Expanding catalytic promiscuity of a bifunctional terpene synthase through a single mutation-induced change in hydrogen-bond network within the catalytic pocket.

Fungal bifunctional terpene synthases (BFTSs) catalyze the formation of numerous di-/sester-/tri-terpenes skeletons. However, the mechanism in controlling the cyclization pattern of terpene scaffolds is rarely deciphered for further application of tuning the catalytic promiscuity of terpene synthases for expanding the chemical space. In this study, we expanded the catalytic promiscuity of Fusarium oxysporum fusoxypene synthase (FoFS) by a single mutation at L89, leading to the production of three new sesterterpenes. Further computational analysis revealed that the reconstitution of the hydrogen-bond (H-bond) network of second-shell residues around the active site of FoFS influences the orientation of the aromatic residue W69 within the first-shell catalytic pocket. Thus, the dynamic orientation of W69 alters the carbocation transport, leading to the production of diverse ring system skeletons. These findings enhance our knowledge on understanding the molecular mechanisms, which could be applied on protein engineering terpene synthases on regulating the terpene skeletons.

Assessment of Six Blackberry Cultivars Using a Combination of Metabolomics, Biological Activity, and Network Pharmacology Approaches.

Blackberries have gained considerable attention due to their high antioxidant content and potential health benefits. This study compared the metabolite profiles of six blackberry cultivars and investigated their biological activities. The metabolites extracted from blackberries were analyzed using metabolomics, and their biological activities and mechanisms were confirmed using in vitro models and network pharmacology. Among the cultivars examined, "Kiowa" ripe berries exhibited the highest antioxidant and anti-inflammatory activities. These effects were primarily attributed to the accumulation of flavonoids (quercitrin and luteolin) and anthocyanin (cyanidin 3-O-glucoside) in the phenylpropanoid pathway. Furthermore, our research identified 13 blackberry metabolites that interacted with 31 genes, including AKT1, CASP3, JUN, MAPK8, NOS3, NQO1, and HMOX1 which play roles in reducing oxidative stress, protecting cells from damage, and suppressing inflammation. These findings suggest that blackberry metabolites, such as quercitrin, luteolin, and cyanidin 3-O-glucoside, may exert therapeutic effects by modulating specific genes and pathways associated with antioxidant and anti-inflammatory responses. This research is promising not only for plant breeders but also for those interested in harnessing the health-promoting properties of blackberries.

Effects of Drying Methods on the Physicochemical and Functional Properties of Cinnamomum camphora Seed Kernel Protein Isolate.

Cinnamomum camphora seed kernel protein isolate (CPI) has attracted increasing attention due to its sustainability and potential applications. This study aimed to investigate the effects of freeze-drying (FD), vacuum-drying (VD), and spray-drying (SD) on the physicochemical and functional properties of CPI. The morphology observation results showed that the SD-CPI, SD-CPI, and VD-CPI were spherical, lamellar, and massive, respectively. Compared to FD and SD, VD had more impact on the color, surface hydrophobicity, intermolecular disulfide bonds, intrinsic fluorescence, and thermal stability of CPI. Fourier transform infrared spectroscopy (FTIR) analyses showed that among three CPI samples, VD-CPI had the highest content of ß-sheet but the lowest contents of α-helix and ß-turn. At different pH values, the solubility, emulsification, and foaming properties of VD-CPI were inferior to those of FD-CPI and SD-CPI. These results provide useful information on the changes in the physicochemical and functional properties of CPI subjected to different drying methods, and offer theoretical guidance for the production and use of CPI in the food industry.

Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).

Sour Jujube (Ziziphus jujuba var. spinosa): A Bibliometric Review of Its Bioactive Profile, Health Benefits and Trends in Food and Medicine Applications.

