The crotonylated and succinylated proteins of jujube involved in phytoplasma-stress responses.

BACKGROUND: Protein posttranslational modifications (PTMs) are fast and early responses to environmental changes, including pathogen infection. Jujube witches' broom (JWB) is a phytoplasma disease causing great economic loss in jujube production. After phytoplasma infection, the transcriptional, translational, and metabolic levels in jujube were activated, enabling it to survive during phytoplasma invasion. However, no study has yet reported on PTMs in jujube. Lysine crotonylation (Kcr) and lysine succinylation (Ksu) have been popular studies in recent years and their function in plant phytoplasma-stress responses remains unclear. RESULTS: Here, 1656 crotonylated and 282 succinylated jujube proteins were first identified under phytoplasma-stress, of which 198 were simultaneously crotonylated and succinylated. Comparative analysis revealed that 656 proteins, 137 crotonylated and 43 succinylated proteins in jujube were regulated by phytoplasma infection, suggesting that Kcr was more universal than Ksu. Kcr differentially expressed proteins (DEPs) were related to ribosomes, photosynthetic and carbon metabolism, while Ksu DEPs were mainly involved in carbon metabolism, the TCA cycle and secondary metabolite biosynthesis. The crosstalk network among proteome, crotonylome and succinylome showed that DEPs related to ribosomal, peroxidases and glutathione redox were enriched. Among them, ZjPOD51 and ZjPHGPX2 significantly increased at the protein and Kcr level under phytoplasma-stress. Notably, 7 Kcr sites were identified in ZjPHGPX2, a unique antioxidant enzyme. After inhibitor nicotinamide (NAM) treatment, GPX enzyme activity in jujube seedlings was reduced. Further, site-directed mutagenesis of key Kcr modification sites K130 and/or K135 in ZjPHGPX2 significantly reduced its activity. CONCLUSIONS: This study firstly provided large-scale datasets of Kcr and Ksu in phytoplasma-infected jujube and revealed that Kcr modification in ZjPHGPX2 positively regulates its activity.

Epidemiological features and prognosis for primary gastrointestinal follicular lymphoma.

Primary gastrointestinal follicular lymphoma (PGI-FL) is a rare extra-nodal lymphoma. Its epidemiology and prognosis remain unclear. We performed a retrospective analysis of eligible patients with 1648 PGI-FL and 34 892 nodal FL (N-FL) in the Surveillance, Epidemiology and End Results (SEER) database. The age-adjusted average annual incidence of PGI-FL was 0.111/100000. The median overall survival (OS) for PGI-FL and N-FL patients was 207 and 165 months respectively. The 5-year diffuse large B-cell lymphoma (DLBCL) transformation rates were 2.1% and 2.6% respectively. Age, sex, grade, Ann Arbor stage, primary site and radiation were independent prognostic factors (p < 0.05). Nomograms were constructed to predict 1-, 5- and 10-year OS and disease-specific survival (DSS). The receiver operating characteristic curves and calibration plots showed the established nomograms had robust and accurate performance. Patients were classified into three risk groups according to nomogram score. In conclusion, the incidence of PGI-FL has increased over the past 40 years, and PGI-FL has a better prognosis and a lower DLBCL transformation rate than N-FL. The nomograms were developed and validated as an individualized tool to predict survival. Patients were divided into three risk groups to assist clinicians in identifying high-risk patients and choosing the optimal individualized treatments.

