Consistent efficacy outcomes between phase 2 and phase 3 trials in Crohn's disease or ulcerative colitis in adults: a meta-analysis.

INTRODUCTION: The approval of novel biologic agents and small molecules for the treatment of Crohn's disease (CD) and ulcerative colitis (UC) is dependent on phase 3 randomized controlled trials (RCTs). However, these trials sometimes fail to achieve the expected efficacy outcomes observed in phase 2 trials. METHODS: We conducted a systematic review of RCTs that evaluated biologic agents and small molecules using paired regimens in both phase 2 and phase 3. We searched Medline, EMBASE, and Cochrane databases up until February 13, 2024. The revised Cochrane tool was utilized to assess the risk of bias. A generalized linear mixed-effects model (GLMM) was employed to estimate the odds ratios (ORs) for efficacy outcomes in phase 2 trials compared to phase 3. RESULTS: We identified a total of 23 trials with 10 paired regimens for CD and 30 trials with 11 paired regimens for UC. The GLMM analysis revealed that phase 2 CD trials had higher outcomes measured by the Crohn's Disease Activity Index (CDAI) by 9-13% without statistical significance: CDAI-150: OR, 1.12 (95% CI 0.83-1.51, p = 0.41); CDAI-100: OR, 1.09 (95% CI 0.88-1.35, p = 0.40); or CDAI-70: OR, 1.13 (95% CI 0.61-2.08, p = 0.66). For UC, two efficacy outcomes were estimated to be equally reported in phase 2/phase 3 pairs: clinical remission: OR, 1.00 (95% CI 0.83-1.20, p = 0.96); endoscopic improvement: OR, 0.98 (95% CI 0.83-1.15, p = 0.79). However, the rate of clinical response was underestimated in phase 2 by 19%: OR, 0.81 (95% CI 0.70-0.95, p = 0.03). The inclusion criterion for the type of Mayo score for UC had a significant interaction with the study phase to influence the difference in clinical response (p = 0.002). CONCLUSIONS: Our findings suggest that the main efficacy outcomes for CD and UC remain consistent between phase 2 and phase 3 trials, except for UC response rates. The efficacy data obtained from phase 2 trials can be considered reliable for the design of subsequent phase 3 trials. REGISTRATION: PROSPERO (CRD42023407947).

The intestinal microbial metabolite acetyl l-carnitine improves gut inflammation and immune homeostasis via CADM2.

Intestinal symbiotic bacteria play a key role in the regulation of immune tolerance in inflammatory bowel disease (IBD) hosts. However, the bacterial strains directly involved in this regulation and their related metabolites are largely unknown. We sought to investigate the effects of intestinal microbial metabolites on intestinal epithelium and to elucidate their therapeutic potential in regulating intestinal mucosal inflammation and immune homeostasis. Here, we used metagenomic data from Crohn's disease (CD) patients to analyze the composition of intestinal flora and identify metabolite profiles associated with disease behavior, and used the mouse model of dextran sodium sulfate (DSS)-induced colitis to characterize the therapeutic effects of the flora metabolite acetyl l-carnitine (ALC) on DSS-induced colitis. We found that intraperitoneal injection of ALC treatment could significantly alleviate the symptoms of DSS-induced colitis in mice, including prevention of weight loss, reduction in disease activity index (DAI) scores, increasing of colonic length, reduction in histological scores, and improvement in intestinal barrier function. Further, transcriptome sequencing analysis and gene silencing experiments revealed that the absence of CADM2 abolished the inhibitory effect of ALC on the TLR-MyD88 pathway in colonic epithelial cells, thereby reducing the release of inflammatory factors in colon epithelial cells. And we confirmed a significant downregulation of CADM2 expression in intestinal tissues of CD patients compared to healthy people in a population cohort. In addition, we also found that ALC increased the ratio of Treg cells in colon, and decreased the ratio of Th17 cells and macrophages, thereby improving the immune tolerance of the organism. The proposed study could be a potential approach for the treatment of CD.

The influence of sleep factors and dietary habits on the disease pattern of ulcerative colitis patients with long and short disease courses - a multicentre cross-sectional analysis.

