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Abstract Background Depression is prevalent among lung cancer patients undergoing chemotherapy, and the symptom cluster of fatigue-pain-insomnia may influence their depression. Identifying characteristics of patients with different depression trajectories can aid in developing more targeted interventions. This study aimed to identify the trajectories of depression and the fatigue-pain-insomnia symptom cluster, and to explore the predictive factors associated with the categories of depression trajectories. Methods In this longitudinal study, 187 lung cancer patients who were undergoing chemotherapy were recruited and assessed at the first (T1), second(T2), and fourth(T3) months using the Patient Health Questionnaire-9 (PHQ-9), the Brief Pain Inventory (BPI), the Brief Fatigue Inventory (BFI), and the Athens Insomnia Scale (AIS). Growth Mixture Model (GMM) and Latent Class Analysis (LCA) were used to identify the different trajectories of the fatigue-pain-insomnia symptom cluster and depression. Binary logistic regression was utilized to analyze the predictive factors of different depressive trajectories. Results GMM identified two depressive trajectories: a high decreasing depression trajectory (40.64%) and a low increasing depression trajectory (59.36%). LCA showed that 48.66% of patients were likely members of the high symptom cluster trajectory. Binary logistic regression analysis indicated that having a history of alcohol consumption, a higher symptom cluster burden, unemployed, and a lower monthly income predicted a high decreasing depression trajectory. Conclusions Depression and fatigue-pain-insomnia symptom cluster in lung cancer chemotherapy patients exhibited two distinct trajectories. When managing depression in these patients, it is recommended to strengthen symptom management and pay particular attention to individuals with a history of alcohol consumption, unemployed, and a lower monthly income.

Abstract The “hologenome” concept is an increasingly popular way of thinking about microbiome-host for marine organisms. However, it is challenging to track hologenome dynamics because of the large amount of material, with tracking itself usually resulting in damage or death of the research object. Here we show the simple and efficient holo-2bRAD approach for the tracking of hologenome dynamics in marine invertebrates (i.e., scallop and shrimp) from one holo-2bRAD library. The stable performance of our approach was shown with high genotyping accuracy of 99.91% and a high correlation of r > 0.99 for the species-level profiling of microorganisms. To explore the host-microbe association underlying mass mortality events of bivalve larvae, core microbial species changed with the stages were found, and two potentially associated host SNPs were identified. Overall, our research provides a powerful tool with various advantages (e.g., cost-effective, simple, and applicable for challenging samples) in genetic, ecological, and evolutionary studies.

Summary: Background: Traumatic brain injury is conventionally categorised as mild, moderate, or severe on the Glasgow Coma Scale (GCS). Recently developed biomarkers can provide more objective and nuanced measures of the extent of brain injury. Methods: Exposure–response relationships were investigated in 2479 patients aged ≥16 enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. Neurofilament protein-light (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) were assayed from serum sampled in the first 24 h; concentrations were divided into quintiles within GCS severity groups. Relationships with the Glasgow Outcome Scale-Extended were examined using modified Poisson regression including age, sex, major extracranial injury, time to sample, and log biomarker concentration as covariates. Findings: Within severity groups there were associations between biomarkers and outcomes after adjustment for covariates: GCS 13–15 and negative CT imaging (relative risks [RRs] from 1.28 to 3.72), GCS 13–15 and positive CT (1.21–2.81), GCS 9–12 (1.16–2.02), GCS 3–8 (1.09–1.94). RRs were associated with clinically important differences in expectations of prognosis. In patients with GCS 3 (RRs 1.51–1.80) percentages of unfavourable outcome were 37–51% in the lowest quintiles of biomarker levels and reached 90–94% in the highest quintiles. Similarly, for GCS 15 (RRs 1.83–3.79), the percentages were 2–4% and 19–28% in the lowest and highest biomarker quintiles, respectively. Interpretation: Conventional TBI severity classification is inadequate and underestimates heterogeneity of brain injury and associated outcomes. The adoption of circulating biomarkers can add to clinical assessment of injury severity. Funding: European Union 7th Framework program (EC grant 602150), Hannelore Kohl Stiftung, One Mind, Integra LifeSciences, Neuro-Trauma Sciences, NIHR Rosetrees Trust.

Abstract Mitogen-activated protein kinase inhibitors (MAPKi) were the first line drugs for advanced melanoma patients with BRAF mutation. Targeted therapies have significant therapeutic effects; however, drug resistance hinders their long-term efficacy. Therefore, the development of new therapeutic strategies against MAPKi resistance is critical. Our previous results showed that MAPKi promote feedback activation of STAT3 signaling in BRAF-mutated cancer cells. Studies have shown that alantolactone inhibited the activation of STAT3 in a variety of tumor cells. Our results confirmed that alantolactone suppressed cell proliferation and promoted apoptosis by inhibiting STAT3 feedback activation induced by MAPKi and downregulating the expression of downstream Oct4 and Sox2. The inhibitory effect of alantolactone combined with a MAPKi on melanoma cells was significantly stronger than that on normal cells. In vivo and in vitro experiments showed that combination treatment was effective against drug-resistant melanomas. Our research indicates a potential novel combination therapy (alantolactone and MAPKi) for patients with BRAF-mutated melanoma.

Abstract Neonatal Encephalopathy (NE) is a major cause of lifelong disability and neurological complications in affected infants. Identifying novel diagnostic biomarkers in this population may assist in predicting MRI injury and differentiate neonates with NE from those with low-cord pH or healthy neonates and may help clinicians make real-time decisions. To compare the microRNA (miRNA) profiles between neonates with NE, healthy controls, and neonates with low cord pH. Moreover, miRNA concentrations were compared to brain injury severity in neonates with NE. This is a retrospective analysis of miRNA profiles from select samples in the biorepository and data registry at the University of Florida Health Gainesville. The Firefly miRNA assay was used to screen a total of 65 neurological miRNA targets in neonates with NE (n = 36), low cord pH (n = 18) and healthy controls (n = 37). Multivariate statistical techniques, including principal component analysis and orthogonal partial least squares discriminant analysis, and miRNA Enrichment Analysis and Annotation were used to identify miRNA markers and their pathobiological relevance. A set of 10 highly influential miRNAs were identified, which were significantly upregulated in the NE group compared to healthy controls. Of these, miR-323a-3p and mir-30e-5p displayed the highest fold change in expression levels. Moreover, miR-34c-5p, miR-491-5p, and miR-346 were significantly higher in the NE group compared to the low cord pH group. Furthermore, several miRNAs were identified that can differentiate between no/mild and moderate/severe injury in the NE group as measured by MRI. MiRNAs represent promising diagnostic and prognostic tools for improving the management of NE.

Prostate cancer (PCa) is the second leading cause of cancer-related death among men in western countries. Evidence has indicated the significant role of the androgen receptor (AR) as the main driving factor in controlling the development of PCa, making androgen receptor inhibition (ARI) therapy a pivotal management approach. In addition, AR independent signaling pathways also contribute to PCa progression. One such signaling pathway that has garnered our attention is N6-Methyladenosine (m6A) signaling, which refers to a chemical modification on RNA with crucial roles in RNA metabolism and disease progression, including PCa. It is important to comprehensively summarize the role of each individual m6A regulator in PCa development and understand its interaction with AR signaling. This review aims to provide a thorough summary of the involvement of m6A regulators in PCa development, shedding light on their upstream and downstream signaling pathways. This summary sets the stage for a comprehensive review that would benefit the scientific community and clinical practice by enhancing our understanding of the biology of m6A regulators in the context of PCa.

ABSTRACT Previous work identified a pair of specific effectors AsCEP19 and AsCEP20 in Alternaria solani as contributors to the virulence of A. solani. Here, we constructed AsCEP19 and AsCEP20 deletion mutants in A. solani strain HWC168 to further reveal the effects of these genes on the biology and pathogenicity of A. solani. Deletion of AsCEP19 and AsCEP20 did not affect vegetative growth but did affect conidial maturation, with an increase in the percentage of abnormal conidia produced. Furthermore, we determined the expression patterns of genes involved in the conidiogenesis pathway and found that the regulatory gene abaA was significantly upregulated and chsA, a positive regulator for conidiation, was significantly downregulated in the mutant strains compared to the wild-type strain. These results suggest that AsCEP19 and AsCEP20 indirectly affect the conidial development and maturation of A. solani. Pathogenicity assays revealed significantly impaired virulence of ΔAsCEP19, ΔAsCEP20, and ΔAsCEP19 + AsCEP20 mutants on potato and tomato plants. Moreover, we performed localization assays with green fluorescent protein-tagged proteins in chili pepper leaves. We found that AsCEP19 can specifically localize to the chloroplasts of chili pepper epidermal cells, while AsCEP20 can localize to both chloroplasts and the plasma membrane. Weighted gene co-expression network analysis revealed enrichment of genes of this module in the photosynthesis pathway, with many hub genes associated with chloroplast structure and photosynthesis. These results suggest that chloroplasts are the targets for AsCEP19 and AsCEP20.IMPORTANCEAlternaria solani is an important necrotrophic pathogen causing potato early blight. Previous studies have provide preliminary evidence that specific effectors AsCEP19 and AsCEP20 contribute to virulence, but their respective functions, localization, and pathogenic mechanisms during the infection process of A. solani remain unclear. Here, we have systematically studied the specific effectors AsCEP19 and AsCEP20 for the first time, which are essential for conidial maturation. The deletion of AsCEP19 and AsCEP20 can significantly impair fungal pathogenicity. Additionally, we preliminarily revealed that AsCEP19 and AsCEP20 target the chloroplasts of host cells. Our findings further enhance our understanding of the molecular mechanisms underlying the virulence of necrotrophic pathogens.

