DAmiRLocGNet: miRNA subcellular localization prediction by combining miRNA-disease associations and graph convolutional networks.

MicroRNAs (miRNAs) are human post-transcriptional regulators in humans, which are involved in regulating various physiological processes by regulating the gene expression. The subcellular localization of miRNAs plays a crucial role in the discovery of their biological functions. Although several computational methods based on miRNA functional similarity networks have been presented to identify the subcellular localization of miRNAs, it remains difficult for these approaches to effectively extract well-referenced miRNA functional representations due to insufficient miRNA-disease association representation and disease semantic representation. Currently, there has been a significant amount of research on miRNA-disease associations, making it possible to address the issue of insufficient miRNA functional representation. In this work, a novel model is established, named DAmiRLocGNet, based on graph convolutional network (GCN) and autoencoder (AE) for identifying the subcellular localizations of miRNA. The DAmiRLocGNet constructs the features based on miRNA sequence information, miRNA-disease association information and disease semantic information. GCN is utilized to gather the information of neighboring nodes and capture the implicit information of network structures from miRNA-disease association information and disease semantic information. AE is employed to capture sequence semantics from sequence similarity networks. The evaluation demonstrates that the performance of DAmiRLocGNet is superior to other competing computational approaches, benefiting from implicit features captured by using GCNs. The DAmiRLocGNet has the potential to be applied to the identification of subcellular localization of other non-coding RNAs. Moreover, it can facilitate further investigation into the functional mechanisms underlying miRNA localization. The source code and datasets are accessed at http://bliulab.net/DAmiRLocGNet.

PDZK1 confers sensitivity to sunitinib in clear cell renal cell carcinoma by suppressing the PDGFR-ß pathway.

BACKGROUND: Sunitinib has emerged as the primary treatment for advanced or metastatic clear cell renal cell carcinoma (ccRCC) due to its significant improvement in patients' average survival time. However, drug resistance and adverse effects of sunitinib pose challenges to its clinical benefits. METHODS: The differentially expressed genes (DEGs) associated with sunitinib sensitivity and resistance in ccRCC were investigated. Cell counting kit-8, plate colony formation, flow cytometry and subcutaneous xenograft tumor model assays were employed to explore the effects of PDZK1 on ccRCC. Further research on the molecular mechanism was conducted through western blot, co-immunoprecipitation, immunofluorescence co-localization and immunohistochemical staining. RESULTS: We elucidated that PDZK1 is significantly downregulated in sunitinib-resistant ccRCC specimens, and PDZK1 negatively regulates the phosphorylation of PDGFR-ß and the activation of its downstream pathways through interaction with PDGFR-ß. The dysregulated low levels of PDZK1 contribute to inadequate inhibition of cell proliferation, tumor growth, and insensitivity to sunitinib treatment. Notably, our preclinical investigations showed that miR-15b antagomirs enhance sunitinib cytotoxic effects against ccRCC cells by upregulating PDZK1 levels, suggesting their potential in overcoming sunitinib resistance. CONCLUSIONS: Our findings establish the miR-15b/PDZK1/PDGFR-ß axis as a promising therapeutic target and a novel predictor for ccRCC patients' response to sunitinib treatment.

TACE combined Lenvatinib plus Camrelizumab versus TACE alone in efficacy and safety for unresectable hepatocellular carcinoma: a propensity score-matching study.

BACKGROUNDS: To compare the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined Lenvatinib plus Camrelizumab (TLC) in unresectable hepatocellular carcinoma (uHCC) with those of TACE alone . METHODS: A retrospective analysis was performed on 222 patients with uHCC who were treated between September 2013 and Jun 2023. One group received TACE + lenvatinib + camrelizumab (TLC) (n = 97) and another group received TACE alone (n = 151). Efficacy and safety were compared after propensity score matching between the TLC and TACE groups. RESULTS: After propensity matching, the TLC group had higher objective response rate (ORR) (88.6% vs. 28.6%, P < 0.001), disease control rate (DCR) (94.3%% vs. 72.9%, P < 0.001), and conversion rates before and after propensity matching were 44.1% and 41.4%, respectively, compared with the TACE group. The median progression free survival (PFS) was longer in the TLC group than in the TACE group (12.7 vs. 6.1 months, P = 0.005). The median overall survival (OS) was longer in the TLC group than in the TACE group (19.4 vs. 13.0 months, P = 0.023). Cox multivariate analysis with different modes of adjustment showed that treatment was an independent influencing factor of PFS and OS. The interaction analysis showed that cirrhosis and Child-Pugh stage an interactive role in the PFS of different treatment. Decreased AFP after treatment portends higher ORR and DCR. CONCLUSION: TACE combined Lenvatinib plus Camrelizumab regimen was safe and superior to TACE alone in improving PFS, OS, and tumor response rates for unresectable recurrent HCC patients.