BACKGROUND: Ulcerative colitis (UC) is a disease characterized by chronic relapsing-remitting inflammatory disorders and is associated with environmental changes. AIM: To explore the disease patterns of Chinese UC patients and to determine controllable related environmental factors. METHODS: This multicentre cross-sectional study was performed using a questionnaire survey. Data on clinical characteristics and environmental factors were collected. Patients with a disease course ≥5 years were defined as the long course group, and those with a disease course < 5 years were defined as the short course group. RESULTS: A total of 588 effective questionnaires were collected. The proportion of the chronic continuous pattern was the highest among patients with a long disease course (46.8%), and in patients with a short disease course, the proportion of the active to remission pattern was the highest (53.3%). In patients with a long disease course, a higher proportion of patients with adequate sleep was found in the active to remission pattern than in the chronic intermittent (72.1% vs. 43.3%, p = 0.008) and chronic continuous (72.1% vs. 52.4%, p = 0.016) patterns. In patients with a short disease course, the frequency of shellfish and shrimp was higher in the chronic continuous pattern group than in the active to remission pattern group (P = 0.001 and 0.017 respectively). CONCLUSIONS: For early diagnosis patients, dietary guidance should be actively carried out. With the prolongation of the disease course, attention should be given to the sleep quality of patients.

1.UC exhibits various disease patterns, which may be associated with differences in patient prognosis and treatment response.2.Environmental factors, especially sleep and dietary factors, correlated strongly with disease patterns, which varied in different disease courses.3.Early diagnosis patients should receive active dietary guidance, while patients with a prolonged disease course require attention to their sleep quality and appropriate drug interventions when necessary.

Involvement of HSP70 in BAG9-mediated thermotolerance in Solanum lycopersicum.

Because of a high sensitivity to high temperature, both the yield and quality of tomato (Solanum lycopersicum L.) are severely restricted by heat stress. The Bcl-2-associated athanogene (BAG) proteins, a family of multi-functional co-chaperones, are involved in plant growth, development, and stress tolerance. We have previously demonstrated that BAG9 positively regulates thermotolerance in tomato. However, the BAG9-mediated mechanism of thermotolerance in tomato has remained elusive. In the present study, we report that BAG9 interacts with heat shock protein 70 (HSP70) in vitro and in vivo. Silencing HSP70 decreased thermotolerance of tomato plants, as reflected by the phenotype, relative electrolyte leakage and malondialdehyde. Furthermore, the photosystem activities, activities of antioxidant enzymes and expression of key genes encoding antioxidant enzymes were reduced in HSP70-silenced plants under heat stress. Additionally, silencing HSP70 decreased thermotolerance of overexpressing BAG9 plants, which was related to decreased photosynthetic rate, increased damage to photosystem I and photosystem II, decreased activity of antioxidant enzymes, and decreased expression of key genes encoding antioxidant enzymes. Taken together, the present study identified that HSP70 is involved in BAG9-mediated thermotolerance by protecting the photosystem stability and improving the efficiency of the antioxidant system in tomato. This knowledge can be helpful to breed improved crop cultivars that are better equipped with thermotolerance.

Virtual Classification: Modulating Domain-Specific Knowledge for Multidomain Crowd Counting.

Multidomain crowd counting aims to learn a general model for multiple diverse datasets. However, deep networks prefer modeling distributions of the dominant domains instead of all domains, which is known as domain bias. In this study, we propose a simple-yet-effective modulating domain-specific knowledge network (MDKNet) to handle the domain bias issue in multidomain crowd counting. MDKNet is achieved by employing the idea of "modulating", enabling deep network balancing and modeling different distributions of diverse datasets with little bias. Specifically, we propose an instance-specific batch normalization (IsBN) module, which serves as a base modulator to refine the information flow to be adaptive to domain distributions. To precisely modulating the domain-specific information, the domain-guided virtual classifier (DVC) is then introduced to learn a domain-separable latent space. This space is employed as an input guidance for the IsBN modulator, such that the mixture distributions of multiple datasets can be well treated. Extensive experiments performed on popular benchmarks, including Shanghai-tech A/B, QNRF, and NWPU validate the superiority of MDKNet in tackling multidomain crowd counting and the effectiveness for multidomain learning. Code is available at https://github.com/csguomy/MDKNet.

Self-renewing human naïve pluripotent stem cells dedifferentiate in 3D culture and form blastoids spontaneously.