Currently, heterosis is an effective method for achieving high crop quality and yield worldwide. Owing to the challenges of breeding and the high cost of the F1 generation, the F2 generation is considered the more desirable hybrid offspring for agricultural production. The use of OJIP fluorescence provides rapid insights into various photosynthetic mechanisms. However, OJIP fluorescence has not been previously studied as an indicator of the rate of heterosis. Consequently, we investigated the relationship between photosynthetic characteristics and growth and developmental parameters in hybrid cotton cultivars. The findings showed a gradual decline in the photosynthetic performance of hybrid cotton as the number of generations increased. In comparison to the F3 generation, both the F1 and F2 generations showed minimal variations in parameters, thus maintaining hybrid dominant and emphasizing the agricultural production potential of the F2 generation. The JIP-test revealed significant differences in the relationship between ψEo and ϕEo parameters, as well as variations in the connections between the photo-response center and electron transfer efficiency, and between cotton yield and fiber quality in the hybrid progeny. These variations can serve as indicators for predicting the extent of hybrid dominance in cotton. The results indicated significant differences in the light and dark responses of the hybrid offspring. By using parents with similar photosynthetic performance as genetic resources for crossbreeding, the photosynthetic capacity of the hybrid progeny can be enhanced to facilitate the efficient absorption and conversion of light energy in crops.

Heterologous prime-boost has broken the protective immune response bottleneck of the COVID-19 vaccines. however, the underlying mechanisms have not been fully elucidated. Here, we investigated antibody responses and explored the response of germinal center (GC) to priming with inactivated vaccines and boosting with heterologous adenoviral-vectored vaccines or homologous inactivated vaccines in mice. Antibody responses were dramatically enhanced by both boosting regimens. Heterologous immunization induced more robust GC activation, characterized by increased Tfh cell populations and enhanced helper function. Additionally, increased B-cell activation and antibody production were observed in a heterologous regimen. Libra-seq was used to compare the differences of S1-, S2- and NTD-specific B cells between homologous and heterologous vaccination, respectively. S2-specific CD19+ B cells presented increased somatic hypermutations (SHMs), which were mainly enriched in plasma cells. Moreover, a heterologous booster dose promoted the clonal expansion of B cells specific to S2 and NTD regions. In conclusion, the functional role of Tfh and B cells following SARS-CoV-2 heterologous vaccination may be important for modulating antibody responses. These findings provide new insights for the development of SARS-CoV-2 vaccines that induce more robust antibody response.

Abstract Background With social transformation, rapid economic development and deepening awareness of psychological health in China, people’s demand for psychological health services is becoming increasingly urgent. A key challenge for Chinese medical organizations is to train enough qualified psychological care nurses. A greater understanding of psychological care competences (PCC) can help in clinical nurse selection, training, and assessment. Objective To develop a PCC framework for Chinese nurses and obtain a consensus on the framework among experts. Methods A descriptive mixed methods study was designed consisting of a literature review and semi-structured interviews followed by three Delphi rounds. The experts (n = 16) involved were nurses, nursing managers and educators from nine Chinese provinces with a specific interest in psychological care. Descriptive statistics assisted in data analysis. Results Using the Iceberg Model as a theoretical foundation, five main dimensions and associated subdomains were integrated from 39 chosen articles. The semi-structured interviews with 24 nursing managers and nurses confirmed all of the themes from the literature review while generating new themes, both of which were incorporated into the initial PCC framework. After three Delphi rounds, the experts reached consensus on the PCC framework, including five domains (knowledge, skills, professional ethics, personal traits, internal motivations) and 22 subdomains with connotations. The response rate (RR) values for the three rounds of consultation were 80.00%, 87.50% and 92.86%, the composite reliability (Cr) values were 0.89–0.90, and the Kendall coordination coefficients were 0.155-0.200 (P

Due to the regular influence of human activities, traffic flow data usually exhibit significant periodicity, which provides a foundation for further research on traffic flow data. However, the temporal dependencies in traffic flow data are often obscured by entangled temporal regularities, making it challenging for general models to capture the intrinsic functional relationships within the data accurately. In recent years, a plethora of methods based on statistics, machine learning, and deep learning have been proposed to tackle these problems of traffic flow forecasting. In this paper, the Transformer is improved from two aspects: (1) an Efficient Attention mechanism is proposed, which reduces the time and memory complexity of the Scaled Dot Product Attention; (2) a Generative Decoding mechanism instead of a Dynamic Decoding operation, which accelerates the inference speed of the model. The model is named EGFormer in this paper. Through a lot of experiments and comparative analysis, the authors found that the EGFormer has better ability in the traffic flow forecasting task. The new model has higher prediction accuracy and shorter running time compared with the traditional model.

Abstract Background Mental health literacy is considered an important factor in promoting professional psychological help-seeking attitudes. However, it is important to clarify the emotional and behavioral factors that underlie this association. Drawing from the ABC model of attitudes and the Health Disclosure Decision-Making Model, this study aimed to examine the mediating role of psychological help-seeking stigma and distress disclosure in the relationship between mental health literacy and professional psychological help-seeking attitudes. Methods We collected data from 827 participants in seven regions of China (597 female; M age = 26.019, SD = 5.592 years old) using self-report measures, including the Mental Health Literacy Scale, Questionnaire of Stigma for Seeking Professional Psychological Help, Distress Disclosure Index, and Attitudes Toward Seeking Professional Psychological Help-Short Form. A chain mediation model was built to examine the relationships among mental health literacy, psychological help-seeking stigma, distress disclosure, and professional psychological help-seeking attitudes. Results The results of the analyses showed a positive association between mental health literacy and professional psychological help-seeking attitudes, with psychological help-seeking stigma and distress disclosure playing mediating roles in this relationship. Furthermore, even after controlling for participants’ age, gender, and education, the chain mediation effect of psychological help-seeking stigma and distress disclosure on the relationship between mental health literacy and professional psychological help-seeking attitudes was observed among the Chinese population. Conclusions These findings underscore the significance of mental health literacy in shaping professional psychological help-seeking attitudes, while emphasizing the need to account for psychological help-seeking stigma and distress disclosure when examining this association. Additionally, the model proposed in this study provides a valuable framework for promoting the utilization of professional mental health services.

BackgroundThe association between psoriasis vulgaris and bullous pemphigoid (BP) remains largely unknown.ObjectivesTo investigate whether there is a causal effect between psoriasis vulgaris and BP.MethodsTwo-sample bidirectional Mendelian randomization (MR) analyses were conducted using publicly released genome-wide association studies (GWAS) summary statistics. The GWAS summary statistics for BP were downloaded online from FinnGen Biobank Documentation of the R12 release, which includes 219 BP cases and 218,066 controls. The GWAS data for psoriasis vulgaris were extracted from Sakaue et al., which comprises 5072 cases and 478,102 controls. Single-nucleotide polymorphisms (SNPs) associated with exposure were selected as instrumental variables by performing additional quality control steps. The inverse-variance-weighted (IVW) method was used for the primary MR analyses, and the MR-Egger regression, weighted mode method, weighted median method, and simple mode were employed for sensitivity analyses. The MR-Egger intercept test and “leave-one-out” sensitivity analysis were performed to evaluate the horizontal pleiotropy and the potentially influential SNPs, respectively.ResultsGenetically determined log odds of psoriasis vulgaris were associated with an increased risk of BP (IVW: odds ratio (OR) = 1.263, 95% confidence interval (CI): 1.013-1.575, P=0.038). Sensitivity analyses by the weighted mode (OR=1.255, 95%CI: 0.973-1.618, P=0.106), MR Egger (OR=1.315, 95%CI: 0.951-1.817, P=0.126), simple mode (OR=1.414, 95%CI: 0.823-2.429, P=0.234) and weighted median method (OR=1.177, 95%CI: 0.889-1.559, P=0.254) derived directionally consistent relationship between the genetically predicted log odds of psoriasis vulgaris and risks of developing BP. On the contrary, we found that genetically predicted BP had no significant effect on psoriasis vulgaris (IVW: OR=0.996, P= 0.707), indicating the unidirectionality of the relationship. MR-Egger intercept tests showed no evidence of horizontal pleiotropy. No influential SNP driving the results was detected by the leave-one-out sensitivity analysis.ConclusionsOur results suggested that psoriasis vulgaris causally increases the risk of BP, highlighting the need for potential strategies for the prevention and early diagnosis of comorbid BP in patients with psoriasis vulgaris. Further researches into this association and underlying mechanisms are warranted.