Research on the comprehensive utilization of sour jujube and its beneficial properties to human health has attracted extensive attention. This study aims to conduct a bibliometric analysis of the bioactive profile of sour jujube and future trends in applications. The research advancements within this field from 2000 to 2023 were addressed using the Web of Science database and VOSviewer. Among the 322 results, the most frequent keywords of bioactivity are flavonoids, antioxidants, saponins, insomnia, polyphenols, terpenoids and anti-inflammatory; the most studied parts of sour jujube are seeds, fruits and leaves; the published articles with high citations mainly focus on identification, biological effects and different parts distribution of bioactive compounds. The bioactivity of various parts of sour jujube was reviewed considering their application potential. The seeds, rich in flavonoids, saponins and alkaloids, exhibit strong effects on central nervous system diseases and have been well-developed in pharmacology, healthcare products and functional foods. The pulp has antioxidant properties and is used to develop added-value foods (e.g., juice, vinegar, wine). The leaves can be used to make tea and flowers are good sources of honey; their extracts are rich sources of flavonoids and saponins, which show promising medicinal effects. The branches, roots and bark have healing properties in traditional folk medicine. Overall, this study provides a reference for future applications of sour jujube in food and medicine fields.

Antihypertensive medication persistence and adherence among non-Hispanic Asian US patients with hypertension and fee-for-service Medicare health insurance.

BACKGROUND: Less than 50% of non-Hispanic Asian adults taking antihypertensive medication have controlled blood pressure. METHODS: We compared non-persistence and low adherence to antihypertensive medication between non-Hispanic Asian and other race/ethnicity groups among US adults ≥66 years who initiated antihypertensive medication between 2011 and 2018 using a 5% random sample of Medicare beneficiaries (non-Hispanic Asian, n = 2,260; non-Hispanic White, n = 56,000; non-Hispanic Black, n = 5,792; Hispanic, n = 4,212; and Other, n = 1,423). Non-persistence was defined as not having antihypertensive medication available to take in the last 90 of 365 days following treatment initiation. Low adherence was defined as having antihypertensive medication available to take on <80% of the 365 days following initiation. RESULTS: In 2011-2012, 2013-2014, 2015-2016 and 2017-2018, the proportion of non-Hispanic Asian Medicare beneficiaries with non-persistence was 29.1%, 25.6%, 25.4% and 26.7% (p-trend = 0.381), respectively, and the proportion with low adherence was 58.1%, 54.2%, 53.4% and 51.6%, respectively (p-trend = 0.020). In 2017-2018, compared with non-Hispanic Asian beneficiaries, non-persistence was less common among non-Hispanic White beneficiaries (risk ratio 0.74 [95%CI, 0.64-0.85]), non-Hispanic Black beneficiaries (0.80 [95%CI 0.68-0.94]) and those reporting Other race/ethnicity (0.68 [95%CI, 0.54-0.85]) but not among Hispanic beneficiaries (1.04 [95%CI, 0.88-1.23]). Compared to non-Hispanic Asian beneficiaries, non-Hispanic White beneficiaries and beneficiaries reporting Other race/ethnicity were less likely to have low adherence to antihypertensive medication (relative risk 0.78 [95%CI 0.72-0.84] and 0.84 [95%CI 0.74-0.95], respectively); there was no association for non-Hispanic Black or Hispanic beneficiaries. CONCLUSIONS: Non-persistence and low adherence to antihypertensive medication were more common among older non-Hispanic Asian than non-Hispanic White adults.

Molecular analyses of exosome-derived miRNAs revealed reduced expression of miR-184-3p and decreased exosome concentration in patients with alveolar echinococcosis.

Both E. multilocularis and host-derived exosomes are involved in the pathogenic process of alveolar echinococcosis (AE). Exosomes secrete miRNAs that have regulatory roles in host-pathogen interactions in multiple ways. In the present study, we collected and purified supernatants of E. multilocularis cultures, as well as human plasma exosomes. High-throughput sequencing showed the identities of 45 exosomal miRNAs in E. multilocularis. The lengths of these miRNAs ranged from 19 to 25 nucleotides (nt), with the majority (n = 18) measuring 22 nt. Notably, emu-let-7-5p emerged as the most abundant among these miRNAs, with a detected count of 33,097 and also length of 22 nt. Nanoparticle tracking analysis (NTA) showed that the concentration of exosomes in the plasma of AE patients was lower compared to that in the healthy individuals. This result suggested that the concentration of plasma exosomes was able to distinguish AE patients from healthy individuals. Using qRT-PCR to assess the relative expression of 10 miRNAs of E. multilocularis, we showed that the expression of miR-184-3p was downregulated significantly in the exosomes of plasma from AE patients compared to that in the control group. In summary, this study indicates that AE induces a reduction in the concentration of human plasma exosomes, as well as downregulating miR-184-3p in infected individuals.