Human naïve pluripotent stem cells (hnPSCs) can generate integrated models of blastocysts termed blastoids upon switch to inductive medium. However, the underlying mechanisms remain obscure. Here we report that self-renewing hnPSCs spontaneously and efficiently give rise to blastoids upon three dimensional (3D) suspension culture. The spontaneous blastoids mimic early stage human blastocysts in terms of structure, size, and transcriptome characteristics and are capable of progressing to post-implantation stages. This property is conferred by the glycogen synthase kinase-3 (GSK3) signalling inhibitor IM-12 present in 5iLAF self-renewing medium. IM-12 upregulates oxidative phosphorylation-associated genes that underly the capacity of hnPSCs to generate blastoids spontaneously. Starting from day one of self-organization, hnPSCs at the boundary of all 3D aggregates dedifferentiate into E5 embryo-like intermediates. Intermediates co-express SOX2/OCT4 and GATA6 and by day 3 specify trophoblast fate, which coincides with cavity and blastoid formation. In summary, spontaneous blastoid formation results from 3D culture triggering dedifferentiation of hnPSCs into earlier embryo-like intermediates which are then competent to segregate blastocyst fates.

A Shortened Diagnostic Interval and Its Associated Clinical Factors and Related Outcomes in Inflammatory Bowel Disease Patients from a Cohort Study in China.

Aim: The diagnosis of inflammatory bowel disease (IBD) worldwide is complicated and results in diagnostic delay. However, the diagnostic interval of IBD and the factors associated with diagnostic delay in patients in China have not been determined. Methods: We retrospectively analyzed clinical data of hospitalized IBD patients in Peking Union Medical College Hospital from January 1998 to January 2018. Patients were divided into non-delayed and delayed groups according to their diagnostic interval. Results: A total of 516 and 848 patients were confirmed to have Crohn's disease (CD) and ulcerative colitis (UC), respectively. The median diagnostic intervals were 6 and 20 months in patients with UC and CD, respectively (P<0.05). A decreasing trend in the diagnostic interval for IBD was observed over time, from 9 months to 1 month in UC patients and from 30 months to 3 months in CD patients. The longest diagnostic interval was 29.5 months in CD patients with first symptoms at the age of 51-60 years and 12.5 months in UC patients at the age of 41-50 years. In patients with CD, intestinal obstruction (OR=2.71), comorbid diabetes (OR=4.42), and appendectomy history (OR=2.18) were risk factors for diagnostic delay, whereas having fever as the first symptom may reduce its risk (OR=0.39). In patients with UC, the misdiagnosis of chronic enteritis (OR=2.10) was a risk factor for diagnostic delay. Conclusion: The diagnostic interval for IBD has decreased over the years. Some clinical manifestations, such as initial symptoms and age at symptom onset, may help to shorten this interval. Diseases such as tuberculosis and infectious enteritis should be considered during differentiation.

Differences in the incidence and mortality of digestive cancer between Global Cancer Observatory 2020 and Global Burden of Disease 2019.

The burden of digestive cancers is increasing worldwide. The Global Cancer Observatory (GLOBOCAN) 2020 and the Global Burden of Disease (GBD) 2019 are two primary cancer databases, which have a significant impact on policy formulation and resource allocation. We aim to compare the incidence and mortality of digestive cancers between them. Digestive cancer (esophageal, stomach, colorectal, liver, gallbladder and pancreatic cancer) incidence was obtained from the Cancer Today and GBD 2019 result tool. The top five countries with the most or minor difference between GLOBOCAN 2020 and GBD 2019 in age-standardized incidence rates (ASIRs) of digestive cancers were identified. A systematic search on the incidence of specific digestive cancer in selected countries from PubMed and Embase was conducted, and 20 of 281 publications were included. The most significant differences in digestive cancers incidence were commonly found in Asian countries (70%), particularly Indonesia, Vietnam and Myanmar, located in Southeast Asia. The ASIRs for most digestive cancers, except liver cancer, in GLOBOCAN 2020 were higher than those in GBD 2019. Gallbladder cancer had the highest average ratio, followed by liver cancer. The most commonly used standard population was Segi's standard population, followed by the World Health Organization standard population. The data sources nor the processing methods of GLOBOCAN 2020 and GBD 2019 were not similar. Low- and middle-income countries without population-based cancer registries were more likely to have selection bias in data collection and amplify regional variations of etiological factors. Better judgments on the quality of cancer data can be made.