Treatment patterns, clinical outcomes and gene mutation characteristics of hepatitis B virus-associated mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an uncommon and incurable B-cell lymphoma subtype that has an aggressive course. Hepatitis B virus (HBV) infection has been associated with an increased risk for B-cell lymphomas, and is characterized by distinct clinical and genetic features. Here, we showed that 9.5% of MCL Chinese patients were hepatitis B surface antigen positive (HBsAg+). Compared to HBsAg-negative (HBsAg-) patients, HBsAg+ MCL patients had a greater incidence of elevated lactate dehydrogenase (LDH), but no difference was observed in the other clinical characteristics, including sex, age, ECOG ps, Ann Arbor stage, MIPI, extranodal involvement and Ki-67. The HD-AraC (high-dose cytarabine) regimen was the main first-line induction regimen for younger HBsAg+ patients, and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) were used for elderly patients. HBsAg seropositivity was associated with a significantly shorter PFS than HBsAg seronegativity when patients were treated with rituximab or CHOP-based regimens. Compared with CHOP, the HD-AraC regimen was associated with longer PFS in HBsAg+ patients. Treatment with a Bruton tyrosine kinase inhibitor (BTKi) alone can also cause HBV reactivation. Among the 74 patients who underwent targeted deep sequencing (TDS), the nonsynonymous mutation load of HBsAg+ MCL patients was greater than that of HBsAg- MCL patients. HDAC1, TRAF5, FGFR4, SMAD2, JAK3, SMC1A, ZAP70, BLM, CDK12, PLCG2, SMO, TP63, NF1, PTPR, EPHA2, RPTOR and FIP1L1 were significantly enriched in HBsAg+ MCL patients.

Metabolic pathway-based subtyping reveals distinct microenvironmental states associated with diffuse large B-cell lymphoma outcomes.

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease that requires personalized clinical treatment. Assigning patients to different risk categories and cytogenetic abnormality and genetic mutation groups has been widely applied for prognostic stratification of DLBCL. Increasing evidence has demonstrated that dysregulated metabolic processes contribute to the initiation and progression of DLBCL. Metabolic competition within the tumor microenvironment is also known to influence immune cell metabolism. However, metabolism- and immune-related stratification has not been established. Here, 1660 genes involved in 84 metabolic pathways were selected and tested to establish metabolic clusters (MECs) of DLBCL. MECs established based on independent lymphoma datasets distinguished different survival outcomes. The CIBERSORT algorithm and EcoTyper were applied to quantify the relative abundance of immune cell types and identify variation in cell states for 13 lineages comprising the tumor micro environment among different MECs, respectively. Functional characterization showed that MECs were an indicator of the immune microenvironment and correlated with distinctive mutational characteristics and oncogenic signaling pathways. The novel immune-related MECs exhibited promising clinical prognostic value and potential for informing DLBCL treatment decisions.

cGAS-STING, inflammasomes and pyroptosis: an overview of crosstalk mechanism of activation and regulation.

BACKGROUND: Intracellular DNA-sensing pathway cGAS-STING, inflammasomes and pyroptosis act as critical natural immune signaling axes for microbial infection, chronic inflammation, cancer progression and organ degeneration, but the mechanism and regulation of the crosstalk network remain unclear. Cellular stress disrupts mitochondrial homeostasis, facilitates the opening of mitochondrial permeability transition pore and the leakage of mitochondrial DNA to cell membrane, triggers inflammatory responses by activating cGAS-STING signaling, and subsequently induces inflammasomes activation and the onset of pyroptosis. Meanwhile, the inflammasome-associated protein caspase-1, Gasdermin D, the CARD domain of ASC and the potassium channel are involved in regulating cGAS-STING pathway. Importantly, this crosstalk network has a cascade amplification effect that exacerbates the immuno-inflammatory response, worsening the pathological process of inflammatory and autoimmune diseases. Given the importance of this crosstalk network of cGAS-STING, inflammasomes and pyroptosis in the regulation of innate immunity, it is emerging as a new avenue to explore the mechanisms of multiple disease pathogenesis. Therefore, efforts to define strategies to selectively modulate cGAS-STING, inflammasomes and pyroptosis in different disease settings have been or are ongoing. In this review, we will describe how this mechanistic understanding is driving possible therapeutics targeting this crosstalk network, focusing on the interacting or regulatory proteins, pathways, and a regulatory mitochondrial hub between cGAS-STING, inflammasomes, and pyroptosis. SHORT CONCLUSION: This review aims to provide insight into the critical roles and regulatory mechanisms of the crosstalk network of cGAS-STING, inflammasomes and pyroptosis, and to highlight some promising directions for future research and intervention.