UCFNNet: Ulcerative colitis evaluation based on fine-grained lesion learner and noise suppression gating.

BACKGROUND AND OBJECTIVE: Ulcerative colitis (UC) is a chronic disease characterized by recurrent symptoms and significant morbidity. The exact cause of the disease remains unknown. The selection of current treatment options for ulcerative colitis depends on the severity and location of the disease in each patient. Therefore, developing a fully automated endoscopic images for evaluating UC is crucial for guiding treatment plans and facilitating early prevention efforts. METHODS: We propose a network called ulcerative colitis evaluation based on fine-grained lesion learner and noise suppression gating (UCFNNet). UCFNNet contains three novel modules. Firstly, a fine-grained lesion feature learner (FG-LF Learner) is proposed by integrating local features and a Softmax category prediction (SCP) module to improve the feature accuracy in small lesion areas. Subsequently, a graph convolutional feature combiner (GCFC) is developed to connect features across adjacent convolutional layers and to incorporate short connections between input and output, thereby mitigating feature loss during transmission. Thereafter, a noise suppression gating (NS gating) technique is designed by implementing a grid attention mechanism and a feature gating (FG) module to prioritize significant lesion features and suppress irrelevant and noisy regions in the input feature map. RESULTS: We evaluate the performance of the proposed network on both privately-collected and publicly-available datasets. The evaluation of UC achieves excellent results on privately-collected dataset, with an accuracy (ACC) of 89.57 %, Matthews correlation coefficient (MCC) of 85.52 %, precision of 89.26 %, recall of 89.48 %, and F1-score of 89.78 %. The results are also impressive on publicly-available dataset, with ACC of 85.47 %, MCC of 80.42 %, precision of 85.62 %, recall of 84.00 %, and F1-score of 84.53 %, surpassing the performance of state-of-the-art techniques. CONCLUSION: Our proposed model introduces three innovative algorithm modules, which outperform the current state-of-the-art methods and achieve high ACC and F1-score. This indicates that our method has superior performance compared to traditional machine learning and existing deep methods, which means that our method has good application prospects. Meanwhile, it has been verified that the proposed model demonstrates good interpretability. The source code is available at github.com/YinLeRenNB/UCFNNet.

Examining the Significance of Intercultural Communicative Competence Development in Trainees during Pre-service Training.

The aim of this study is to discuss the need for improved intercultural communicative competence (ICC) training for pre-service Chinese as a Second Language (CSL) teachers who travel abroad to teach. Previous studies have shown that pre-service CSL teachers often struggle with intercultural communication, and this study investigates the reasons behind their difficulties and suggests ways to address them. The researchers used the Intercultural Sensitivity Scale (ISS) and the Intercultural Effectiveness Scale (IES) to measure the ICC of 217 pre-service CSL teachers. The study found that while pre-service CSL teachers have strong intercultural communicative emotional ability, their behavioral ability in intercultural communication is weak. In particular, they lacked skills in interactive control, interactive relaxation, identity management, information skills, and behavioral flexibility. The study proposes several strategies to improve ICC training for pre-service CSL teachers. One potential approach is the use of Computer Assisted Language Learning to provide teacher-trainee students with opportunities to practice intercultural communication skills in simulated contexts, receive personalized feedback, and engage with authentic materials and cultural information relevant to their host country. CALL could also facilitate communication between pre-service CSL teachers and former CSL teachers, providing a platform for information exchange and additional psychological support. The study also suggests that pre-service training should distinguish between foreign language learning and intercultural communication skills training. Specifically, it recommends that foreign language proficiency should be improved, while training should focus on educational culture and work culture in the host country, rather than providing a general introduction to the national conditions of the country. Finally, the study proposes that pre-service training should establish contact between pre-service CSL teachers and former CSL teachers as early as possible so that trainees can learn specific relevant information in advance, which can help them get ready, avoid intercultural communication mistakes, and obtain additional psychological support. By incorporating CALL and addressing the areas of weakness identified in the study, pre-service CSL teachers can be better prepared to navigate the challenges of intercultural communication and provide effective and culturally sensitive instruction abroad.