A novel surgical scheme for hepatectomy in hepatocellular carcinoma patients with clinically significant portal hypertension.

OBJECTIVE: Clinically significant portal hypertension (CSPH) seriously affects the feasibility and safety of surgical treatment for hepatocellular carcinoma (HCC) patients. The aim of this study was to establish a new surgical scheme defining risk classification of post-hepatectomy liver failure (PHLF) to facilitate the surgical decision-making and identify suitable candidates for individual hepatectomy among HCC patients with CSPH. BACKGROUNDS: Hepatectomy is the preferred treatment for HCC. Surgeons must maintain a balance between the expected oncological outcomes of HCC removal and short-term risks of severe PHLF and morbidity. CSPH aggravates liver decompensation and increases the risk of severe PHLF thus complicating hepatectomy for HCC. METHODS: Multivariate logistic regression and stochastic forest algorithm were performed, then the independent risk factors of severe PHLF were included in a nomogram to determine the risk of severe PHLF. Further, a conditional inference tree (CTREE) through recursive partitioning analysis validated supplement the misdiagnostic threshold of the nomogram. RESULTS: This study included 924 patients, of whom 137 patients (14.8%) suffered from mild-CSPH and 66 patients suffered from (7.1%) with severe-CSPH confirmed preoperatively. Our data showed that preoperative prolonged prothrombin time, total bilirubin, indocyanine green retention rate at 15 min, CSPH grade, and standard future liver remnant volume were independent predictors of severe PHLF. By incorporating these factors, the nomogram achieved good prediction performance in assessing severe PHLF risk, and its concordance statistic was 0.891, 0.850 and 0.872 in the training cohort, internal validation cohort and external validation cohort, respectively, and good calibration curves were obtained. Moreover, the calculations of total points of diagnostic errors with 95% CI were concentrated in 110.5 (range 76.9-178.5). It showed a low risk of severe PHLF (2.3%), indicating hepatectomy is feasible when the points fall below 76.9, while the risk of severe PHLF is extremely high (93.8%) and hepatectomy should be rigorously restricted at scores over 178.5. Patients with points within the misdiagnosis threshold were further examined using CTREE according to a hierarchic order of factors represented by the presence of CSPH grade, ICG-R15, and sFLR. CONCLUSION: This new surgical scheme established in our study is practical to stratify risk classification in assessing severe PHLF, thereby facilitating surgical decision-making and identifying suitable candidates for individual hepatectomy.

Preoperative clinical characteristics and risk assessment in Sun's modified classification of Stanford type A acute aortic dissection.

OBJECTIVES: This study aims to retrospectively analyze the clinical features of Stanford type A acute aortic dissection (TAAAD) based on Sun's modified classification, and to investigate whether the Sun's modified classification can be used to assess the risk of preoperative rupture. METHODS: Clinical data was collected between January 2018 and June 2019. Data included patient demographics, history of disease, type of dissection according to the Sun's modified classification, time of onset, biochemical tests, and preoperative rupture. RESULTS: A total of 387 patients with TAAAD who met the inclusion criteria of Sun's modified classification were included. There were more complex types, with 75, 151 and 140 patients in the type A1C, A2C and A3C groups, respectively. The age of the entire group of patients was 51.46 ± 12.65 years and 283 (73.1%) were male. The time from onset to the emergency room was 25.37 ± 30.78 h. There were a few cases of TAAAD combined with stroke, pericardial effusion, pleural effusion, and lower extremity and organ ischemia in the complex type group. The white blood cell count (WBC), neutrophil count (NEC) and blood amylase differed significantly between the groups. Three independent risk factors for preoperative rupture were identified: neutrophil count, blood potassium ion level, and platelet count. Binary logistic regression analysis showed that the Sun's modified classification could not be used to assess the risk of preoperative rupture in TAAAD. CONCLUSION: TAAAD was classified as the complex type in most patients. WBC, NEC and blood amylase were significantly different between the groups. NEC and serum potassium ion level were independent risk factors for preoperative rupture of TAAAD, while platelet count was its protective factor. More samples are needed to determine whether Sun's modified classification can be used to evaluate the risk of preoperative rupture.