Abstract Effective components and related target genes of Folium Artemisiae argyi were screened from Traditional Chinese Medicines for Systems Pharmacology Database and Analysis Platform. The therapeutic targets of atherosclerosis were searched in the MalaCards and OMIM databases. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed in WebGestalt online and verified according to ClueGo and Pedia apps in Cytoscape. Then, the protein-protein interaction network was analyzed using the STRING database and constructed using Cytoscape. Differential expression of target genes was identified in GSE9128 and GSE71226 by GEO2R. And then, molecular docking was performed using the Molecular Operating Environment. Finally, we validated the protein expression of Interleukin-6 (IL-6)/IL-1β /MMP9 by qRT-PCR and Western blot in Raw264.7 which was induced by LPS. A total of 232 potential target genes and 8 ingredients of Folium Artemisiae argyi were identified. Quercetin and naringenin are potential candidate bioactive agents in treating atherosclerosis. Vascular endothelial growth factor (VEGFA), MMP9 and IL-1β could be potential target genes. KEGG analysis demonstrated that the fluid shear stress and atherosclerosis pathway play a crucial role in the anti-atherosclerosis effect of Folium Artemisiae argyi. Gene Expression Omnibus (GEO) validation demonstrated that VEGFA was downregulated, while MMP9 and IL-1β were upregulated in patients with atherosclerosis. Molecular docking suggested that only MMP9 had a good combination with quercetin. The cell experiment results suggested that naringenin and quercetin have strong anti-inflammation effects, and significantly inhibit the expression of MMP9. Practical Applications Artemisiae argyi is a traditional Chinese herbal medicine that has been widely used for its antibacterial and anti-inflammatory effects. This research demonstrated the bioactive ingredients, potential targets, and molecular mechanism of Folium Artemisiae argyi in treating atherosclerosis. It also suggests a reliable approach in investigating the therapeutic effect of traditional Chinese herbal medicine in treating Atherosclerotic cardiovascular disease (ASCVD).

Alzheimer’s disease (AD) is characterized by progressive cognitive decline and late-stage neurobehavioral issues marked by amyloid-beta plaques and Tau protein tangles. This study aims to investigate Fibulin-1(FBLN1) gene expression in the hippocampal tissue of Presenilin-1/Presenilin-2 conditional double-knockout (DKO) and double-transgenic (DTG) mice, using single-cell sequencing and experimental methods to verify abnormal methylation status and correlation with AD. Genomic DNA from DKO and DTG mice was used for genotyping. Reduced Representation Bisulfite Sequencing (RRBS) identified 10 genes with abnormal methylation changes, with protein–protein interaction (PPI) analysis highlighting five core genes, including FBLN1. Single-cell sequencing, RT-PCR, and Western blotting (WB) were used to analyze FBLN1 mRNA and protein levels in the hippocampal tissues of early-stage and mid-stage AD DKO, DTG, and CBAC57 mice. RRBS identified 10 genes with abnormal methylation, with PPI highlighting five core genes. Single-cell sequencing showed significant FBLN1 expression in AD groups. RT-PCR and WB indicated elevated FBLN1 mRNA and protein levels in mid-stage AD DKO and DTG mice compared to CBAC57 mice, with no differences in early-stage AD DKO and CBAC57 mice. RRBS revealed hypomethylation of the FBLN1 gene in mid-stage AD DKO mice. Elevated FBLN1 expression in AD models suggests an age-dependent neurodegenerative mechanism independent of amyloid-beta deposition. This study enhances our understanding of AD’s epigenetic mechanisms, which will aid targeted diagnosis, treatment, and prognosis.

Sexually dimorphic traits such as growth and body size are often found in various crustaceans. Methyl farnesoate (MF), the main active form of sesquiterpenoid hormone in crustaceans, plays vital roles in the regulation of their molting and reproduction. However, understanding on the sex differences in their hormonal regulation is limited. Here, we carried out a comprehensive investigation on sexual dimorphic responses to MF in the hepatopancreas of the most dominant aquacultural crustacean—the white-leg shrimp (Litopenaeus vannamei). Through comparative transcriptomic analysis of the main MF target tissue (hepatopancreas) from both female and male L. vannamei, two sets of sex-specific and four sets of sex–dose-specific differentially expressed transcripts (DETs) were identified after different doses of MF injection. Functional analysis of DETs showed that the male-specific DETs were mainly related to sugar and lipid metabolism, of which multiple chitinases were significantly up-regulated. In contrast, the female-specific DETs were mainly related to miRNA processing and immune responses. Further co-expression network analysis revealed 8 sex-specific response modules and 55 key regulatory transcripts, of which several key transcripts of genes related to energy metabolism and immune responses were identified, such as arginine kinase, tropomyosin, elongation of very long chain fatty acids protein 6, thioredoxin reductase, cysteine dioxygenase, lysosomal acid lipase, estradiol 17-beta-dehydrogenase 8, and sodium/potassium-transporting ATPase subunit alpha. Altogether, our study demonstrates the sex differences in the hormonal regulatory networks of L. vannamei, providing new insights into the molecular basis of MF regulatory mechanisms and sex dimorphism in prawn aquaculture.

Abstract Background I kappa B kinase interacting protein, a highly conserved gene, has rarely been reported in cancer. According to previous study, IKBIP has only been shown to promote malignant progression of glioma. In other malignant tumors, few reports have examined the function of IKBIP, especially in papillary renal cell carcinoma. Therefore, the molecular profiles and clinical prognostic values of the IKBIP in papillary renal cell carcinoma remain undetermined. Methods Several bioinformatic platforms and Immunohistochemistry were used to clarify the expression and prognostic values of IKBIP in Papillary renal cell carcinoma. Results In this study, GEPIA and TIMER platform were used to identify mRNA expression of IKBIP in papillary renal cell carcinoma. And our results revealed that IKBIP mRNA expression was up-regulated in papillary renal cell carcinoma than in its corresponding normal tissues. In addition, high mRNA expression levels of IKBIP were correlated with age, pathological stage, pathological T stage and pathological N stage. Moreover, High IKBIP mRNA expression was negatively correlated with overall survival (OS) and disease-free survival (DFS) in patients of papillary renal cell carcinoma. Besides, Multivariate analysis indicated that IKBIP mRNA expression was an independent prognostic factor for patients of papillary renal cell carcinoma. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed IKBIP co-expressed genes were enriched in homologous recombination, DNA replication, cell cycle, Mismatch repair, Fanconi anemia pathway, P53 signaling pathway and nucleotide excision repair. And Immunohistochemical profile showed that protein expression of IKBIP was higher in papillary renal cell carcinoma than adjacent normal tissue. Conclusions Overall, our findings reveled that IKBIP may act as a novel and potential tumor factor to accelerate papillary renal cell carcinoma progression, meanwhile, IKBIP could serve as a promising target for treating papillary renal cell carcinoma.

Objectives The personalised treatment demands of patients with psoriasis did not get significant attention during the pandemic lockdown. This study aimed to investigate the treatment demands of patients with psoriasis with different severities, stratified by COVID-19 pandemic conditions.Design Cross-sectional study design.Setting Multicentre study based on a national psoriasis registry in China.Participants A total of 22 425 adult patients with psoriasis were enrolled between August 2020 and September 2021.Primary and secondary outcome measures The primary outcomes were patient demands for quick healing of skin lesions and improving mental health, which were collected by questionnaires. Multivariable logistic models were used to examine the impact of disease severity, as measured by Psoriasis Area and Severity Index (PASI), body surface area (BSA) and Investigator’s Global Assessment (IGA), on treatment demands, as stratified by COVID-19 pandemic conditions (lockdown vs non-lockdown).Results Increasing PASI score significantly increased patient demands for rapid healing of skin lesions and improving mental health during non-lockdown periods. The magnitude of both associations further increased during the COVID-19 lockdown from an OR of 1.45 (95% CI 1.27 to 1.65) to 2.19 (95% CI 1.57 to 3.05) and 2.21 (95% CI 2.03 to 2.40) to 2.82 (95% CI 2.24 to 3.55), respectively. The skin lesion healing demand was more triggered by the overall irritation level (measured by IGA, OR 1.64, 95% CI 1.35 to 1.99 during non-lockdown periods vs OR 2.70, 95% CI 1.63 to 4.49 during lockdowns), while the mental health improving demand was more triggered by lesion coverage (measured by BSA, OR 2.01, 95% CI 1.85 to 2.19 vs OR 3.27, 95% CI 2.57 to 4.15).Conclusions Psoriasis aggravation significantly increased patients’ treatment demands, especially during lockdowns. The used psoriasis severity measures highlighted patients’ treatment demands differently. This suggests more accessible and personalised healthcare for patients with psoriasis should be available during future pandemics.

