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Background There is an increasing prevalence of cardiovascular disease (CVD) in China, which represents the leading cause of mortality. Precise CVD risk identification is the fundamental prevention component. This study sought to systematically review the CVD risk prediction models derived and/or validated in the Chinese population to promote primary CVD prevention. Methods Reports were included if they derived or validated one or more CVD risk prediction models in the Chinese population. PubMed, Embase, CINAHL, Web of Science, Scopus, China National Knowledge Infrastructure (CNKI), VIP database , etc. , were searched. The risk of bias was assessed with the Prediction Model Risk of Bias Assessment Tool (PROBAST). Meta-analysis was performed in R using the package metamisc. Results From 55,183 records, 22 studies were included. Twelve studies derived 18 CVD risk prediction models, of which seven models were derived based on a multicentre cohort including more than two provinces of mainland China, and one was a model developed based on a New Zealand cohort including Chinese individuals. The number of predictors ranged from 6 to 22. The definitions of predicted outcomes showed considerable heterogeneity. Fourteen articles described 29 validations of 8 models. The Framingham model and pooled cohort equations (PCEs) are the most frequently validated foreign tools. Discrimination was acceptable and similar for men and women among models (0.60–0.83). The calibration estimates changed substantially from one population to another. Prediction for atherosclerotic cardiovascular disease Risk in China (China-PAR) showed good calibration [observed/expected events ratio = 0.99, 95% PI (0.57,1.70)] and female sex [1.10, 95% PI (0.23,5.16)]. Conclusions Several models have been developed or validated in the Chinese population. The usefulness of most of the models remains unclear due to incomplete external validation and head-to-head comparison. Future research should focus on externally validating or tailoring these models to local settings. Trail registration This systematic review was registered at PROSPERO (International Prospective Register of Systematic Reviews, CRD42021277453).

In clinical nursing, neonatal pain assessment is a challenging task for preventing and controlling the impact of pain on neonatal development. To reduce the adverse effects of repetitive painful treatments during hospitalization on newborns, we propose a novel method (namely pain concept-cognitive computing model, PainC3M) for evaluating facial pain in newborns. In the fusion system, we first improve the attention mechanism of vision transformer by revising the node encoding way, considering the spatial structure, edge and centrality of nodes, and then use its corresponding encoder as a feature extractor to comprehensively extract image features. Second, we introduce a concept-cognitive computing model as a classifier to evaluate the level of pain. Finally, we evaluate our PainC3M on various open pain data sets and a real clinical pain data stream, and the experimental results demonstrate that our PainC3M is very effective for dynamic classification and superior to other comparative models. It also provides a good approach for pain assessment of individuals with aphasia (or dementia).

The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling 1 and is altered in over 20% of cancers 2 , 3 . Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR) + forkhead box A1 (FOXA1) + prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis -regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supra-physiologic expression of the AR , FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumour growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers. PROTAC degrader–induced SWI/SNF inactivation abolishes DNA accessibility at enhancer elements of oncogenes and also tempers supra-physiologic expression of driver transcription factors, resulting in potent inhibition of tumour growth in mouse models.

Background Health Information-Seeking Behaviour (HISB) is necessary for self-management and medical decision-making among patients with inflammatory bowel disease (IBD). With the advancement of information technology, health information needs and seeking are reshaped among patients with IBD. This scoping review aims to gain a comprehensive understanding of HISB of people with IBD in the digital age. Methods This scoping review adhered to Arksey and O'Malley's framework and Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews frameworks (PRISMA-ScR). A comprehensive literature search was conducted in PubMed, Embase, Web of Science, PsycINFO, CINAHL, and three Chinese databases from January 1, 2010 to April 10, 2023. Employing both deductive and inductive content analysis, we scrutinized studies using Wilson's model. Results In total, 56 articles were selected. Within the information dimension of HISB among patients with IBD, treatment-related information, particularly medication-related information, was identified as the most critical information need. Other information requirements included basic IBD-related information, daily life and self-management, sexual and reproductive health, and other needs. In the sources dimension, of the eight common sources of information, the internet was the most frequently mentioned source of information, while face-to-face communication with healthcare professionals was the preferred source. Associated factors were categorized into six categories: demographic characteristics, psychological aspects, role-related or interpersonal traits, environmental aspects, source-related characteristics, and disease-related factors. Moreover, the results showed five types of HISB among people with IBD, including active searching, ongoing searching, passive attention, passive searching, and avoid seeking. Notably, active searching, especially social information seeking, appeared to be the predominant common type of HISB among people with IBD in the digital era. Conclusion Information needs and sources for patients with IBD exhibit variability, and their health information-seeking behaviour is influenced by a combination of diverse factors, including resource-related and individual factors. Future research should focus on the longitudinal changes in HISB among patients with IBD. Moreover, efforts should be made to develop information resources that are both convenient and provide credible information services, although the development of such resources requires further investigation and evaluation.