Interaction of Glycemic Control and Statin Use on Diabetes-Tuberculosis Treatment Outcome: A Nested Case-Control Study.

This study aims to explore the interaction of glycemic control and statin use on the treatment outcomes of pulmonary tuberculosis-diabetes comorbidity (PTB-DM) patients. A nested case-control study was conducted in a tuberculosis patients' cohort. We defined cases as patients who experienced unfavorable outcomes. Glycemic control was estimated at the baseline. Statin use was obtained from medical records. The multivariate logistic regression models were developed, and the interaction table invented by Andersson was adopted to analyze the interaction of glycemic control and statin use on treatment outcomes. A total of 2,047 patients were included in this study. There was a significant interaction between glycemic control and statin use on the treatment outcomes. Patients with good glycemic control and no statin use (OR = 0.464, 95% CI: 0.360-0.623) had a lower risk of unfavorable outcomes than those with poor glycemic control and statin use (OR = 0.604, 95% CI: 0.401-0.734). Patients with good glycemic control and statin use had the lowest risk of unfavorable outcomes (OR = 0.394, 95% CI: 0.264-0.521). Glycemic control in diabetes-tuberculosis treatment should be paid considerable attention. Patients can benefit from statin use even if they have poor glycemic control. Patients with good glycemic control and statin use can have the best outcomes.

Integrative genomic and transcriptomic analysis reveals genetic alterations associated with the early progression of follicular lymphoma.

Follicular lymphoma (FL), the most common indolent lymphoma, is a clinically and genetically heterogeneous disease. However, the prognostic value of driver gene mutations and copy number alterations has not been systematically assessed. Here, we analysed the clinical-biological features of 415 FL patients to identify variables associated with disease progression within 24 months of first-line therapy (POD24). Patients with B symptoms, elevated lactate dehydrogenase and ß2-microglobulin levels, unfavourable baseline haemoglobin levels, advanced stage, and high-risk FL International Prognostic Index (FLIPI) scores had an increased risk of POD24, with FLIPI being the most important factor in logistic regression. HIST1H1D, identified as a driver mutation, was correlated with POD24. Gains of 6p22.2 (HIST1H1D) and 18q21.33 (BCL2) and loss of 1p36.13 (NBPF1) predicted POD24 independent of FLIPI. Gene expression profiling of FL samples showed that the POD24 cohort was significantly enriched in the inflammatory response (mediated by interferon and tumour necrosis factor), cell cycle regulation (transcription, replication and proliferation) sets and PI3K-AKT-mTOR signalling. This result was further validated with transcriptome-wide information provided by RNA-seq at single-cell resolution. Our study, performed on a large cohort of FL patients, highlights the importance of distinctive genetic alterations and gene expression relevant to disease diagnosis and early progression.

170-W Nd:YAG InnoSlab laser at 1319†nm.

In this paper, a continuous-wave Nd:YAG InnoSlab laser at 1319 nm with high output power and high beam quality is demonstrated. The maximum output power of 170 W at 1319-nm single wavelength is obtained with an optical-to-optical efficiency of 15.3% from absorbed pump power to laser output and the corresponding slope efficiency of 26.7%. The beam quality factors of M2 are 1.54 and 1.78 in the horizontal and vertical directions, respectively. To the best of our knowledge, this is the first report on Nd:YAG 1319-nm InnoSlab lasers with such high output power and good beam quality.

Improved method to stratify lymphoma patients with risk of secondary central nervous system involvement: A multicenter retrospective analysis.