TGFß signaling links early life endocrine-disrupting chemicals exposure to suppression of nucleotide excision repair in rat myometrial stem cells.

Environmental exposure to endocrine-disrupting chemicals (EDCs) is linked to the development of uterine fibroids (UFs) in women. UFs, non-cancerous tumors, are thought to originate from abnormal myometrial stem cells (MMSCs). Defective DNA repair capacity may contribute to the emergence of mutations that promote tumor growth. The multifunctional cytokine TGFß1 is associated with UF progression and DNA damage repair pathways. To investigate the impact of EDC exposure on TGFß1 and nucleotide excision repair (NER) pathways, we isolated MMSCs from 5-month-old Eker rats exposed neonatally to diethylstilbestrol (DES), an EDC, or to vehicle (VEH). EDC-MMSCs exhibited overactivated TGFß1 signaling and reduced mRNA and protein levels of NER pathway components compared to VEH-MMSCs. EDC-MMSCs also demonstrated impaired NER capacity. Exposing VEH-MMSCs to TGFß1 decreased NER capacity while inhibiting TGFß signaling in EDC-MMSCs restored it. RNA-seq analysis and further validation revealed decreased expression of Uvrag, a tumor suppressor gene involved in DNA damage recognition, in VEH-MMSCs treated with TGFß1, but increased expression in EDC-MMSCs after TGFß signaling inhibition. Overall, we demonstrated that the overactivation of the TGFß pathway links early life exposure to EDCs with impaired NER capacity, which would lead to increased genetic instability, arise of mutations, and fibroid tumorigenesis. We demonstrated that the overactivation of the TGFß pathway links early life exposure to EDCs with impaired NER capacity, which would lead to increased fibroid incidence.

Radiotherapy is superior to transarterial chemoembolization as adjuvant therapy after narrow-margin hepatectomy in patients with hepatocellular carcinoma: A single-center prospective randomized study.

BACKGROUND: This study was recruited to compare the efficacy and safety of radiotherapy (RT) and transarterial chemoembolization (TACE) as postoperative adjuvant therapy after narrow-margin hepatectomy in hepatocellular carcinoma (HCC) patients. METHODS: This single-center prospective randomized study was conducted in the Cancer Hospital, Guang Xi Medical University, Nanning. A total of 72 patients who received treatment in this hospital between August 2017 and July 2019 were included and randomly allocated to TACE group (n = 48) and RT group (n = 24). Next, overall survival (OS) and progression-free survival (PFS) rates, recurrence patterns, financial burden, and safety were evaluated. RESULTS: The difference between the RT and TACE groups was not significant in one-, three-, and five-year OS (87.5%, 79.0%, and 62.5% vs. 93.8%, 75.9%, and 63.4%, respectively, P = 0.071) and PFS rates (79.0%, 54.2%, and 22.6% vs. 75.0%, 47.9%, and 32.6%, respectively, P = 0.071). Compared to the TACE group, the RT group had significantly lower intrahepatic recurrence rate (20.8% vs. 52.1%, P = 0.011), higher extrahepatic recurrence rate (37.5% vs. 14.6%, P = 0.034), and no marginal and diffuse recurrences (0% vs. 16.7%, P < 0.05). The mean overall treatment cost was higher (¥62,550.59 ± 4397.27 vs. ¥40,732.56 ± 9210.54, P < 0.01), the hospital stay (15.1 ± 3.7 vs. 11.8 ± 4.1 days, P < 0.01) was longer, and the overall treatment stay (13.3 ± 5.3 vs. 41.29 ± 12.4 days, P < 0.01) was shorter in the TACE group than in the RT group. Besides, both groups did not exhibit significant differences in the frequency and severity of adverse events. CONCLUSION: Both adjuvant TACE and RT can better the OS and PFS of patients with HCC. However, RT has a significantly better performance than TACE in terms of improving intrahepatic recurrence rate, treatment cost and hospital stay.