Abstract Expanding wearable technologies to artificial tactile perception will be of significance for intelligent human–machine interface, as neuromorphic sensing devices are promising candidates due to their low energy consumption and highly effective operating properties. Skin‐compatible and conformable features are required for the purpose of realizing wearable artificial tactile perception. Here, we report an intrinsically stretchable, skin‐integrated neuromorphic system with triboelectric nanogenerators as tactile sensing and organic electrochemical transistors as information processing. The integrated system provides desired sensing, synaptic, and mechanical characteristics, such as sensitive response (~0.04 kPa−1) to low‐pressure, short‐ and long‐term synaptic plasticity, great switching endurance (>10 000 pulses), symmetric weight update, together with high stretchability of 100% strain. With neural encoding, demonstrations are capable of recognizing, extracting, and encoding features of tactile information. This work provides a feasible approach to wearable, skin‐conformable neuromorphic sensing system with great application prospects in intelligent robotics and replacement prosthetics.

DNA repair is a vital mechanism in cells that protects against DNA damage caused by internal and external factors. It involves a network of signaling pathways that monitor and transmit damage signals, activating various cellular activities to repair DNA damage and maintain genomic integrity. Dysfunctions in this repair pathway are strongly associated with the development and progression of cancer. However, they also present an opportunity for targeted therapy in breast cancer. Extensive research has focused on developing inhibitors that play a crucial role in the signaling pathway of DNA repair, particularly due to the remarkable success of PARP1 inhibitors (PARPis) in treating breast cancer patients with BRCA1/2 mutations. In this review, we summarize the current research progress and clinical implementation of BRCA and BRCAness in targeted treatments for the DNA repair pathway. Additionally, we present advancements in diverse inhibitors of DNA repair, both as individual and combined approaches, for treating breast cancer. We also discuss the clinical application of DNA repair-targeted therapy for breast cancer, including the rationale, indications, and summarized clinical data for patients with different breast cancer subtypes. We assess their influence on cancer progression, survival rates, and major adverse reactions. Last, we anticipate forthcoming advancements in targeted therapy for cancer treatment and emphasize prospective areas of development.

Abstract Background Gastrointestinal (GI)‐neuroendocrine neoplasms (NENs) are subclassified in neuroendocrine tumors (NETs), neuroendocrine carcinomas (NECs), and mixed neuroendocrine–non‐neuroendocrine neoplasms (MiNENs). The genetic characteristics of GI‐NEN has been a hot issue in recent years, but more studies are needed to provide further details. This study aims to provide additional data about genomic characteristics of GI‐NENs and the genetic differences between NETs and NECs. Patients and Methods Thirteen samples were selected for next‐generation sequencing (NGS) analysis with a 425‐gene panel. Microsatellite instability (MSI) and tumor mutational burden (TMB) were calculated as well as immunohistochemistry (IHC) was used to test for protein expression. Results Genetic alterations were very common in NECs, but rare in NETs. The average TMB of NETs and NECs was 2.3 and 6.9, respectively. The TMB of NECs was significantly higher compared to NETs. The TP53 mutation rate was significantly higher in NECs than in NETs (100% vs. 20%), other mutations involved MTOR (n = 2, 15.4%), DDR2 (n = 3, 23.1%), ERBB4 (n = 1, 7.7%), BRCA1 (n = 1, 7.7%), BRCA2 (n = 1, 7.7%), ATM (n = 1, 7.7%), and SMAD4 (n = 1, 7.7%). Deep loss of SMAD4 (1/3, 33.3%), SDHB (1/3, 33.3%), RB1 (1/3, 33.3%), and BRCA2 (1/3, 33.3%), high‐level amplification of CRKL (1/3, 33.3%), CCNE1(1/3, 33.3%), and MCL1(1/3, 33.3%) were found in NECs. The integrated analysis found these genetic alterations frequently involve DNA repair and cell cycle, PI3K/AKT/mTOR and TGF‐β/SMAD4 signaling pathways. Conclusion Genetic alterations were very common in NECs and rare in NETs, and frequently involved three main signaling pathways. NEC patients harboring these genetic alterations may benefit from targeted therapy and PD‐1/PD‐L1 immunotherapy.

The relationship between systemic inflammation and secondary injury in traumatic brain injury (TBI) is complex. We investigated associations between inflammatory markers and clinical confirmation of TBI diagnosis and prognosis. The prospective TRACK-TBI Pilot (Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot) study enrolled TBI patients triaged to head computed tomography (CT) and received blood draw within 24?h of injury. Healthy controls (HCs) and orthopedic controls (OCs) were included. Thirty-one inflammatory markers were analyzed from plasma. Area under the receiver operating characteristic curve (AUC) was used to evaluate discriminatory ability. AUC >0.7 was considered acceptable. Criteria included: TBI diagnosis (vs. OC/HC); moderate/severe vs. mild TBI (Glasgow Coma Scale; GCS); radiographic TBI (CT positive vs. CT negative); 3- and 6-month Glasgow Outcome Scale-Extended (GOSE) dichotomized to death/greater relative disability versus less relative disability (GOSE 1?4/5?8); and incomplete versus full recovery (GOSE

Abstract Background Alternaria solani (A. solani), the main pathogen of potato early blight, causes serious yield reductions every year. The application of fungicides is the most common and effective method of controlling Alternaria-caused diseases. The differentially expressed transcripts of A. solani infecting potato were identified, revealing a group of valuable candidate genes for a systematic analysis to increase the understanding of the molecular pathogenesis of A. solani, and providing scientific data for formulating additional measures to prevent and control potato early blight. In this study, a deep RNA-sequencing approach was applied to gain insights into A. solani pathogenesis. At 3, 4, and 5 days post inoculation (dpi), RNA samples from the susceptible potato cultivar Favorita infected with A. solani strain HWC-168, were sequenced and utilized for transcriptome analysis, and compared to the transcriptome obtained 0 dpi. Results A total of 4430 (2167 upregulated, 2263 downregulated), 4736 (2312 upregulated, 2424 downregulated), and 5043 (2411 upregulated, 2632 downregulated) genes were differentially expressed 3, 4 and 5 dpi, respectively, compared with genes analysed at 0 dpi. KEGG enrichment analysis showed that genes involved in the pathways of amino acid metabolism, glucose metabolism, and enzyme activity were significantly differentially expressed at the late infection stage. Correspondingly, symptoms developed rapidly during the late stage of A. solani infection. In addition, a short time-series expression miner (STEM) assay was performed to analyse the gene expression patterns of A. solani and Profile 17 and 19 showed significant change trends 3, 4 and 5 dpi. Both profiles, but especially Profile 17, included enzymes, including transferases, oxidoreductases, hydrolases and carbohydrate-active enzymes (CAZYmes), which may play important roles in late fungal infection. Furthermore, possible candidate effectors were identified through the adopted pipelines, with 137 differentially expressed small secreted proteins identified, including some enzymes and proteins with unknown functions. Conclusions Collectively, the data presented in this study show that amino acid metabolism, and glucose metabolism pathways, and specific pathway-related enzymes may be key putative pathogenic factors, and play important roles in late stage A. solani infection. These results contribute to a broader base of knowledge of A. solani pathogenesis in potato, as indicated by the transcriptional level analysis, and provide clues for determining the effectors of A. solani infection.

Many efforts have been exerted toward screening potential drugs for targets, and conducting wet experiments remains a laborious and time-consuming approach. Artificial intelligence methods, such as Convolutional Neural Network (CNN), are widely used to facilitate new drug discovery. Owing to the structural limitations of CNN, features extracted from this method are local patterns that lack global information. However, global information extracted from the whole sequence and local patterns extracted from the special domain can influence the drug-target affinity. A fusion of global information and local patterns can construct neural network calculations closer to actual biological processes. This paper proposes a Fingerprint-embedding framework for Drug-Target binding Affinity prediction (FingerDTA), which uses CNN to extract local patterns and utilize fingerprints to characterize global information. These fingerprints are generated on the basis of the whole sequence of drugs or targets. Furthermore, FingerDTA achieves comparable performance on Davis and KIBA data sets. In the case study of screening potential drugs for the spike protein of the coronavirus disease 2019 (COVID-19), 7 of the top 10 drugs have been confirmed potential by literature. Ultimately, the docking experiment demonstrates that FingerDTA can find novel drug candidates for targets. All codes are available at http://lanproxy.biodwhu.cn:9099/mszjaas/FingerDTA.git.

