-controlled, phase 3 study.

AIM: This study aimed to assess the efficacy and safety of prusogliptin (DBPR108), a novel and highly selective dipeptidyl peptidase-4 inhibitor, in individuals with type 2 diabetes who had not been using glucose-lowering agents regularly for the 8 weeks before the screening period. MATERIALS AND METHODS: In this multicentre, randomized, double-blind, phase 3 study, adult patients with type 2 diabetes were randomly assigned to receive either DBPR108 100 mg, sitagliptin 100 mg, or placebo once daily during the initial 24-week double-blind treatment period, followed by a 28-week open-label extension period during which all patients received DBPR108 100 mg once daily. The primary endpoint was the mean change in glycated haemoglobin (HbA1c) levels from baseline to week 24. RESULTS: In total, 766 patients were enrolled and received DBPR108 100 mg (n = 462), sitagliptin 100 mg (n = 152), or placebo (n = 152). The mean age of all patients was 54.3 ± 10.5 years, with 58% being men. The median duration of type 2 diabetes was 0.38 (0.02, 2.65) years, and the mean HbA1c (SD) at baseline was 7.94% (0.62), 7.88% (0.61) and 7.83% (0.59) for DBPR108, sitagliptin and placebo groups, respectively. At week 24, the least square mean (SE) changes from baseline in HbA1c were -0.63% (0.04%) for DBPR108, -0.60% (0.07%) for sitagliptin and -0.02% (0.07%) for placebo. The mean treatment difference between DBPR108 and placebo was -0.61% (95% CI -0.77% to -0.44%), and between DBPR108 and sitagliptin was -0.03% (95% CI -0.19% to 0.13%). These results indicate that DBPR108 was superior to placebo and non-inferior to sitagliptin. DBPR108 also significantly reduced fasting and postprandial plasma glucose levels and had little effect on body weight. The mean (SD) changes in HbA1c from baseline to week 52 were -0.50% (0.97%) for the DBPR108 group, -0.46% (0.96%) for the sitagliptin group and -0.41% (0.95%) for the placebo group. The incidence of adverse events was comparable across all three groups. CONCLUSIONS: DBPR108 showed superiority to placebo and non-inferiority to sitagliptin in terms of glycaemic control over the initial 24 weeks in treatment-naïve patients with type 2 diabetes. Furthermore, its efficacy was sustained for up to 52 weeks.