Negative association of atmospheric pollutants with semen quality: A cross-sectional study in Taiyuan, China.

BACKGROUND: In recent decades, the quality of male semen has decreased worldwide. Air pollution has been linked to lower semen quality in several studies. However, the effects of atmospheric pollutants on different semen characteristics have not always been consistent. The aim of this study was to investigate the association between the Air Quality Index (AQI) and six atmospheric pollutants (PM2.5, PM10, SO2, NO2, CO, and O3), semen quality, and their key exposure window periods. METHODS: This study included 1711 semen samples collected at the reproductive clinics of the First Affiliated Hospital of Shanxi Medical University in Taiyuan, Shanxi, China, from October 10, 2021, to September 30, 2022. We evaluated the association of AQI and six atmospheric pollutants with semen quality parameters throughout sperm development and three key exposure windows in men using single-pollutant models, double-pollutant models, and subgroup analyses of semen quality-eligible groups. RESULTS: Both the single-pollutant model and subgroup analyses showed that PM, CO, and O3 levels were negatively correlated with total and progressive motility. At 70-90 d before semen collection, CO exposure and semen volume (ß =-1.341, 95 % CI: -1.805, -0.877, P <0.001), total motility (ß =-2.593, 95 % CI: -3.425, -1.761, P <0.001), and progressive motility (ß =-4.658, 95 % CI: -5.556, -3.760, P <0.001) were negatively correlated. At 0-9 days before semen collection, CO was negatively correlated with normal morphology (ß =-3.403, 95 % CI: -5.099, -1.708, P <0.001). Additionally, the AQI was adversely associated with total and progressive motility in subgroup analyses of the semen quality-eligible groups. CONCLUSIONS: During the entire sperm development process, multiple air pollutants were determined to have an adverse correlation with semen quality parameters. AQI was significant marker for the combined effects of various atmospheric pollutants on male reproductive health.

Value of hepatic artery digital subtraction angiography in the detection of small hepatocellular carcinoma lesions.

OBJECTIVE: To compare the detection rates of hepatic artery digital subtraction angiography (HA-DSA) and magnetic resonance imaging (MRI) gadolinium diethylenetriaminepentaacetic acid (MRI-Gd-DTPA) and MRI gadolinium diethylenetriaminepentaacetic acid (MRI-Gd-EOB-DTPA) for small (diameter ≤2 cm) hepatocellular carcinoma (HCC) lesions. METHODS: A prospective analysis of patients admitted to the Tumor Hospital of Guangxi Medical University between January 1, 2015, and December 30, 2016, was conducted. The detection rates of the three methods were analyzed. The diameter of small HCC lesions detected using HA-DSA and MRI-Gd-EOB-DTPA were evaluated. The diagnostic value of HCC Barcelona staging for HA-DSA was analyzed. RESULTS: For 107 small lesions detected in 57 patients, the detection rates of HA-DSA and MRI-Gd-DTPA were 86.0% (92/107) and 71.0% (76/107), respectively (p < .05). Of 77 small lesions detected in 42 patients using MRI-Gd-EOB-DTPA and HA-DSA, 67 were detected using HA-DSA, all of which had a rich blood supply, and 72 were detected using MRI-Gd-EOB-DTPA. The minimum diameter of lesions detected using MRI-Gd-EOB-DTPA was approximately 0.4 cm, whereas that of lesions detected using HA-DSA was approximately 0.5 cm. After HA-DSA, a change in the Barcelona staging occurred in 33.3% (62/186) of cases but not after MRI-Gd-DTPA; HA-DSA was significantly better than MRI-Gd-DTPA for staging (p = .03). CONCLUSION: HA-DSA and MRI-Gd-EOB-DTPA have high diagnostic values for the detection of small HCC lesions, which is helpful for accurate staging of HCC and provides the most valuable information for patient treatment and prognosis.