Cationic lead/cadmium and anionic arsenic exhibit opposite geochemical behaviors in soils, which makes the synchronous remediation of As, Cd, and Pb challenging. In this study, we developed an iron-manganese modified biochar (BC-Fe-Mn) that prepared from straw with iron (Fe) and manganese (Mn) loading at a pyrolysis temperature of 550 °C. After BC-Fe-Mn immobilization for 90 days, the simultaneous immobilization efficiency of Pb, Cd, and As reached 57%, 51%, and 35%, respectively. Speciation distributions shows that As transformed from specific bound state into weakly low crystallinity iron bound state. Cd transformed from carbonate fraction into Fe-Mn oxide bound fraction, and Pb transformed from carbonate fraction into residual state. During the procedure, simultaneous immobilization mechanisms might involve heavy metal morphological transformation, precipitation/co-precipitation, and surface complexation. Cd and Pb absorbed onto BC-Fe-Mn. Then the increased free iron oxides (Fed) reacted with the dissolved As to form iron-arsenic precipitation. The results show that BC-Fe-Mn is a promising material for the simultaneous immobilization of Pb, Cd, and As in multi-metal contaminated soil.

Zinc (Zn) is considered as one of the heavy metal pollutants in soil affecting agriculture. Salicylic acid (SA) is an important phytohormone that can mitigate effects against various abiotic stresses in plants, however, its exploration to improve Zn stress tolerance in alfalfa plants is still elusive. Thus, in the present study, exogenous SA treatment was conducted on alfalfa plants under Zn stress. The effects of exogenous SA on the physiological effects of alfalfa plants and the expression levels related genes were studied. This study tested the biomass, relative water content, chlorophyll levels, photosynthetic capacity, proline and soluble sugar contents, detected the activity of antioxidant enzymes (such as peroxidase and superoxide dismutase), glutathione biosynthesis, and endogenous SA levels, and quantified the genes associated with the antioxidant system and glutathione metabolism-mediated Zn stress. The results showed that exogenous SA could elevate the physiological adaptability of alfalfa plants through enhancing photosynthesis, proline and soluble sugar levels, stimulating antioxidant system and glutathione metabolism, and inducing the transcription level of related genes, thereby diminishing oxidative stress, inhibiting excessive Zn accumulation of alfalfa plants, increasing tolerance to Zn stress, and reducing the toxicity of Zn. Collectively, the application of SA alleviates Zn toxicity in alfalfa plants. The findings gave first insights into the regulatory mechanism of the Zn stress tolerance of alfalfa by exogenous SA and this might have positive implications for managing other plants which are suffering Zn stress.

Summary: Background: Limited evidence existed on the comparative effectiveness of decompressive craniectomy (DC) versus craniotomy for evacuation of traumatic acute subdural hematoma (ASDH) until the recently published randomised clinical trial RESCUE-ASDH. In this study, that ran concurrently, we aimed to determine current practice patterns and compare outcomes of primary DC versus craniotomy. Methods: We conducted an analysis of centre treatment preference within the prospective, multicentre, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (known as CENTER-TBI) and NeuroTraumatology Quality Registry (known as Net-QuRe) studies, which enrolled patients throughout Europe and Israel (2014–2020). We included patients with an ASDH who underwent acute neurosurgical evacuation. Patients with severe pre-existing neurological disorders were excluded. In an instrumental variable analysis, we compared outcomes between centres according to treatment preference, measured by the case-mix adjusted proportion DC per centre. The primary outcome was functional outcome rated by the 6-months Glasgow Outcome Scale Extended, estimated with ordinal regression as a common odds ratio (OR), adjusted for prespecified confounders. Variation in centre preference was quantified with the median odds ratio (MOR). CENTER-TBI is registered with ClinicalTrials.gov, number NCT02210221, and the Resource Identification Portal (Research Resource Identifier SCR_015582). Findings: Between December 19, 2014 and December 17, 2017, 4559 patients with traumatic brain injury were enrolled in CENTER-TBI of whom 336 (7%) underwent acute surgery for ASDH evacuation; 91 (27%) underwent DC and 245 (63%) craniotomy. The proportion primary DC within total acute surgery cases ranged from 6 to 67% with an interquartile range (IQR) of 12–26% among 46 centres; the odds of receiving a DC for prognostically similar patients in one centre versus another randomly selected centre were trebled (adjusted median odds ratio 2.7, p

The use of UCH-L1 detection with point-of-care (POC) assay alone has not been characterized for clinical use. This study compares the accuracies of POC UCH-L1 and Neuron-Specific Enolase (NSE) Elecsys® levels for identifying TBI patients with structural abnormalities on neuroimaging.The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Phase 1 Cohort, enrolled 1375 TBI patients (GCS 3–15) presenting to one of 18 US Level I trauma centers within 24 h of injury who had an admission head CT; blood samples were collected, along with 122 orthopedic and 209 healthy controls. The TBI cohort consisted of 810 CT-negative (CT-) and 549 CT-positive (CT+) subjects. Of the CT- subjects who had MRIs, 121 were MRI-positive (MRI+) and 333 were MRI-negative (MRI-). UCH-L1 POC showed best diagnostic performance for CT + versus CT-, 0–8 h post-injury with an AUC of 0·779 [0·708–0.850] when compared to the 0–25 h interval, with an AUC of 0.684 [0.655–0.712]. NSE assay has an AUC of 0.695 [0.619–0.770] for the 0–8 h interval and 0.634 [0.603–0.665] for the 0–25 h interval. During the first 8 after injury, POC UCH-L1 outperforms NSE in identifying TBI patients with structural abnormalities on neuroimaging.

Abstract Background Magnetic resonance imaging (MRI) carries prognostic importance after traumatic brain injury (TBI), especially when computed tomography (CT) fails to fully explain the level of unconsciousness. However, in critically ill patients, the risk of deterioration during transfer needs to be balanced against the benefit of detecting prognostically relevant information on MRI. We therefore aimed to assess if day of injury serum protein biomarkers could identify critically ill TBI patients in whom the risks of transfer are compensated by the likelihood of detecting management-altering neuroimaging findings. Methods Data were obtained from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Eligibility criteria included: TBI patients aged ≥ 16 years, Glasgow Coma Score (GCS)

Abstract Background Alternaria solani is a typical necrotrophic pathogen that can cause severe early blight on Solanaceae crops and cause ring disease on plant leaves. Phytopathogens produce secretory effectors that regulate the host immune response and promote pathogenic infection. Effector proteins, as specialized secretions of host-infecting pathogens, play important roles in disrupting host defense systems. At present, the role of the effector secreted by A. solani during infection remains unclear. We report the identification and characterization of AsCEP112, an effector required for A. solani virulence. Result The AsCEP112 gene was screened from the transcriptome and genome of A. solani on the basis of typical effector signatures. Fluorescence quantification and transient expression analysis showed that the expression level of AsCEP112 continued to increase during infection. The protein localized to the cell membrane of Nicotiana benthamiana and regulated senescence-related genes, resulting in the chlorosis of N. benthamiana and tomato leaves. Moreover, comparative analysis of AsCEP112 mutant obtained by homologous recombination with wild-type and revertant strains indicated that AsCEP112 gene played an active role in regulating melanin formation and penetration in the pathogen. Deletion of AsCEP112 also reduced the pathogenicity of HWC-168. Conclusion Our findings demonstrate that AsCEP112 was an important effector protein that targeted host cell membranes. AsCEP112 regulateed host senescence-related genes to control host leaf senescence and chlorosis, and contribute to pathogen virulence.