Immunotherapy with immune checkpoint inhibitors (ICIs) for solid tumors had significantly improved overall survival. This type of therapy is still not available for acute myeloid leukemia (AML). One major issue is the lack of knowledge for the expression patterns of immune checkpoints (IC) in AML. In this study, we first explored the prognostic value of ICs for AML patients by analyzing RNA-seq and mutation data from 176 AML patients from the Cancer Genome Atlas (TCGA) database. We further validated the results of the database analysis by analyzing bone marrow (BM) samples from 62 patients with de novo AML. Both TCGA data and validation results indicated that high expression of PD-1, PD-L1, and PD-L2 was associated with poor overall survival (OS) in AML patients. In addition, increased co-expression of PD-1/CTLA-4 or PD-L2/CTLA-4 correlated with poor OS in AML patients (3-year OS: TGCA data 30% vs 0% and 20% vs 0%, validation group 57% vs 31% and 57% vs 33%, respectively) ( P < 0.05). Moreover, co-expression of PD-1/PD-L1, PD-1/PD-L1/PD-L2, and PD-1/LAG-3 was found to correlate with poor OS in AML patients with FLT3 mut , RUNX1 mut , and TET2 mut , respectively. In conclusion, high expression of ICs in the BM leukemia cells of AML patients correlated with poor outcome. The co-expression patterns of PD-1/CTLA-4, PD-L2/CTLA-4, PD-1/PD-L1, PD-1/PD-L1/PD-L2, and PD-1/LAG-3 might be potential immune biomarkers for designing novel AML therapy.

Background RNA secondary structure has broad impact on the fate of RNA metabolism. The reduced stability of secondary structures near the translation initiation site/start codon of the coding region promotes the efficiency of translation in both prokaryotic and eukaryotic species. However, the inaccuracy of in silico folding and the focus on the coding region limit our understanding of the global relationship between the whole mRNA structure and translation efficiency. Leveraging high-throughput RNA structure probing data in the transcriptome, we aim to systematically investigate the role of RNA structure in regulating translation efficiency. Results Here, we analyze the influences of hundreds of sequence and structural features on translation efficiency in the mouse embryonic stem cells (mESCs) and zebrafish developmental stages. Our findings reveal that overall in vivo RNA structure has a higher relative importance in predicting translation efficiency than in vitro RNA structure in both mESCs and zebrafish. Also, RNA structures in 3’ untranslated region (UTR) have much stronger influence on translation efficiency compared to those in coding regions or 5' UTR. Furthermore, strong alternation between in vitro and in vivo structures in 3' UTR are detected in highly translated mRNAs in mESCs but not zebrafish. Instead, moderate alteration between in vitro and in vivo RNA structures in the 5’ UTR and proximal coding regions are detected in highly translated mRNAs in zebrafish. Conclusions Our results suggest the openness of the 3’ UTR promotes the translation efficiency in both mice and zebrafish, with the in vivo structure in 3’ UTR more important in mice than in zebrafish. This reveals a novel role of RNA secondary structure on translational regulation.

Abtract Forkhead box A1 (FOXA1) is a pioneer transcription factor that is essential for the normal development of several endoderm-derived organs, including the prostate gland 1 , 2 . FOXA1 is frequently mutated in hormone-receptor-driven prostate, breast, bladder and salivary-gland tumours 3 – 8 . However, it is unclear how FOXA1 alterations affect the development of cancer, and FOXA1 has previously been ascribed both tumour-suppressive 9 – 11 and oncogenic 12 – 14 roles. Here we assemble an aggregate cohort of 1,546 prostate cancers and show that FOXA1 alterations fall into three structural classes that diverge in clinical incidence and genetic co-alteration profiles, with a collective prevalence of 35%. Class-1 activating mutations originate in early prostate cancer without alterations in ETS or SPOP, selectively recur within the wing-2 region of the DNA-binding forkhead domain, enable enhanced chromatin mobility and binding frequency, and strongly transactivate a luminal androgen-receptor program of prostate oncogenesis. By contrast, class-2 activating mutations are acquired in metastatic prostate cancers, truncate the C-terminal domain of FOXA1, enable dominant chromatin binding by increasing DNA affinity and—through TLE3 inactivation—promote metastasis driven by the WNT pathway. Finally, class-3 genomic rearrangements are enriched in metastatic prostate cancers, consist of duplications and translocations within the FOXA1 locus, and structurally reposition a conserved regulatory element—herein denoted FOXA1 mastermind (FOXMIND)—to drive overexpression of FOXA1 or other oncogenes. Our study reaffirms the central role of FOXA1 in mediating oncogenesis driven by the androgen receptor, and provides mechanistic insights into how the classes of FOXA1 alteration promote the initiation and/or metastatic progression of prostate cancer. These results have direct implications for understanding the pathobiology of other hormone-receptor-driven cancers and rationalize the co-targeting of FOXA1 activity in therapeutic strategies. Comprehensive genomic analyses and mechanistic studies uncover three structural, functional and clinical classes of activating FOXA1 mutations and locus rearrangements in prostate cancer.