Bromodomain-Containing Protein 9 Regulates Signaling Pathways and Reprograms the Epigenome in Immortalized Human Uterine Fibroid Cells.

Bromodomain-containing proteins (BRDs) are involved in many biological processes, most notably epigenetic regulation of transcription, and BRD dysfunction has been linked to many diseases, including tumorigenesis. However, the role of BRDs in the pathogenesis of uterine fibroids (UFs) is entirely unknown. The present study aimed to determine the expression pattern of BRD9 in UFs and matched myometrium and further assess the impact of a BRD9 inhibitor on UF phenotype and epigenetic/epitranscriptomic changes. Our studies demonstrated that the levels of BRD9 were significantly upregulated in UFs compared to matched myometrium, suggesting that the aberrant BRD expression may contribute to the pathogenesis of UFs. We then evaluated the potential roles of BRD9 using its specific inhibitor, I-BRD9. Targeted inhibition of BRD9 suppressed UF tumorigenesis with increased apoptosis and cell cycle arrest, decreased cell proliferation, and extracellular matrix deposition in UF cells. The latter is the key hallmark of UFs. Unbiased transcriptomic profiling coupled with downstream bioinformatics analysis further and extensively demonstrated that targeted inhibition of BRD9 impacted the cell cycle- and ECM-related biological pathways and reprogrammed the UF cell epigenome and epitranscriptome in UFs. Taken together, our studies support the critical role of BRD9 in UF cells and the strong interconnection between BRD9 and other pathways controlling the UF progression. Targeted inhibition of BRDs might provide a non-hormonal treatment option for this most common benign tumor in women of reproductive age.

Optimizing Trilobatin Production via Screening and Modification of Glycosyltransferases.

Trilobatin (TBL) is a key sweet compound from the traditional Chinese sweet tea plant (Rubus suavissimus S. Lee). Because of its intense sweetness, superior taste profile, and minimal caloric value, it serves as an exemplary natural dihydrochalcone sweetener. It also has various health benefits, including anti-inflammatory and glucose-lowering effects. It is primarily produced through botanical extraction, which impedes its scalability and cost-effectiveness. In a novel biotechnological approach, phloretin is used as a precursor that is transformed into TBL by the glycosyltransferase enzyme ph-4'-OGT. However, this enzyme's low catalytic efficiency and by-product formation limit the large-scale synthesis of TBL. In our study, the enzyme Mdph-4'-OGT was used to screen 17 sequences across species for TBL synthesis, of which seven exhibited catalytic activity. Notably, PT577 exhibited an unparalleled 97.3% conversion yield within 3 h. We then optimized the reaction conditions of PT577, attaining a peak TBL bioproduction of 163.3 mg/L. By employing virtual screening, we identified 25 mutation sites for PT577, thereby creating mutant strains that reduced by-products by up to 50%. This research enhances the enzymatic precision for TBL biosynthesis and offers a robust foundation for its industrial-scale production, with broader implications for the engineering and in silico analysis of glycosyltransferases.

Rational Design and Modification of NphB for Cannabinoids Biosynthesis.

The rapidly growing field of cannabinoid research is gaining recognition for its impact in neuropsychopharmacology and mood regulation. However, prenyltransferase (NphB) (a key enzyme in cannabinoid precursor synthesis) still needs significant improvement in order to be usable in large-scale industrial applications due to low activity and limited product range. By rational design and high-throughput screening, NphB's catalytic efficiency and product diversity have been markedly enhanced, enabling direct production of a range of cannabinoids, without the need for traditional enzymatic conversions, thus broadening the production scope of cannabinoids, including cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerovarin (CBGV), and cannabigerovarinic acid (CBGVA). Notably, the W3 mutant achieved a 10.6-fold increase in CBG yield and exhibited a 10.3- and 20.8-fold enhancement in catalytic efficiency for CBGA and CBGV production, respectively. The W4 mutant also displayed an 9.3-fold increase in CBGVA activity. Molecular dynamics simulations revealed that strategic reconfiguration of the active site's hydrogen bonding network, disulfide bond formation, and enhanced hydrophobic interactions are pivotal for the improved synthetic efficiency of these NphB mutants. Our findings advance the understanding of enzyme optimization for cannabinoid synthesis and lay a foundation for the industrial-scale production of these valuable compounds.