Abstract Background Making clear what kinds of metabolic pathways a drug compound involves in can help researchers understand how the drug is absorbed, distributed, metabolized, and excreted. The characteristics of a compound such as structure, composition and so on directly determine the metabolic pathways it participates in. Methods We developed a novel hybrid framework based on the graph attention network (GAT) to predict the metabolic pathway classes that a compound involves in, named HFGAT, by making use of its global and local characteristics. The framework mainly consists of a two-branch feature extracting layer and a fully connected (FC) layer. In the two-branch feature extracting layer, one branch is responsible to extract global features of the compound; and the other branch introduces a GAT consisting of two graph attention layers to extract local structural features of the compound. Both the global and the local features of the compound are then integrated into the FC layer which outputs the predicted result of metabolic pathway categories that the compound belongs to. Results We compared the multi-class classification performance of HFGAT with six other representative methods, including five classic machine learning methods and one graph convolutional network (GCN) based deep learning method, on the benchmark dataset containing 6999 compounds belonging to 11 pathway categories. The results showed that the deep learning-based methods (HFGAT, GCN-based method) outperformed the traditional machine learning methods in the prediction of metabolic pathways and our proposed HFGAT method performed better than the GCN-based method. Moreover, HFGAT achieved higher $$F_1$$ F 1 scores on 8 of 11 classes than the GCN-based method. Conclusions Our proposed HFGAT makes use of both the global and local information of the compounds to predict their metabolic pathway categories and has achieved a significant performance. Compared with the GCN model, the introduction of the GAT can help our model pay more attention to substructures of the compound that are useful for the prediction task. The study provided a potential method for drug discovery with all types of metabolic reactions that may be involved in the decomposition and synthesis of pharmaceutical compounds in the organism.

Abstract Background Retrosynthesis prediction is the task of deducing reactants from reaction products, which is of great importance for designing the synthesis routes of the target products. The product molecules are generally represented with some descriptors such as simplified molecular input line entry specification (SMILES) or molecular fingerprints in order to build the prediction models. However, most of the existing models utilize only one molecular descriptor and simply consider the molecular descriptors in a whole rather than further mining multi-scale features, which cannot fully and finely utilizes molecules and molecular descriptors features. Results We propose a novel model to address the above concerns. Firstly, we build a new convolutional neural network (CNN) based feature extraction network to extract multi-scale features from the molecular descriptors by utilizing several filters with different sizes. Then, we utilize a two-branch feature extraction layer to fusion the multi-scale features of several molecular descriptors to perform the retrosynthesis prediction without expert knowledge. The comparing result with other models on the benchmark USPTO-50k chemical dataset shows that our model surpasses the state-of-the-art model by 7.4%, 10.8%, 11.7% and 12.2% in terms of the top-1, top-3, top-5 and top-10 accuracies. Since there is no related work in the field of bioretrosynthesis prediction due to the fact that compounds in metabolic reactions are much more difficult to be featured than those in chemical reactions, we further test the feasibility of our model in task of bioretrosynthesis prediction by using the well-known MetaNetX metabolic dataset, and achieve top-1, top-3, top-5 and top-10 accuracies of 45.2%, 67.0%, 73.6% and 82.2%, respectively. Conclusion The comparison result on USPTO-50k indicates that our proposed model surpasses the existing state-of-the-art model. The evaluation result on MetaNetX dataset indicates that the models used for retrosynthesis prediction can also be used for bioretrosynthesis prediction.

This study investigated the prevalence and genetic diversity of gastroenteric viruses in mussels and oysters in Rio de Janeiro, Brazil. One hundred and thirty-four marketed bivalve samples were obtained between January and December 2022. The viral analysis was performed according to ISO/TS 15216, and the screening revealed the detection of norovirus GII/GI (40.3%), sapovirus (SaV; 12.7%), human mastadenovirus (7.5%), and rotavirus A (RVA; 5.9%). In total, 44.8% (60) of shellfish samples tested positive for one or more viruses, 46.7% (28/60) of the positive samples tested positive for a single viral agent, 26.7% (16) tested positive for two viral agents, 8.3% (5) for three viral agents, and 13.3% (8) for four viral agents. Additionally, three mussel samples were contaminated with the five investigated viruses (5%, 3/60). Norovirus GII showed the highest mean viral load (3.4 × 105 GC/g), followed by SaV (1.4 × 104 GC/g), RVA (1.1 × 104 GC/g), human mastadenovirus (3.9 × 103 GC/g), and norovirus GI (6.7 × 102 GC/g). Molecular characterization revealed that the recovered norovirus strains belonged to genotypes GII.2, GII.6, GII.9, GII.17, and GII.27; SaV belonged to genotypes GI.1 and GIV.1; RVA to genotypes G6, G8, P[8]-III, and human mastadenovirus to types F40 and F41. The GII.27 norovirus characterized in this study is the only strain of this genotype reported in Brazil. This study highlights the dissemination and diversity of gastroenteric viruses present in commercialized bivalves in a touristic area, indicating the potential risk to human health and the contribution of bivalves in the propagation of emerging pathogens.

Diamide insecticides have always been a hot research topic in the field of pesticides. To further discover new compounds with high activity and safety, indane and its analogs were introduced into chlorantraniliprole, and a battery of chlorfenil derivatives, including indane and its analogs, were designed and prepared for biological testing. Their characterization and verification were carried out through nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). Biological detection showed that all the compounds exhibited good insecticidal activity against Mythimna separata. At 0.8 mg/L, the insecticidal activity of compound 8q against Mythimna separata was 80%, which was slightly better than that of chlorantraniliprole. The results of the structure–activity relationship (SAR) analysis indicated that the indane moiety had a significant effect on insecticidal activity, especially in the R-configuration. The results indicated that chlorantraniliprole derivatives containing indane groups could serve as pilot compounds for the further development of new insecticides.

Abstract The effectome of the necrotrophic fungal pathogen, Alternaria solani, was determined using multiomics. In total, 238 effector candidates were predicted from the A. solani genome, and apoplastic effectors constitute most of the total candidate effector proteins (AsCEPs). Comparative genomics revealed two main groups of AsCEPs: lineage-specific and conserved effectors. RNA-Seq analysis revealed that the most highly expressed genes encoding AsCEPs were enriched with lineage-specific forms. Two lineage-specific effector genes, AsCEP19 and AsCEP20, were found to form a ‘head-to-head’ gene pair located near an AT-rich region on the chromosome. To date, AsCEP19 and AsCEP20 have been found only in a few fungal species. Phylogenetic inference revealed that AsCEP19 and AsCEP20 were likely acquired by the common ancestor of A. solani and A. tomatophila via horizontal gene transfer, probably mediated by long terminal repeat retrotransposon. RT-qPCR analysis showed that AsCEP19 and AsCEP20 are tightly coexpressed in a host-specific manner and that they are upregulated at advanced stages of A. solani infection only in solanaceous hosts. Transient expression of AsCEP19 and AsCEP20 in Nicotiana benthamiana plants showed that these effectors could promote Phytophthora infestans infection. AsCEP19 and AsCEP20 were required for the full virulence of A. solani on host potato, because deletion of this gene pair significantly reduced the size of necrotic lesions on potato leaves. Transient expression of AsCEP20 could elicit plant cell death depending on the presence of its signal peptide, indicating that AsCEP20 is a necrosis-inducing apoplastic effector with the mature form localized specifically in chloroplasts. Our work provides a better understanding of the function and evolution of necrotrophic fungal effectors, and helps explain the high aggressiveness of A. solani against solanaceous crops.

Abstract Background The inflammatory bowel disease, containing Crohn’s disease and ulcerative colitis, was rare in the population, especially in the complication of kidney disease. A few studies had found proteinuria played a potential indicator of inflammatory bowel disease occurrence and activity. This study aimed to better define the histopathologic spectrum and study the outcome of renal disease in Crohn’s disease. Methods A retrospective study of 3557 Crohn's disease from January 1st, 2016 to July 1st, 2021 in the Sixth Affiliated Hospital of Sun Yat-sen University identified 20 (0.56% [20/3557]) patients who underwent kidney biopsy. All biopsy specimens were examined by standard procedures containing light microscopy, immunofluorescence, and electron microscopy. Results Twenty cases were shown in this review study. Subnephrotic proteinuria (30% [6 of 20]), persistent hematuria and proteinuria (25% [5 of 20]), and isolated hematuria with acanthocytes (25% [5 of 20]) were the main indications for kidney biopsy. The most common diagnosis was IgA nephropathy (70% [14/20]), followed by minimal change disease (10% [2/20]), acute interstitial nephritis (5% [1/20]), granulomatous interstitial nephritis (5% [1/20]), non-IgA mesangial proliferative nephritis (5% [1/20]) and thin basement membrane nephropathy (5% [1/20]). The Lee classification of IgA nephropathy was mostly II or III level. Glomerular mesangial hyperplasia was the most common pathologic manifestation according to the MEST-C Sore. After twelve-month treatment, the majority of patients turned to complete remission of renal disease by measuring proteinuria, while 3 patients still stayed in the relapse stage and 6 patients turned to partial remission by measuring hematuria. Conclusions IgA nephropathy is the most common kidney biopsy diagnosis in Crohn's disease. Renal damage in Crohn's disease mainly involves the glomerulus, especially the mesangial matrix. After the treatment, proteinuria might be in remission, but hematuria remains.