The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly identified and translated to clinical care. Traditional drug discovery methods have a >90% failure rate and can take 10 to 15 y from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious agents against SARS-CoV-2. From a library of 1,425 US Food and Drug Administration (FDA)-approved compounds and clinical candidates, we identified 17 hits that inhibited SARS-CoV-2 infection and analyzed their antiviral activity across multiple cell lines, including lymph node carcinoma of the prostate (LNCaP) cells and a physiologically relevant model of alveolar epithelial type 2 cells (iAEC2s). Additionally, we found that inhibitors of the Ras/Raf/MEK/ERK signaling pathway exacerbate SARS-CoV-2 infection in vitro. Notably, we discovered that lactoferrin, a glycoprotein found in secretory fluids including mammalian milk, inhibits SARS-CoV-2 infection in the nanomolar range in all cell models with multiple modes of action, including blockage of virus attachment to cellular heparan sulfate and enhancement of interferon responses. Given its safety profile, lactoferrin is a readily translatable therapeutic option for the management of COVID-19.

Background The use of mulberry leaves has long been limited to raising silkworms, but with the continuous improvement of mulberry ( Morus alba ) resource development and utilization, various mulberry leaf extension products have emerged. However, the fresh leaves of mulberry trees have a specific window of time for picking and are susceptible to adverse factors, such as drought stress. Therefore, exploring the molecular mechanism by which mulberry trees resist drought stress and clarifying the regulatory network of the mulberry drought response is the focus of the current work. Results In this study, natural and drought-treated mulberry grafted seedlings were used for transcriptomic and proteomic analyses (CK vs. DS9), aiming to clarify the molecular mechanism of the mulberry drought stress response. Through transcriptome and proteome sequencing, we identified 9889 DEGs and 1893 DEPs enriched in stress-responsive GO functional categories, such as signal transducer activity, antioxidant activity, and transcription regulator activity. KEGG enrichment analysis showed that a large number of codifferentially expressed genes were enriched in flavonoid biosynthesis pathways, hormone signalling pathways, lignin metabolism and other pathways. Through subsequent cooperation analysis, we identified 818 codifferentially expressed genes in the CK vs. DS9 comparison group, including peroxidase ( POD ), superoxide dismutase ( SOD ), aldehyde dehydrogenase ( ALDHs ), glutathione s-transferase ( GST ) and other genes closely related to the stress response. In addition, we determined that the mulberry gene MaWRKYIII8 (XP_010104968.1) underwent drought- and abscisic acid (ABA)-induced expression, indicating that it may play an important role in the mulberry response to drought stress. Conclusions Our research shows that mulberry can activate proline and ABA biosynthesis pathways and produce a large amount of proline and ABA, which improves the drought resistance of mulberry. MaWRKYIII8 was up-regulated and induced by drought and exogenous ABA, indicating that MaWRKYIII8 may be involved in the mulberry response to drought stress. These studies will help us to analyse the molecular mechanism underlying mulberry drought tolerance and provide important gene information and a theoretical basis for improving mulberry drought tolerance through molecular breeding in the future.

DNA methylation plays a significant role in many biological processes. Although some studies of DNA methylation have been performed in woody plant, none is known about the methylation patterns of mulberry ( Morus alba ). In this study, we performed whole genome bisulfite sequencing under drought stress to generate a methylated cytosines map and assessed the effects of the changes on gene expression combined with transcriptomics. We found that the percentage of methylated cytosines varied depending on the local sequence context (CG, CHG and CHH) and external treatment (control, CK; drought stress, DS). The methylation levels under DS were 8.64% higher than that of CK, and differences that were mainly due to the contribution of mCG (6.24%). Additionally, there were 3,243 different methylation and expression associated genes. In addition, methylated genes were enriched within GO subcategories including catalytic activity, cellular process, metabolic process, response to stimulus and regulation of biological process. This is the first study to comprehensively present methylation patterns in mulberry and reveal widespread DNA methylation changes in response to drought stress, which has the potential to enhance our understanding of links between DNA methylation and the modulation of gene expression in plants subjected to abiotic stresses.