Secondary central nervous system (SCNS) involvement is an infrequent but universally fatal event in diffused large B-cell lymphoma. The occurrence rate of SCNS involvement is approximately 5% but comes with a poor prognosis ever after. However, existing risk models to predict the incidence and prognosis of these patients with SCNS involvement lack both efficiency and accuracy. Controversy has also been reported regarding which risk factor may best identify the population with a high CNS relapse rate. In this study, we retrospectively analyzed 831 patients with diffused large B-cell lymphoma, diagnosed between March 2008 and June 2018 in Tianjin Medical University Cancer Institute and Hospital, Beijing Cancer Hospital, and Cancer Hospital of The University of Chinese Academy of Science. Risk factors and nomogram were identified and established based on Fine and Gray's competing risk analysis. Among these patients, 55 (6.6%) of them eventually developed SCNS involvement. The 1- and 2-year incidence for SCNS involvement were 3.9% and 4.7%, respectively. The median time from de novo diagnosis to CNS relapse was 8 months, and the median overall survival of these patients was 28 months. Considering the competing mortality before SCNS involvement, Fine and Gray's competing risk model was performed to analyze the characteristics related to SCNS involvement, and identified risk factors as the multiple extranodal involvements, elevated LDH and AMC level, and the involvement of breast, adrenal gland/kidney, pulmonary and bone. Corresponding factors were integrated into the competing nomogram for SCNS involvement (c-index = 0.778). In conclusion, we present the first predictive nomogram to evaluate the risk to develop SCNS involvement in de novo DLBCL patients, which may help in both prognostic evaluation and clinical decision for this subgroup.

Short- and long-term impacts of the COVID-19 epidemic on urban PM2.5 variations: Evidence from a megacity, Chengdu.

As the new coronavirus pandemic enters its third year, its long-term impact on the urban environment cannot be ignored, especially in megacities with more than millions of people. Here, we analyzed the changes in the concentration levels, emission sources, temporal variations and holiday effects of ambient fine particulate matter (PM2.5) and its chemical components in the pre- and post-epidemic eras based on high-resolution, long time-series datasets of PM2.5 and its chemical components in Chengdu. In the post-epidemic era, the PM2.5 concentration in Chengdu decreased by 7.4%, with the components of PM2.5 decreasing to varying degrees. The positive matrix factorization (PMF) results indicated that the emissions from soil dust and industrial production were significantly lower during the COVID-19 lockdown period and post-epidemic era than those in the pre-epidemic era. In contrast, the contribution of secondary aerosols to PM2.5 during these two periods increased by 2.7% and 6.6%, respectively. Notably, we found that PM2.5 and its components substantially decreased on workdays and holidays in the post-epidemic era due to the reduced traffic volume and outdoor activities. This provides direct evidence that changes in the habitual behavior patterns of urban residents in the post-epidemic era could exert an evident positive impact on the urban environment. However, the higher PM2.5 concentration was observed due to the increased consumption of regular (As4S4, Xionghuang in Chinese) and "sulfur incense" during the Dragon Boat Festival holiday in the post-epidemic era. Finally, we examined the potential effects of sporadic COVID-19 outbreaks on the PM2.5 concentration in Chengdu, and there was no decrease in PM2.5 during two local COVID-19 outbreak events due to the strong influence of secondary pollution processes.