Effect of Different Medium-Chain Triglycerides on Glucose Metabolism in High-Fat-Diet Induced Obese Rats.

Obesity can be associated with significant metabolic disorders. Our previous study found that medium-chain triglycerides (MCTs) improved lipid metabolism in obese rats. However, scant attention has been given to exploring the impact of MCTs on glucose metabolism in obese rats. This study is designed to examine the effects and mechanisms of three distinct MCTs on glucose metabolism in obese rats. To induce obesity, Sprague-Dawley (SD) rats were fed a high-fat diet, followed by a 12-week treatment with caprylic triglyceride (CYT), capric triglyceride (CT), and lauric triglyceride (LT). The results showed that three types of MCT intervention reduced the levels of lipids (TC, TG, LDL-c, and HDL-c), hyperglycemia, insulin resistance (insulin, OGTT, HOMA-IR, and ISI), and inflammatory markers (IL-4, IL-1ß, and TNF-α) in obese rats (p < 0.01), The above parameters have been minimally improved in the high-fat restoring group (HR) group. MCTs can modulate the PI3K/AKT signaling pathways to alleviate insulin resistance and improve glucose metabolism in obese rats. Furthermore, MCTs can activate peroxisome proliferator-activated receptor (PPAR) γ and reduce the phosphorylation of PPARγser237 mediated by CDK5, which can improve insulin sensitivity without lipid deposition in obese rats. Among the MCT group, CT administration performed the best in the above pathways, with the lowest blood glucose level and insulin resistance. These findings contribute to a deeper understanding of the connection between health benefits and the specific type of MCT employed.

The function and keystone microbiota in typical habitats under the influence of anthropogenic activities in Baiyangdian Lake.

Microbe is an essential driver in regulating the biochemical cycles of carbon, nitrogen, and sulfur. In freshwater lake, microbial communities and functions are influenced by multiple factors, especially anthropogenic activities. Baiyangdian Lake consisted of various habitats, and was frequently interfered with human activities. In this study, 16 S rRNA sequencing and metagenomic sequencing were performed to characterize the microbial communities, determine keystone taxa and reveal dominated metabolic functions in typical habitats in Baiyangdian Lake. The results showed that the diversity of microbial community was significantly higher in sediment compared with corresponding water sample. Microbial community showed strong spatial heterogeneity in sediment, and temporal heterogeneity in water. As for different habitats, significantly higher alpha diversity was observed in ecotone, where the interference of human activities was relatively weak. The shared OTUs were distinguished from the keystone taxa, which indicated the uniqueness of microbiota in different ecological habitat. Moreover, the interactions of microbial in ecological restoration area (abandoned fish pond) were relatively simple, suggesting that this ecosystem was relatively fragile compared with others. Based on the metagenomic sequencing, we recognized that the canal, open water, and abandoned fish pond were beneficial for methanogenic and the ecotone might be a hot zone for the oxidation of methane. Notably, most of the microbes that participated in these predominant metabolisms were unclassified, which indicated the hug potential for exploring functional microorganisms in Baiyangdian Lake. This study provided a comprehensive understanding of the ecology characteristics of microbiota in habitats undergoing various human interference in Baiyangdian Lake.

Study on morphology optimization of open-pit mine slope based on section and spatial morphology effect.