Targeted genotyping is an extremely powerful approach for the detection of known genetic variations that are biologically or clinically important. However, for non-model organisms, large-scale target genotyping in a cost-effective manner remains a major challenge. To address this issue, we present an ultrahigh-multiplex, in-solution probe array-based high-throughput diverse marker genotyping (HD-Marker) approach that is capable of targeted genotyping of up to 86 000 loci, with coverage of the whole gene repertoire, in what is a 27-fold and six-fold multiplex increase in comparison with the conventional Illumina GoldenGate and original HD-Marker assays, respectively. We perform extensive analyses of various ultrahigh-multiplex levels of HD-Marker (30 k-plex, 56 k-plex, and 86 k-plex) and show the power and excellent performance of the proposed method with an extremely high capture rate (about 96%) and genotyping accuracy (about 96%). With great advantages in terms of cost (as low as 0.0006 USD per genotype) and high technical flexibility, HD-Marker is a highly efficient and powerful tool with broad application potential for genetic, ecological, and evolutionary studies of non-model organisms.

Objective: To explore the association between the pain-fatigue-sleep disturbance-depression symptom cluster (SC) and cancer-related cognitive impairment (CRCI) in patients having lung cancer and to identify other factors influencing CRCI. Methods: A cross-sectional study was conducted to investigate 378 patients having lung cancer in China from October 2021 to July 2022. The perceived cognitive impairment scale and the general anxiety disorder-7 were used to assess patients’ cognitive impairment and anxiety, respectively. The pain-fatigue-sleep disturbance-depression SC was assessed with the brief fatigue inventory, the brief pain inventory, the Patient Health Questionnaire-9, and the Athens Insomnia Scale. Latent class analysis by Mplus.7.4 was used to identify latent classes of the SC. We adjusted for covariates in the multivariable logistic regression model to examine the relationship between the pain-fatigue-sleep disturbance-depression SC and CRCI. Results: Among patients having lung cancer, two SC classes were identified: high and low symptom burden groups. In the crude model, compared to the low symptom burden group, the high symptom group had greater odds of developing CRCI (odds ratio: 10.065, 95% confidence interval: 4.138–24.478). After adjusting for covariates, in model 1, the high symptom group still had greater odds of developing CRCI (odds ratio: 5.531, 95% confidence interval: 2.133–14.336). Additionally, a diagnosis of over 6 months, anxiety, leisure activity, and a high platelet-to-lymphocyte ratio were found to be influencing factors of CRCI (all P ​

Blackleg and aerial stem rot of potato (Solanum tuberosum L.), caused by soft rot enterobacteria of the genera Pectobacterium and Dickeya, has recently increased years in Hebei Province, China. Field surveys were performed during the 2021 potato growing season in Hebei to identify and characterize bacterial pathogens. Sixteen potato plants showing blackleg or aerial stem rot were collected from three potato-producing areas, and ten representative pectinolytic bacteria were isolated from symptomatic plants. 16S rDNA sequencing and multilocus sequence analysis were performed to determine the taxonomic position of the bacterial isolates. The isolates belonged to the genus Pectobacterium, including Pectobacterium atrosepticum, Pectobacterium carotovorum, Pectobacterium brasiliense, and Pectobacterium parmentieri. The exceptions were isolates BY21311 and BY21312, which belonged to a new species of Pectobacterium polonicum previously found in groundwater. The taxonomy of isolate BY21311 was confirmed using whole genome-based analysis. P. polonicum has only been identified in potato plants on one farm in Baoding region in China. Isolates BY21311 and BY21312 displayed similar physiological and biochemical traits to the type strain DPMP315T. Artificial inoculation assays revealed that isolate BY21311 fulfilled Koch’s postulates for potato blackleg. These findings represent the first time P. polonicum, a water-associated Pectobacterium species may be the cause of blackleg in the field. Interestingly, P. polonicum BY21311 has reduced ability to macerate potato tubers when compared to P. atrosepticum, P. brasiliense, P. versatile, and P. parvum, which is more virulent in tubers than the type strain DPMP315T. The host range of isolate BY21311 was determined by injection method, which can impregnate five plants. Although the genome of isolate BY21311 harbors gene clusters encoding a type III secretion system, it did not elicit a hypersensitive response (HR) in Nicotiana benthamiana or N. tabacum leaves. T3SS effector AvrE and T4SS effector PilN were obtained by predicting isolate BY21311 genome. P. polonicum appears to show significant variations in gene content between two genomes, and gene content varies between isolates BY21311 and DPMP315T, with strain specific-genes involved in many aspects, including lipopolysaccharide biosynthesis, substrate translocation, T4SS and T6SS among others, suggesting that isolates BY21311 and DPMP315T might represent distinct clades within the species.

Abstract Background Suicidal ideation in cancer patients is a critical challenge. At present, few studies focus on factors associated with suicidal ideation, and predictive models are still lacking. This study aimed at investigating the risk factors for suicidal ideation among cancer patients, and developed a predictive nomogram to screen high risk cancer patients for early prevention and intervention. Methods A questionnaire survey was conducted among cancer patients between May 2021 and January 2022. The factors associated with suicidal ideation were used to construct a multivariate logistic regression model, which was visualized as a predictive nomogram to evaluate the risk of suicidal ideation. Areas under the curve, calibration plot, decision curve analysis, and internal and external validation were used to validate the discrimination, calibration and clinical usefulness of the model. Results A total of 820 patients with cancer were recruited for this study and 213 (25.98%) developed suicidal ideation. Levels of demoralization, depression and cancer staging, marital status, residence, medical financial burden, and living condition were influence factors for suicidal ideation. Comparing nomogram with Self-rating Idea of Suicide Scale (SIOSS), the nomogram had a satisfactory discrimination ability with an AUC of 0.859 (95% CI: 0.827–0.890) and 0.818 (95% CI: 0.764–0.873) in the training and validation sets, respectively. The calibration plot and decision curve analysis revealed that this nomogram was in good fitness and could be beneficial in clinical applications. Conclusions Suicidal ideation is common in cancer patients. Levels of demoralization, depression and cancer staging were independent predictors of suicidal ideation. The nomogram is an effective and simple tool for predictive suicidal ideation in cancer patients.

Abstract Background Genome-wide association studies (GWASs) have identified multiple risk loci for bipolar disorder (BD). However, pinpointing functional (or causal) variants in the reported risk loci and elucidating their regulatory mechanisms remain challenging. Methods We first integrated chromatin immunoprecipitation sequencing (ChIP-Seq) data from human brain tissues (or neuronal cell lines) and position weight matrix (PWM) data to identify functional single-nucleotide polymorphisms (SNPs). Then, we verified the regulatory effects of these transcription factor (TF) binding–disrupting SNPs (hereafter referred to as “functional SNPs”) through a series of experiments, including reporter gene assays, allele-specific expression (ASE) analysis, TF knockdown, CRISPR/Cas9-mediated genome editing, and expression quantitative trait loci (eQTL) analysis. Finally, we overexpressed PACS1 (whose expression was most significantly associated with the identified functional SNPs rs10896081 and rs3862386) in mouse primary cortical neurons to investigate if PACS1 affects dendritic spine density. Results We identified 16 functional SNPs (in 9 risk loci); these functional SNPs disrupted the binding of 7 TFs, for example, CTCF and REST binding was frequently disrupted. We then identified the potential target genes whose expression in the human brain was regulated by these functional SNPs through eQTL analysis. Of note, we showed dysregulation of some target genes of the identified TF binding–disrupting SNPs in BD patients compared with controls, and overexpression of PACS1 reduced the density of dendritic spines, revealing the possible biological mechanisms of these functional SNPs in BD. Conclusions Our study identifies functional SNPs in some reported risk loci and sheds light on the regulatory mechanisms of BD risk variants. Further functional characterization and mechanistic studies of these functional SNPs and candidate genes will help to elucidate BD pathogenesis and develop new therapeutic approaches and drugs.