BAG8 positively regulates cold stress tolerance by modulating photosystem, antioxidant system and protein protection in Solanum lycopersicum.

The B-cell lymphoma 2 (Bcl-2)-associated athanogene (BAG) family is a relatively conserved and multifunctional co-chaperones in animals and plants, which can flexibly interact with a variety of proteins and regulate various processes from growth and development to stress response. However, compared with animals, the function of BAG family in plant remains largely unknown, especially in response to cold stress. In this study, we have found that the expression of BAG8 was significantly induced in tomato under cold stress. Results showed that bag8 mutants exhibit significantly reduced tolerance towards cold stress, while BAG8 overexpressing lines were relatively resistant as reflected by the phenotype and membrane peroxidation. Measuring of gas exchange parameters, photosystem I (PSI) and photosystem II (PSII) of tomato leaves under cold stress further revealed that BAG8 mitigated cold-induced damage in photosynthetic system. Additionally, bag8 mutants exhibited more cold-induced reactive oxygen species, which were substantially normalized in BAG8 overexpressing plants. Nevertheless, the activities of antioxidant enzymes which were compromised in bag8 mutants were improved in BAG8 overexpressing plants facing cold stress. Additionally, BAG8 interacted with heat shock protein Hsp70 and protein phosphatase PP2A both in vitro and in vivo. Our results demonstrate that BAG8 plays a positive role in cold tolerance in tomato probably by the improvement of photosystems and antioxidant systems, and by interacting with Hsp70 involved in photosynthesis and PP2A involved in stomatal development.

Diurnal oscillations of epigenetic modifications are associated with variation in rhythmic expression of homoeologous genes in Brassica napus.

BACKGROUND: Epigenetic modifications that exhibit circadian oscillations also promote circadian oscillations of gene expression. Brassica napus is a heterozygous polyploid species that has undergone distant hybridization and genome doubling events and has a young and distinct species origin. Studies incorporating circadian rhythm analysis of epigenetic modifications can offer new insights into differences in diurnal oscillation behavior among subgenomes and the regulation of diverse expressions of homologous gene rhythms in biological clocks. RESULTS: In this study, we created a high-resolution and multioscillatory gene expression dataset, active histone modification (H3K4me3, H3K9ac), and RNAPII recruitment in Brassica napus. We also conducted the pioneering characterization of the diurnal rhythm of transcription and epigenetic modifications in an allopolyploid species. We compared the evolution of diurnal rhythms between subgenomes and observed that the Cn subgenome had higher diurnal oscillation activity in both transcription and active histone modifications than the An subgenome. Compared to the A subgenome in Brassica rapa, the An subgenome of Brassica napus displayed significant changes in diurnal oscillation characteristics of transcription. Homologous gene pairs exhibited a higher proportion of diurnal oscillation in transcription than subgenome-specific genes, attributed to higher chromatin accessibility and abundance of active epigenetic modification types. We found that the diurnal expression of homologous genes displayed diversity, and the redundancy of the circadian system resulted in extensive changes in the diurnal rhythm characteristics of clock genes after distant hybridization and genome duplication events. Epigenetic modifications influenced the differences in the diurnal rhythm of homologous gene expression, and the diurnal oscillation of homologous gene expression was affected by the combination of multiple histone modifications. CONCLUSIONS: Herein, we presented, for the first time, a characterization of the diurnal rhythm characteristics of gene expression and its epigenetic modifications in an allopolyploid species. Our discoveries shed light on the epigenetic factors responsible for the diurnal oscillation activity imbalance between subgenomes and homologous genes' rhythmic expression differences. The comprehensive time-series dataset we generated for gene expression and epigenetic modifications provides a valuable resource for future investigations into the regulatory mechanisms of protein-coding genes in Brassica napus.

From rodents to humans: Rodent behavioral paradigms for social behavioral disorders.

Social cognition guides social behavior. Subjects with proper social cognition should be able to: (1) have reasonable social motivation, (2) recognize other people and infer their intentions, and (3) weigh social hierarchies and other values. The choice of appropriate behavioral paradigms enables the use of rodents to study social behavior disorders in humans, thus enabling research to go deeper into neural mechanisms. This paper reviews commonly used rodent behavioral paradigms in studies of social behavior disorders. We focused specifically on sorting out ways to transfer the study of human social behavior to rodents through behavioral paradigms.