The promotion action of AURKA on post-ischemic angiogenesis in diabetes-related limb ischemia.

BACKGROUND: Diabetes-related limb ischemia is a challenge for lower extremity amputation. Aurora Kinase A (AURKA) is an essential serine/threonine kinase for mitosis, while its role in limb ischemia remains unclear. METHOD: Human microvascular endothelial cells (HMEC-1) were cultured in high glucose (HG, 25 mmol/L D-glucose) and no additional growth factors (ND) medium to mimic diabetes and low growth factors deprivation as in vitro model. Diabetic C57BL/6 mice were induced by streptozotocin (STZ) administration. After seven days, ischemia was surgically performed by left unilateral femoral artery ligation on diabetic mice. The vector of adenovirus was utilized to overexpress AURKA in vitro and in vivo. RESULTS: In our study, HG and ND-mediated downregulation of AURKA impaired the cell cycle progression, proliferation, migration, and tube formation ability of HMEC-1, which were rescued by overexpressed AURKA. Increased expression of vascular endothelial growth factor A (VEGFA) induced by overexpressed AURKA were likely regulatory molecules that coordinate these events. Mice with AURKA overexpression exhibited improved angiogenesis in response to VEGF in Matrigel plug assay, with increased capillary density and hemoglobin content. In diabetic limb ischemia mice, AURKA overexpression rescued blood perfusion and motor deficits, accompanied by the recovery of gastrocnemius muscles observed by H&E staining and positive Desmin staining. Moreover, AURKA overexpression rescued diabetes-related impairment of angiogenesis, arteriogenesis, and functional recovery in the ischemic limb. Signal pathway results revealed that VEGFR2/PI3K/AKT pathway might be involved in AURKA triggered angiogenesis procedure. In addition, AURKA overexpression impeded oxidative stress and subsequent following lipid peroxidation both in vitro and in vivo, indicating another protective mechanism of AURKA function in diabetic limb ischemia. The changes in lipid peroxidation biomarkers (lipid ROS, GPX4, SLC7A11, ALOX5, and ASLC4) in in vitro and in vivo were suggestive of the possible involvement of ferroptosis and interaction between AUKRA and ferroptosis in diabetic limb ischemia, which need further investigation. CONCLUSIONS: These results implicated a potent role of AURKA in diabetes-related impairment of ischemia-mediated angiogenesis and implied a potential therapeutic target for ischemic diseases of diabetes.

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19.

BACKGROUND: No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. METHODS: We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first. RESULTS: A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. CONCLUSIONS: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).

The Short-Term Efficacy of Bifidobacterium Quadruple Viable Tablet in Patients With Diarrhea-Predominant Irritable Bowel Syndrome: Potentially Mediated by Metabolism Rather Than Diversity Regulation.