Regional anesthesia did not improve postoperative long-term survival of tumor patients: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Experimental research and clinical trials have reported a positive effect of regional anesthesia (RA) on prognosis of cancers. We systematically reviewed the efficacy of RA on recurrence-free survival (RFS) and overall survival (OS) after oncology surgeries. METHODS: PubMed, Cochrane library, and Embase were searched from inception to June 20, 2022 for RCTs in which any form of RA was initiated perioperatively. Time-to-event data (hazard ratio (HR)) were extracted independently and in duplicate. The primary outcome was the association of RA with RFS and OS, while the secondary outcomes included time to tumor progression, 5-year RFS, and 5-year OS. RESULTS: Fifteen RCTs with 5981 participants were included. Compared to GA, RA has no positive effect on RFS (HR, - 0.02; 95% CI, - 0.11 to 0.07), OS (HR, - 0.03; 95% CI, - 0.28 to 0.23), time to tumor progression (0.11; 95% CI, - 0.33 to 0.55), 5-year RFS (risk ratio (RR), 1.24; 95% CI, 0.88 to 1.76)), and 5-year OS (RR, 1.11; 95% CI, 0.85 to 1.44). Subgroup analysis based on study design, patient characteristics and tumor types also showed no effect of RA on RFS or OS. CONCLUSIONS: Our results demonstrated that there is no significant evidence supporting the role of RA in improving long-term survival after oncology surgeries.

Foretinib Is Effective against Triple-Negative Breast Cancer Cells MDA-MB-231 In Vitro and In Vivo by Down-Regulating p-MET/HGF Signaling.

This study investigated the antitumor effects of foretinib on triple-negative breast cancer cells MDA-MB-231 xenograft tumors in vivo underlying phosphorylated mesenchymal to epithelial transition (p-MET)/ hepatocyte growth factor (HGF)-related mechanism, as well as its pharmacokinetic characteristics. The MDA-MB-231 human breast cancer cell line was used for in vitro experiments, and the tumor xenograft model was established for in vivo experiments. MDA-MB-231 xenograft mice received oral foretinib (15 or 50 mg/kg/day) or vehicle for 18 days. The xenograft tumors were collected. Protein expressions of p-MET and HGF were examined with Western blotting and immunohistochemical staining. The mRNA expression of MET was examined with real-time PCR. Blood samples were collected from the mice treated with foretinib under different doses of 2, 10, and 50 mg/kg, and the pharmacokinetic profiles of foretinib were evaluated. We found that foretinib treatment caused a significant inhibition in tumor growth in a dose-dependent manner, whereas the continuous administration did not result in weight loss in treated nude mice. In both MDA-MB-231 cells and xenograft tumors, foretinib suppressed the expression of p-MET and HGF. These findings reveal that the decrease of p-MET and HGF may play an important role in the anti-breast cancer properties of foretinib.

[Oral absorption and effect of macromolecules in traditional Chinese medicine: a new perspective and research mode of phase structure].

Protein polypeptides and polysaccharides, the indispensable macromolecular active components in traditional Chinese medicine, are widely found in Chinese medicine decoction after the decoction of traditional Chinese medicine. However, through oral administration, these macromolecules are digested by the stomach and intestine and thus fail to be absorbed in prototype. This is inconsistent with the actual clinical efficacy of Chinese medicine decoction. According to modern research, new phase structures and effects of the macromolecules emerge during the decoction of traditional Chinese medicine, but the phase change law caused by the interaction among the components of traditional Chinese medicine and the relationship between phase structure and effect are still unclear. Thus, this study reviewed the oral absorption of macromolecular components of traditional Chinese medicine, analyzed the internal relationship of the form of macromolecules in traditional Chinese medicine with the absorption and effect based on phase structure, and summarized the research mode of oral absorption and effect of macromolecules in traditional Chinese medicine with phase structures as the core, providing new ideas and methods for future research.

Alcohol consumption, DNA methylation and colorectal cancer risk: Results from pooled cohort studies and Mendelian randomization analysis.