Reasonable design of the slopes of mining field is an important prerequisite for optimizing open-pit mine boundary, ensuring safe production and improving economic benefits of open-pit mines. This study took the open-pit coal mine coal mine in Block I of Thar coal field in Pakistan as the research background, based on the section morphology effect of slope stability and the occurrence characteristics of coal seam and weak layer, the section morphology of slope was optimized step by step from two-dimensional angle by using the rigid body limit equilibrium method. The three-dimensional numerical simulation method is used to analyze the three-dimensional spatial effect of slope stability and reveal the influence of the spatial geometry of the slope stability. The spatial morphology of the slope was optimized and the evolutionary mechanism of slope instability was revealed. By comparing the optimized slope morphology with the preliminary design and the slope morphology of the straight slope with equal flat plate, the economic benefits were further analyzed. The results showed that under the premise of meeting the safety reserve coefficient, compared with the preliminary design and the design of equal plate. The slope angle of the optimized section morphology was increased by 1° and 3° respectively, and the coal resource recovery was increased by 332 m2 and 1790 m2 respectively, and the economic benefits were $ 18,065,859 and $ 54,408,251 respectively. And the slope angle of the optimized spatial morphology was increased by 3° and 5° respectively, and the coal resource recovery was increased by 1188 m2 and 2726 m2 respectively, and the economic benefits were $ 72,082,808 and $ 108,417,368 respectively.

Differential expressions and potential clinical values of lncRNAs in the plasma exosomes of rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a common autoimmune disease with unclear pathogenesis. Progress in its clinical diagnosis and treatment mainly depends on the elucidation of its pathogenesis and the exploration of new biomarkers. Exosomes contain various biomolecules, including long non-coding ribonucleic acids (lncRNAs). lncRNAs may participate in the regulation of autoimmune and inflammatory processes during RA pathogenesis by transmitting these biomolecules via exosomes among different cells. Therefore, the investigation of lncRNAs in RA exosomes may be a feasible pathway to elucidate RA pathogenesis, identify new diagnostic biomarkers, and identify potential therapeutic targets. METHODS: In the first phase of exosomal non-coding RNAs screening, exosomes were isolated from the peripheral blood of six patients with RA and healthy controls (HC). High-throughput RNA sequencing was performed to obtain lncRNA expression profiles, and 15 lncRNAs with the highest differential expression were selected as candidate lncRNAs. In the second phase of validation using real-time quantitative polymerase chain reaction (qRT-PCR), differential expression of the 15 candidate lncRNAs was verified in 42 patients with RA and their matched HC. Their potential value as RA diagnostic biomarkers was assessed using receiver operating characteristic (ROC) curve analysis. Their relationships with common clinical indices of RA were explored using Spearman's rank correlation and linear regression analyses. RESULT: Compared to HC, patients with RA had 206 upregulated and 2,332 downregulated lncRNAs. Fifteen candidate lncRNAs were validated by qRT-PCR, of which 12 (SNHG6, RPS18P9, RPL21P28, EBLN3P, FAM153CP, RPL23P8, SNHG31, NORAD, H3P6, DLEU2, TUG1, and OIP5-AS1) were upregulated, and three (CXXC4-AS1, OLMALINC, and NPHP3-AS1) were downregulated. In the ROC analysis of the 15 candidate lncRNAs, the area under the curve (AUC) ranged from 0.847 (0.767, 0.927) for OLMALINC to 0.994 (0.984, 1.000) for CXXC4-AS1. Spearman rank correlation analysis revealed erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and disease activity score of 28 (DAS28) were correlated with seven, six, and five lncRNAs, respectively. Further linear regression analysis revealed a negative relationship between exosomal SNHG6 and ESR (B = -0.384, P = 0.006), and a positive relationship between SNHG31 and ESR (B = 0.381, P = 0.007). Exosomal SNHG6 also showed a negative relationship with CRP (B = -0.361, P = 0.019). Moreover, exosomal RPS18P9 and SNGH31 had a negative effect and a positive effect on DAS28, respectively (B = -0.463, P < 0.001; B = 0.586, P < 0.001), implying novel exosomal lncRNAs were the independent influencing factors of the main RA-related clinical indices. CONCLUSIONS: lncRNAs in RA plasma exosomes have characteristic expression profiles, including some lncRNAs with potential as diagnostic biomarkers and therapeutic targets for RA.

Effects of dietary supplementation with tea polyphenols and probiotics on laying performance, biochemical parameters intestinal morphology and microflora of laying hens.