Abstract Purpose To investigate the status of astigmatism in preschool children in Wuxi City, and explore the risk factors related to astigmatism. The risk factors related to astigmatism development as predictors can help us identify preschool children who need vision screening at an early stage to ensure good visual quality. Methods The cross-sectional study was conducted in 10 kindergartens randomly selected in five districts of Wuxi City in November 2018. All preschool children were measured by objective refractometry under non-cycloplegic refraction. The basic information of preschool children was collected. The relevant factors of astigmatism in the questionnaire were completed by parents. Spss 26. 0 software was used for univariate and multivariate correlation analysis. Results A total of 889 preschool children participated in the study, 864 were finally included in the study. The prevalence of astigmatism was 36.0%. The risk of astigmatism in premature children was higher than that in non-premature children (adjusted odds ratio = 1.841). The prevalence of astigmatism with parents’ astigmatism history was higher, compared with preschool children without parents’ astigmatism history (adjusted odds ratio = 2.037). When maternal age at childbirth was older (≥ 35 years old), the risk of astigmatism increased in preschool children (adjusted odds ratio = 2.181). Compared with bottle feeding, the risk of astigmatism for mixed feeding and breastfeeding reduced in preschool children. Compared with preschool children exposed to electronic screen for less than 2 h every day, preschool children exposed to electronic screen for more than 2 h had an increased risk of astigmatism (P = 0.004). Conclusion The prevalence of astigmatism among preschool children in Wuxi City was high. Some risk factors such as premature birth, parents’ astigmatism history, maternal age at childbirth, feeding pattern, and electronic screen exposure time were closely related to the occurrence of astigmatism among preschool children. For preschool children with significant risk factors, their eyesight should be checked regularly to ensure their visual quality.

Objective: To systematically explore the effect and mechanism of melastomatis dodecandri herba (Melastoma dodecandrum Lour.) in the treatment of hepatitis based on network pharmacology. Method: We evaluated the hepatoprotective effects of M. dodecandrum in concanavalin A (Con A)-induced hepatitis in mice by assessing survival rate, histological analysis, serum transaminases, and related cytokines. Then the mechanism of action was predicted by a network pharmacology-based strategy. Based on the results, we measured the hepatic expression of related genes at mRNA level and proteins related to the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) and nuclear factor-kappa B (NF-кB) pathways. Results: Our study results clearly demonstrated that M. dodecandrum pretreatment significantly alleviated liver injury. This was demonstrated by an increase in survival rate, decreased severity of liver damage, and reduced serum transaminase levels compared with those in the Con A group. Moreover, M. dodecandrum significantly reduced the serum levels of tumor necrosis factor-α, interleukin-6, and interferon-γ and increased the liver levels of superoxide dismutase, which indicated that M. dodecandrum exhibits anti-inflammatory and antioxidant activities. On the basis of network pharmacology, 50 nodes were selected as major hubs based on their topological importance. Pathway enrichment analyses indicated that the putative targets of M. dodecandrum mostly participate in various pathways associated with the anti-inflammation response, which implies the underlying mechanism by which M. dodecandrum acts on hepatitis. Real-time fluorescent quantitative PCR analysis showed that M. dodecandrum downregulates the mRNA expression of interleukin-6, Toll-like receptor 7, interleukin-1 receptor-associated kinase-4, NF-кB and tumor necrosis factor-α in liver tissues. Western blotting showed that M. dodecandrum pretreatment protected against inflammation through activating the PI3K-Akt pathway by upregulating phosphorylated Akt (p-Akt) expression and suppressing NF-кB activation by inhibiting the phosphorylation of IKK, IκBα, and p65. Conclusion: The present work demonstrated the hepatoprotective effects of M. dodecandrum by regulating the PI3K/Akt and NF-кB pathways in Con A-induced mice, which provide insights into the treatment of hepatitis using M. dodecandrum.

Early blight, caused by the necrotrophic fungus Alternaria solani, is an important foliar disease that causes major yield losses of potato. Effector proteins secreted by pathogens to host cells can inhibit host immune response to pathogens. Currently, the function of effector proteins secreted by A. solani during infection is poorly understood. In this study, we identified and characterized a novel candidate effector protein, AsCEP50. AsCEP50 is a secreted protein that is highly expressed throughout the infection stages of A. solani. Agrobacterium tumefaciens-mediated transient expression in Nicotiana benthamiana and tomato demonstrated that AsCEP50 is located on the plasma membrane of N. benthamiana and regulates senescence-related genes, resulting in the chlorosis of N. benthamiana and tomato leaves. Δ50 mutants were unaffected in vegetative growth, spore formation and mycelium morphology. However, the deletion of AsCEP50 significantly reduced virulence, melanin production and penetration of A. solani. These results strongly supported that AsCEP50 is an important pathogenic factor at the infection stage and contributes to the virulence of Alternaria solani.

ABSTRACT Purpose: Tanshinone IIA is a well-known lipophilic active constituent refined from traditional Chinese medicines, danshen. It has been previously demonstrated to possess various biological properties, including anti-inflammatory, antioxidant, promoting angiogenesis effect and so on. However, the mechanism of tanshinone IIA on myocardial ischemia-reperfusion injury (MI/RI) remains unclear. In this study, we investigated the effect of tanshinone IIA on MI/RI. Methods: MI/RI rat models were set up. Echocardiographic evaluation and hematoxylin and eosin staining were performed to analyze the cardiac function and morphology of MI/RI. Western blot was conducted for the detection of protein expression of pyrin domain containing 3 (NLRP3) and caspase-1 in heart tissues. Flow cytometry and real-time polymerase chain reaction were used for the detection of proinflammatory cytokines and Th17 cells differentiation. Results: We found that tanshinone IIA alleviated the myocardial damage of MI/RI, ameliorated the overall and local inflammatory reaction, and produced a cardioprotective effect by inhibiting of NLRP3 inflammasome activation and Th17/Treg cells differentiation. Conclusions: Our results highlighted the cardio-protective effect of tanshinone IIA on MI/RI and uncovered its underlying mechanism related to the NLRP3 inflammasome inhibition and the modulation of Th17/Treg cells differentiation.

Colorectal diseases are threatening human health, especially inflammatory bowel disease (IBD) and colorectal cancer (CRC). IBD is a group of chronic, recurrent and incurable disease, which may affect the entire gastrointestinal tract, increasing the risk of CRC. Eukaryotic gene expression is a complicated process, which is mainly regulated at the level of gene transcription and mRNA translation. Protein translation in tissue is associated with a sequence of steps, including initiation, elongation, termination and recycling. Abnormal regulation of gene expression is the key to the pathogenesis of CRC. In the early stages of cancer, it is vital to identify new diagnostic and therapeutic targets and biomarkers. This review presented current knowledge on aberrant expression of eIFs, eEFs and eRFs in colorectal diseases. The current findings of protein synthesis on colorectal pathogenesis showed that eIFs, eEFs and eRFs may be potential targets for CRC treatment.

Silicosis is a systemic disease characterized by diffuse fibrosis of the lung tissue caused by long-term inhalation of large amounts of free silica (SiO2) dust. The pathogenesis of silicosis has not been fully elucidated, and there is a lack of effective treatment methods. N-acetylcysteine (NAC) can potentially treat pulmonary fibrosis by exerting antioxidant effects. Desipramine (DMI) can influence pulmonary fibrosis development by inhibiting acid sphingomyelinase (ASMase) activity and regulating ceramide concentrations. Both can interfere with pulmonary fibrosis through different mechanisms, but the intervention effects of NAC combined with DMI on silicosis fibrosis have not been reported. Therefore, this study established a rat silicosis model using a single tracheal drip of SiO2 dust suspension in Wistar rats to investigate the effect of NAC combined with DMI on SiO2 dust-induced silicosis and its related molecular mechanisms. The histopathological examination of the SiO2 dust-induced silicosis rats suggested that NAC and DMI alone or in combination could decrease the severity of pulmonary fibrosis in rats. The combined intervention had a better effect on reducing fibrosis than the individual interventions. NAC and DMI, alone or in combination, decreased the levels of markers related to pulmonary fibrosis in rats (smooth muscle α-actin (α-SMA), collagen (Col) I, Col III, hydroxyproline (HYP), inflammatory factors (transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α)), and lipid peroxidase malondialdehyde (MDA)). The nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme-oxygenase-1 (HO-1) and ASMase/ceramide pathways were inhibited to some extent by increasing the superoxide dismutase (SOD) levels of antioxidant enzymes and 8-iso-prostaglandin F2α (8-iso-PGF2α) levels of lipid peroxides. The combined intervention and NAC alone inhibited the SiO2 dust-induced elevation of matrix metalloproteinase 1 (MMP-1) and tissue inhibitor matrix metalloproteinase 1 (TIMP-1), but the effect was not significant in the DMI-treated group. Combining DMI and NAC inhibited Col I deposition and reduced HO-1, TIMP-1, and ASMase levels in lung tissues compared to individual treatments. In summary, the SiO2 dust could induce oxidative stress and inflammation in rats, resulting in an imbalance in extracellular matrix (ECM) synthesis/catabolism and ASMase/ceramide signaling pathway activation, leading to silicosis development.The combined intervention of DMI and NAC may synergistically regulate the Nrf2/HO-1 pathway, maintain the anabolic balance of the ECM, inhibit ASMase/ceramide signaling pathway activation by suppressing the inflammatory response and effectively delay silicosis fibrosis progression.