In vitro generation of mouse morula-like cells.

Generating cells with the molecular and functional properties of embryo cells and with full developmental potential is an aim with fundamental biological significance. Here we report the in vitro generation of mouse transient morula-like cells (MLCs) via the manipulation of signaling pathways. MLCs are molecularly distinct from embryonic stem cells (ESCs) and cluster instead with embryo 8- to 16-cell stage cells. A single MLC can generate a blastoid, and the efficiency increases to 80% when 8-10 MLCs are used. MLCs make embryoids directly, efficiently, and within 4 days. Transcriptomic analysis shows that day 4-5 MLC-derived embryoids contain the cell types found in natural embryos at early gastrulation. Furthermore, MLCs introduced into morulae segregate into epiblast (EPI), primitive endoderm (PrE), and trophectoderm (TE) fates in blastocyst chimeras and have a molecular signature indistinguishable from that of host embryo cells. These findings represent the generation of cells that are molecularly and functionally similar to the precursors of the first three cell lineages of the embryo.

Oxidative stress, the blood-brain barrier and neurodegenerative diseases: The critical beneficial role of dietary antioxidants.

In recent years, growing awareness of the role of oxidative stress in brain health has prompted antioxidants, especially dietary antioxidants, to receive growing attention as possible treatments strategies for patients with neurodegenerative diseases (NDs). The most widely studied dietary antioxidants include active substances such as vitamins, carotenoids, flavonoids and polyphenols. Dietary antioxidants are found in usually consumed foods such as fresh fruits, vegetables, nuts and oils and are gaining popularity due to recently growing awareness of their potential for preventive and protective agents against NDs, as well as their abundant natural sources, generally non-toxic nature, and ease of long-term consumption. This review article examines the role of oxidative stress in the development of NDs, explores the 'two-sidedness' of the blood-brain barrier (BBB) as a protective barrier to the nervous system and an impeding barrier to the use of antioxidants as drug medicinal products and/or dietary antioxidants supplements for prevention and therapy and reviews the BBB permeability of common dietary antioxidant suplements and their potential efficacy in the prevention and treatment of NDs. Finally, current challenges and future directions for the prevention and treatment of NDs using dietary antioxidants are discussed, and useful information on the prevention and treatment of NDs is provided.

Clinical analysis of cervical lymph node metastasis patterns and multivariate factors in differentiated thyroid carcinoma.

The incidence rate of thyroid cancer is rising rapidly in numerous parts of the world, but the mortality rate is relatively stable or even declining. The aim of the present study was to analyze the risk factors of cervical lymph node metastasis (LNM) in differentiated thyroid carcinoma (DTC). The clinical data of 846 patients with DTC were collected from the Department of General Surgery of Chifeng Municipal Hospital of Inner Mongolia Medical University (Chifeng, China) from June 2018 to June 2022. The relationship between central LNM (CLNM) and lateral LNM (LLNM) was explored in terms of sex, age, tumor diameter, multifocality, capsular invasion and Hashimoto's thyroiditis. It was revealed that male sex, age <35 years, tumor size >1 cm, multifocality and capsular invasion were associated with CLNM and LLNM (P<0.001), while there was no relationship between Hashimoto's thyroiditis, CLNM and LLNM (P>0.05). The number of positive lymph nodes in CLNM dissection, accounting for ≥50% of the total number of lymph nodes dissected, was significantly associated with LLNM (P<0.0001). In conclusion, there was no correlation between Hashimoto's thyroiditis and CLNM and LLNM. The present study revealed that patients with the characteristics of sex, age <35 years, tumor size >1 cm, multifocality and capsular invasion were associated with cervical LNM. The proportion of the number of central lymph node metastases to the total number of lymph nodes cleared during surgery is more than or equal to 50%, indicating a susceptibility to external cervical lymph node metastasis. The results of multivariate logistic analysis showed that male sex, multifocality, capsular invasion and CLNM were risk factors for LLNM, and age was a protective factor for LLNM in DTC.

Conjugated linoleic acid (CLA) as a functional food: Is it beneficial or not?