This study was conducted to investigate the effects of tea polyphenols (TP) and probiotics (PB) on the production performance, biochemical indices, and gut health of laying hens. A total of 400 Hy-line Brown layers (45 weeks old) were randomly assigned to 8 diet groups for 8-week feeding trial. Compared with the control basal diet (CT), dietary high dosage of TP and PB (HTP-PB) increased egg mass (P < 0.05). Supplementation with HTP-PB improved the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreased the malonic dialdehyde (MDA) content (P < 0.05) without affecting the contents of immunoglobulins in the serum. The combination of HTP and PB supplementation promoted the secretion of estradiol (E2) and progesterone (PROG) compared with treatment with TP or PB alone (P < 0.05). The combined use of HTP and PB induced higher jejunal villus height (VH) than the CT group (P < 0.05). Dietary TP and PB could optimize the functional network of intestinal microflora and the interactions between the intestinal microflora and the host. Therefore, the combined use of the high dosage of TP and PB affected laying performance, improved antioxidant capacity, and promoted intestinal health, which may be associated with regulation of the intestinal microbiota.

A comparative cadaveric study for percutaneous scaphoid fixation: robotic vs freehand.

PURPOSES: To compare the robotic-assisted and the traditional freehand percutaneous scaphoid fixation in number of guidewire attempts, duration of fluoroscopy time, amount of radiation dose, and screw centrality. METHODS: Twenty cadaveric specimens were randomized into either the robotic or freehand group. The scaphoids in both groups were fixed by either the same attending or resident from our hand surgery department. The operation duration, amount of radiation from intraoperative fluoroscopy, total fluoroscopy time, and the number of guidewire attempts were documented and compared. Postoperatively, all the specimens had a computed tomography (CT) scan performed, and the difference in the final position of the screw and the central axis of the scaphoid was examined. RESULTS: In the robotic group, all the guide wires were satisfactorily positioned within a single attempt, while the median number of attempts in the traditional freehand group was 18 (quaternion 14-65). This also meant that the surgeon in the robotic group experienced significantly lower radiation exposure dose and time as compared to the freehand group. There were no significant differences in the final screw position as compared to the central axis of the scaphoid in both groups. Although there was no difference in surgeon performance in the robotic group, the operative time for the attending was significantly lower as compared to the resident in the freehand group. CONCLUSION: Robotic-assisted surgery for scaphoid fracture fixation is superior to the traditional freehand method as it facilitates accurate screw placement with lower radiation exposure and fewer guide wire attempts.

Biallelic truncating TTN variants in M-band encoding exons cause a fetal lethal titinopathy.

To report two novel TTN variants associated with fetal recessive titinopathy, thereby broadening the range of TTN variants that can lead to titinopathy. Clinical information on the fetus and parents was gathered, and genomic DNAs were extracted from the fetal tissue and family members' peripheral blood samples. Exome sequencing on fetal DNA was performed and following bioinformatics analysis, the suspected pathogenic variants were confirmed through Sanger sequencing. Prenatal ultrasound performed at 29 weeks of gestation revealed hydrops fetalis, decreased fetal movements, multiple joint contractures and polyhydramnios. Intrauterine fetal death was noted in the third trimester. Exome sequencing revealed compound heterozygous variants in the TTN gene: a paternally inherited allele c.101227C>T (p.Arg33743Ter) and a maternally inherited c.104254C>T (p.Gln34752Ter) allele. These variants have not been previously reported and are evaluated to be likely pathogenic according to the American College of Medical Genetics and Genomics guidelines. We report a fetus with hydrops fetalis and arthrogryposis multiplex congenita associated with a compound heterozygote in the TTN gene. Our report broadens the clinical and genetic spectrum associated with the TTN-related conditions.

GAABind: a geometry-aware attention-based network for accurate protein-ligand binding pose and binding affinity prediction.