INTRODUCTION: The therapeutic effect of probiotics for irritable bowel syndrome (IBS) was controversial. This study aims to evaluate the short-term efficacy of Bifidobacterium quadruple viable tablet in patients with diarrhea-predominant IBS and explore factors associated with response to probiotics. METHODS: A randomized, double-blind, placebo-controlled, multicenter trial was performed in 15 hospitals. A total of 290 patients who fulfilled the eligibility criteria were assigned to the probiotics or placebo group randomly with a ratio of 1:1 for a 4-week treatment and a 2-week follow-up. The primary outcome was the response rate. It was regarded as the proportion of patients with composite responses of improvement in both abdominal pain and diarrhea simultaneously. RESULTS: After 4-week continuous administration, the response rates of the probiotics and the placebo were 67.59% and 36.55%, respectively ( P < 0.001). In the probiotics, those with higher abdominal pain scores (2.674 [1.139-6.279]) were more likely to respond, but responders in placebo had lower Hamilton Depression Scale score (0.162 [0.060-0.439]), lower Hamilton Anxiety Scale score (0.335 [0.148-0.755]), and higher degree of bloating (2.718 [1.217-6.074]). Although the diversity of the microbiota was not significantly changed by probiotics, the abundance of bacteria producing short-chain fatty acids (SCFAs), including Butyricimonas ( P = 0.048), Pseudobutyrivibrio ( P = 0.005), Barnesiella ( P = 0.020), and Sutterella ( P = 0.020), and the concentration of SCFAs including butyric acid ( P = 0.010), valeric acid ( P = 0.019), and caproic acid ( P = 0.046) in feces increased. DISCUSSION: A Bifidobacterium quadruple viable tablet had a significant short-term efficacy for the treatment of diarrhea-predominant IBS and was more effective in patients with higher abdominal pain scores. This kind of probiotics could improve the abundance of several bacteria producing SCFAs and the concentration of fecal SCFAs compared with placebos.

Gut microbiome alterations in patients with COVID-19-related coagulopathy.

COVID-19 is characterized by a predominantly prothrombotic state, which underlies severe disease and poor outcomes. Imbalances of the gut microbiome have been linked with abnormal hemostatic processes. Understanding the relationship between the gut microbiome and abnormal coagulation parameters in COVID-19 could provide a novel framework for the diagnosis and management of COVID-related coagulopathies (CRC). This cross-sectional study used shotgun metagenomic sequencing to examine the gut microbiota of patients with CRC (n = 66) and compared it to COVID control (CCs) (n = 27) and non-COVID control (NCs) (n = 22) groups. Three, 1, and 3 taxa were found enriched in CRCs, CCs, and NCs. Next, random forest models using 7 microbial biomarkers and differential clinical characteristics were constructed and achieved strong diagnostic potential in distinguishing CRC. Specifically, the most promising biomarker species for CRC were Streptococcus thermophilus, Enterococcus faecium, and Citrobacter portucalensis. Conversely, Enterobacteriaceae family and Fusicatenibacter genus are potentially protective against CRC in COVID patients. We further identified 4 species contributing to 20 MetaCyc pathways that were differentially abundant among groups, with S. thermophilus as the main coding species in CRCs. Our findings suggest that the alterations of gut microbiota compositional and functional profiles may influence the pathogenesis of CRC and that microbiota-based diagnosis and treatment could potentially benefit COVID patients in preventing and alleviating thrombosis-related clinical outcomes.

Asia-Pacific guidelines for managing functional dyspepsia overlapping with other gastrointestinal symptoms.

Contemporary systems for the diagnosis and management gastrointestinal symptoms not attributable to organic diseases (Functional GI Disorders, FGID, now renamed Disorders of Gut-Brain Interaction, DGBI) seek to categorize patients into narrowly defined symptom-based sub-classes to enable targeted treatment of patient cohorts with similar underlying putative pathophysiology. However, an overlap of symptom categories frequently occurs and has a negative impact on treatment outcomes. There is a lack of guidance on their management. An Asian Pacific Association of Gastroenterology (APAGE) working group was set up to develop clinical practice guidelines for management of patients with functional dyspepsia (FD) who have an overlap with another functional gastrointestinal disorder: FD with gastroesophageal reflux (FD-GERD), epigastric pain syndrome with irritable bowel syndrome (EPS-IBS), postprandial distress syndrome with IBS (PDS-IBS), and FD-Constipation. We identified putative pathophysiology to provide a basis for treatment recommendations. A management algorithm is presented to guide primary and secondary care clinicians.

Research on Six-Axis Sensor-Based Step-Counting Algorithm for Grazing Sheep.