Conjugated linoleic acid (CLA) has attracted great attention in recent years as a popular class of functional food that is broadly used. It refers to a group of geometric and positional isomers of linoleic acid (LA) with a conjugated double bond. The main natural sources of CLA are dairy products, beef and lamb, whereas only trace amounts occur naturally in plant lipids. CLA has been shown to improve various health issues, having effects on obesity, inflammatory, anti-carcinogenicity, atherogenicity, immunomodulation, and osteosynthesis. Also, compared to studies on humans, many animal researches reveal more positive benefits on health. CLA represents a nutritional avenue to improve lifestyle diseases and metabolic syndrome. Most of these effects are attributed to the two major CLA isomers [conjugated linoleic acid cis-9,trans-11 isomer (c9,t11), and conjugated linoleic acid trans-10,cis-12 isomer (t10,c12)], and their mixture (CLA mix). In contrast, adverse effects of CLA have been also reported, such as glucose homeostasis, insulin resistance, hepatic steatosis and induction of colon carcinogenesis in humans, as well as milk fat inhibition in ruminants, lowering chicken productivity, influencing egg quality and altering growth performance in fish. This review article aims to discuss the health benefits of CLA as a nutraceutical supplement and highlight the possible mechanisms of action that may contribute to its outcome. It also outlines the feasible adverse effects of CLA besides summarizing the recent peer-reviewed publications on CLA to ensure its efficacy and safety for proper application in humans.

Autophagy promotes jasmonate-mediated defense against nematodes.

Autophagy, as an intracellular degradation system, plays a critical role in plant immunity. However, the involvement of autophagy in the plant immune system and its function in plant nematode resistance are largely unknown. Here, we show that root-knot nematode (RKN; Meloidogyne incognita) infection induces autophagy in tomato (Solanum lycopersicum) and different atg mutants exhibit high sensitivity to RKNs. The jasmonate (JA) signaling negative regulators JASMONATE-ASSOCIATED MYC2-LIKE 1 (JAM1), JAM2 and JAM3 interact with ATG8s via an ATG8-interacting motif (AIM), and JAM1 is degraded by autophagy during RKN infection. JAM1 impairs the formation of a transcriptional activation complex between ETHYLENE RESPONSE FACTOR 1 (ERF1) and MEDIATOR 25 (MED25) and interferes with transcriptional regulation of JA-mediated defense-related genes by ERF1. Furthermore, ERF1 acts in a positive feedback loop and regulates autophagy activity by transcriptionally activating ATG expression in response to RKN infection. Therefore, autophagy promotes JA-mediated defense against RKNs via forming a positive feedback circuit in the degradation of JAMs and transcriptional activation by ERF1.

Bilineage embryo-like structure from EPS cells can produce live mice with tetraploid trophectoderm.

Self-organized blastoids from extended pluripotent stem (EPS) cells possess enormous potential for investigating postimplantation embryo development and related diseases. However, the limited ability of postimplantation development of EPS-blastoids hinders its further application. In this study, single-cell transcriptomic analysis indicated that the "trophectoderm (TE)-like structure" of EPS-blastoids was primarily composed of primitive endoderm (PrE)-related cells instead of TE-related cells. We further identified PrE-like cells in EPS cell culture that contribute to the blastoid formation with TE-like structure. Inhibition of PrE cell differentiation by inhibiting MEK signaling or knockout of Gata6 in EPS cells markedly suppressed EPS-blastoid formation. Furthermore, we demonstrated that blastocyst-like structures reconstituted by combining the EPS-derived bilineage embryo-like structure (BLES) with either tetraploid embryos or tetraploid TE cells could implant normally and develop into live fetuses. In summary, our study reveals that TE improvement is critical for constructing a functional embryo using stem cells in vitro.

CFAGO: cross-fusion of network and attributes based on attention mechanism for protein function prediction.