Protein-ligand interactions are increasingly profiled at high-throughput, playing a vital role in lead compound discovery and drug optimization. Accurate prediction of binding pose and binding affinity constitutes a pivotal challenge in advancing our computational understanding of protein-ligand interactions. However, inherent limitations still exist, including high computational cost for conformational search sampling in traditional molecular docking tools, and the unsatisfactory molecular representation learning and intermolecular interaction modeling in deep learning-based methods. Here we propose a geometry-aware attention-based deep learning model, GAABind, which effectively predicts the pocket-ligand binding pose and binding affinity within a multi-task learning framework. Specifically, GAABind comprehensively captures the geometric and topological properties of both binding pockets and ligands, and employs expressive molecular representation learning to model intramolecular interactions. Moreover, GAABind proficiently learns the intermolecular many-body interactions and simulates the dynamic conformational adaptations of the ligand during its interaction with the protein through meticulously designed networks. We trained GAABind on the PDBbindv2020 and evaluated it on the CASF2016 dataset; the results indicate that GAABind achieves state-of-the-art performance in binding pose prediction and shows comparable binding affinity prediction performance. Notably, GAABind achieves a success rate of 82.8% in binding pose prediction, and the Pearson correlation between predicted and experimental binding affinities reaches up to 0.803. Additionally, we assessed GAABind's performance on the severe acute respiratory syndrome coronavirus 2 main protease cross-docking dataset. In this evaluation, GAABind demonstrates a notable success rate of 76.5% in binding pose prediction and achieves the highest Pearson correlation coefficient in binding affinity prediction compared with all baseline methods.

Comparative effectiveness of multiple different treatment regimens for nonalcoholic fatty liver disease with type 2 diabetes mellitus: a systematic review and Bayesian network meta-analysis of randomised controlled trials.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are closely related and mutually contribute to the disease's development. There are many treatment options available to patients. We provide a comprehensive overview of the evidence on the treatment effects of several potential interventions for NAFLD with T2DM. METHODS: This systematic review and network meta-analysis included searches of PubMed, Embase, Cochrane Library, and Web of Science from inception to June 30, 2023, for randomised controlled trials of treatment of NAFLD with T2DM. We performed Bayesian network meta-analyses to summarise effect estimates of comparisons between interventions. We applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) frameworks to rate all comparative outcomes' certainty in effect estimates, categorise interventions, and present the findings. This study was registered with PROSPERO, CRD42022342373. RESULTS: Four thousand three hundred and sixty-nine records were retrieved from the database and other methods, of which 24 records were eligible for studies enrolling 1589 participants. Eight clinical indicators and 14 interventions were finally in focus. Referring to the lower surface under the cumulative ranking curves (SUCRA) and the league matrix table, exenatide and liraglutide, which are also glucagon-like peptide-1 receptor agonists (GLP-1RAs), showed excellent potential to reduce liver fat content, control glycemia, reduce body weight, and improve liver function and insulin resistance. Exenatide was more effective in reducing glycated haemoglobin (HbA1c) (mean difference (MD) 0.32, 95%CI 0.12 to 0.52), lowering BMI (MD 0.81, 95%CI 0.18 to 1.45), and lowering alanine transaminase (ALT) (MD 10.96, 95%CI 5.27 to 16.66) compared to liraglutide. However, this evidence was assessed as low certainty. Omega-3 was the only intervention that did not have a tendency to lower HbA1c, with standard-treatment (STA-TRE) as reference (MD - 0.17, 95%CI - 0.42 to 0.07). Glimepiride is the only intervention that causes an increase in ALT levels, with standard-treatment (STA-TRE) as reference (MD - 11.72, 95%CI - 17.82 to - 5.57). Based on the available evidence, the treatment effects of pioglitazone, dapagliflozin, and liraglutide have a high degree of confidence. CONCLUSIONS: The high confidence mandates the confident application of these findings as guides for clinical practice. Dapagliflozin and pioglitazone are used for glycaemic control in patients with NAFLD combined with T2DM, and liraglutide is used for weight loss therapy in patients with abdominal obesity. The available evidence does not demonstrate the credibility of the effectiveness of other interventions in reducing liver fat content, visceral fat area, ALT, and insulin resistance. Future studies should focus on the clinical application of GLP-1Ras and the long-term prognosis of patients.