Step counting is an effective method to assess the activity level of grazing sheep. However, existing step-counting algorithms have limited adaptability to sheep walking patterns and fail to eliminate false step counts caused by abnormal behaviors. Therefore, this study proposed a step-counting algorithm based on behavior classification designed explicitly for grazing sheep. The algorithm utilized regional peak detection and peak-to-valley difference detection to identify running and leg-shaking behaviors in sheep. It distinguished leg shaking from brisk walking behaviors through variance feature analysis. Based on the recognition results, different step-counting strategies were employed. When running behavior was detected, the algorithm divided the sampling window by the baseline step frequency and multiplied it by a scaling factor to accurately calculate the number of steps for running. No step counting was performed for leg-shaking behavior. For other behaviors, such as slow and brisk walking, a window peak detection algorithm was used for step counting. Experimental results demonstrate a significant improvement in the accuracy of the proposed algorithm compared to the peak detection-based method. In addition, the experimental results demonstrated that the average calculation error of the proposed algorithm in this study was 6.244%, while the average error of the peak detection-based step-counting algorithm was 17.556%. This indicates a significant improvement in the accuracy of the proposed algorithm compared to the peak detection method.

Grazing Sheep Behaviour Recognition Based on Improved YOLOV5.

Fundamental sheep behaviours, for instance, walking, standing, and lying, can be closely associated with their physiological health. However, monitoring sheep in grazing land is complex as limited range, varied weather, and diverse outdoor lighting conditions, with the need to accurately recognise sheep behaviour in free range situations, are critical problems that must be addressed. This study proposes an enhanced sheep behaviour recognition algorithm based on the You Only Look Once Version 5 (YOLOV5) model. The algorithm investigates the effect of different shooting methodologies on sheep behaviour recognition and the model's generalisation ability under different environmental conditions and, at the same time, provides an overview of the design for the real-time recognition system. The initial stage of the research involves the construction of sheep behaviour datasets using two shooting methods. Subsequently, the YOLOV5 model was executed, resulting in better performance on the corresponding datasets, with an average accuracy of over 90% for the three classifications. Next, cross-validation was employed to verify the model's generalisation ability, and the results indicated the handheld camera-trained model had better generalisation ability. Furthermore, the enhanced YOLOV5 model with the addition of an attention mechanism module before feature extraction results displayed a mAP@0.5 of 91.8% which represented an increase of 1.7%. Lastly, a cloud-based structure was proposed with the Real-Time Messaging Protocol (RTMP) to push the video stream for real-time behaviour recognition to apply the model in a practical situation. Conclusively, this study proposes an improved YOLOV5 algorithm for sheep behaviour recognition in pasture scenarios. The model can effectively detect sheep's daily behaviour for precision livestock management, promoting modern husbandry development.

Scale-invariant sensitivity for multi-purpose water reservoirs management with temporal scale-dependent modeling.

High-resolution temporal data (e.g., daily) is valuable for the decision-making of water resources management because it more accurately captures fine-scale processes and extremes than the coarse temporal data (e.g., weekly or monthly). However, many studies rarely consider this superior suitability for water resource modeling and management; instead, they often use whichever data is more readily available. So far, no comparative investigations have been conducted to determine if access to different time-scale data would change decision-maker perceptions or the rationality of decision making. This study proposes a framework for assessing the impact of different temporal scales on water resource management and the performance objective's sensitivity to uncertainties. We built the multi-objective operation models and operating rules of a water reservoir system based on daily, weekly, and monthly scales, respectively, using an evolution multi-objective direct policy search. The temporal scales of the input variables (i.e., streamflow) affect both the model structures and the output variables. In exploring these effects, we reevaluated the temporal scale-dependent operating rules under uncertain streamflow sets generated from synthetic hydrology. Finally, we obtained the output variable's sensitivities to the uncertain factors at different temporal scales using the distribution-based sensitivity analysis method. Our results show that water management based on too coarse resolution might give decision makers the wrong perception because the effect of actual extreme streamflow process on the performance objectives is ignored. The streamflow uncertainty is more influential than the uncertainty associated with operating rules. However, the sensitivities are characterized by temporal scale invariance, as the differences of the sensitivity between different temporal scales are not obvious over the uncertainties in streamflow and thresholds. These results show that water management should consider the resolution-dependent effect of temporal scales for balancing modeling complexity and computational cost.