MOTIVATION: Protein function annotation is fundamental to understanding biological mechanisms. The abundant genome-scale protein-protein interaction (PPI) networks, together with other protein biological attributes, provide rich information for annotating protein functions. As PPI networks and biological attributes describe protein functions from different perspectives, it is highly challenging to cross-fuse them for protein function prediction. Recently, several methods combine the PPI networks and protein attributes via the graph neural networks (GNNs). However, GNNs may inherit or even magnify the bias caused by noisy edges in PPI networks. Besides, GNNs with stacking of many layers may cause the over-smoothing problem of node representations. RESULTS: We develop a novel protein function prediction method, CFAGO, to integrate single-species PPI networks and protein biological attributes via a multi-head attention mechanism. CFAGO is first pre-trained with an encoder-decoder architecture to capture the universal protein representation of the two sources. It is then fine-tuned to learn more effective protein representations for protein function prediction. Benchmark experiments on human and mouse datasets show CFAGO outperforms state-of-the-art single-species network-based methods by at least 7.59%, 6.90%, 11.68% in terms of m-AUPR, M-AUPR, and Fmax, respectively, demonstrating cross-fusion by multi-head attention mechanism can greatly improve the protein function prediction. We further evaluate the quality of captured protein representations in terms of Davies Bouldin Score, whose results show that cross-fused protein representations by multi-head attention mechanism are at least 2.7% better than that of original and concatenated representations. We believe CFAGO is an effective tool for protein function prediction. AVAILABILITY AND IMPLEMENTATION: The source code of CFAGO and experiments data are available at: http://bliulab.net/CFAGO/.

Micronutrient perspective on COVID-19: Umbrella review and reanalysis of meta-analyses.

INTRODUCTION: Micronutrients are clinically important in managing COVID-19, and numerous studies have been conducted, but inconsistent findings exist. OBJECTIVE: To explore the association between micronutrients and COVID-19. METHODS: PubMed, Web of Science, Embase, Cochrane Library and Scopus for study search on July 30, 2022 and October 15, 2022. Literature selection, data extraction and quality assessment were performed in a double-blinded, group discussion format. Meta-analysis with overlapping associations were reconsolidated using random effects models, and narrative evidence was performed in tabular presentations. RESULTS: 57 reviews and 57 latest original studies were included. 21 reviews and 53 original studies were of moderate to high quality. Vitamin D, vitamin B, zinc, selenium, and ferritin levels differed between patients and healthy people. Vitamin D and zinc deficiencies increased COVID-19 infection by 0.97-fold/0.39-fold and 1.53-fold. Vitamin D deficiency increased severity 0.86-fold, while low vitamin B and selenium levels reduced severity. Vitamin D and calcium deficiencies increased ICU admission by 1.09 and 4.09-fold. Vitamin D deficiency increased mechanical ventilation by 0.4-fold. Vitamin D, zinc, and calcium deficiencies increased COVID-19 mortality by 0.53-fold, 0.46-fold, and 5.99-fold, respectively. CONCLUSION: The associations between vitamin D, zinc, and calcium deficiencies and adverse evolution of COVID-19 were positive, while the association between vitamin C and COVID-19 was insignificant.REGISTRATION: PROSPERO CRD42022353953.

TAGLN2 promotes papillary thyroid carcinoma invasion via the Rap1/PI3K/AKT axis.

TAGLN2, an actin-binding protein, functions as a binding protein to actin to facilitate the formation of intracellular cytoskeleton structures. TAGLN2 overexpression in papillary thyroid carcinoma (PTC) is reported in our previous study. This study aimed to examine the functions and molecular mechanisms of TAGLN2 in PTC. The clinical data analysis showed that TAGLN2 expression was associated with cervical lymph node metastasis in PTC. Gain- and loss-of-function approaches, as well as various cellular function, gene expression profiles, quantitative proteomics, and molecular biology experiments, were further exploited to explore the roles of TAGLN2 in PTC. The results showed that TAGLN2 overexpression significantly promoted the invasion of PTC cell lines (K1, TPC-1, and BCPAP). Besides, the results also indicated that TAGLN2 was associated with regulating proliferation, migration, angiogenesis, and adhesion of PTC cells. Gene expression profile, quantitative proteomics, and Western blotting were performed to identify the relevant pathways and key downstream molecules, and Rap1/PI3K/AKT signalling pathway, ITGB5, LAMC2, CRKL, vimentin, N-cadherin, and E-cadherin were finally focused on. Moreover, rescue experiments validated the involvement of the Rap1/PI3K/AKT signalling pathway in the TAGLN2-mediated invasion of PTC cells. Therefore, TAGLN2 may promote the invasion of PTC cells via the Rap1/PI3K/AKT signalling pathway and may be served as a potential therapeutic target for PTC. Developing antagonists targeting TAGLN2 may be a potentially effective therapeutic strategy for PTC.