Alcohol consumption is thought to be one of the modifiable risk factors for colorectal cancer (CRC). However, the causality and mechanisms by which alcohol exerts its carcinogenic effect are unclear. We evaluated the association between alcohol consumption and CRC risk by analyzing data from 32 cohort studies and conducted two-sample Mendelian randomization (MR) analysis to examine for casual relationship. To explore the effect of alcohol related DNA methylation on CRC risk, we performed an epigenetic MR analysis with data from an epigenome-wide association study (EWAS). We additionally performed gene-alcohol interaction analysis nested in the UK Biobank to assess effect modification between alcohol consumption and susceptibility genes. We discovered distinct effects of alcohol on CRC incidence and mortality from the meta-analyses, and genetic predisposition to alcohol drinking was causally associated with an increased CRC risk (OR = 1.79, 95% CI: 1.23-2.61) using two-sample MR approaches. In epigenetic MR analysis, two alcohol-related CpG sites (cg05593667 and cg10045354 mapped to COLCA1/COLCA2 gene) were identified causally associated with an increased CRC risk (P < 8.20 × 10-4 ). Gene-alcohol interaction analysis revealed that carriage of the risk allele of the eQTL (rs3087967) and mQTL (rs11213823) polymorphism of COLCA1/COLCA2 would interact with alcohol consumption to increase CRC risk (PInteraction  = .027 and PInteraction  = .016). Our study provides comprehensive evidence to elucidate the role of alcohol in CRC and highlights that the pathogenic effect of alcohol on CRC could be partly attributed to DNA methylation by regulating the expression of COLCA1/COLCA2 gene.

Codon usage patterns across seven Rosales species.

BACKGROUND: Codon usage bias (CUB) analysis is an effective method for studying specificity, evolutionary relationships, and mRNA translation and discovering new genes among various species. In general, CUB analysis is mainly performed within one species or between closely related species and no such study has been applied among species with distant genetic relationships. Here, seven Rosales species with high economic value were selected to conduct CUB analysis. RESULTS: The results showed that the average GC1, GC2 and GC3 contents were 51.08, 40.52 and 43.12%, respectively, indicating that the A/T content is more abundant and the Rosales species prefer A/T as the last codon. Neutrality plot and ENc plot analysis revealed that natural selection was the main factor leading to CUB during the evolution of Rosales species. All 7 Rosales species contained three high-frequency codons, AGA, GTT and TTG, encoding Arg, Val and Leu, respectively. The 7 Rosales species differed in high-frequency codon pairs and the distribution of GC3, though the usage patterns of closely related species were more consistent. The results of the biclustering heat map among 7 Rosales species and 20 other species were basically consistent with the results of genome data, suggesting that CUB analysis is an effective method for revealing evolutionary relationships among species at the family or order level. In addition, chlorophytes prefer using G/C as ending codon, while monocotyledonous and dicotyledonous plants prefer using A/T as ending codon. CONCLUSIONS: The CUB pattern among Rosales species was mainly affected by natural selection. This work is the first to highlight the CUB patterns and characteristics of Rosales species and provides a new perspective for studying genetic relationships across a wide range of species.

Synthesis of pyrrole disulfides via umpolung of ß-ketothioamides.

A Na2CO3-promoted reaction of ß-ketothioamides (KTAs) and cyanoacetates was developed for the synthesis of pyrrole disulfides using air as a green oxidant. This protocol features a broad substrate scope and mild reaction conditions. Preliminary mechanistic studies indicate that the reaction involves a tandem unusual umpolung of KTAs, N-cyclization, tautomerization and oxidative coupling process.

FX5, a non-steroidal glucocorticoid receptor antagonist, ameliorates diabetic cognitive impairment in mice.

Diabetic cognitive impairment (DCI) is a common diabetic complication characterized by learning and memory deficits. In diabetic patients, hyperactivated hypothalamic-pituitary-adrenal (HPA) axis leads to abnormal increase of glucocorticoids (GCs), which causes the damage of hippocampal neurons and cognitive impairment. In this study we investigated the cognition-improving effects of a non-steroidal glucocorticoid receptor (GR) antagonist 5-chloro-N-[4-chloro-3-(trifluoromethyl) phenyl]thiophene-2-sulfonamide (FX5) in diabetic mice. Four weeks after T1DM or T2DM was induced, the mice were administered FX5 (20, 40 mg·kg-1·d-1, i.g.) for 8 weeks. Cognitive impairment was assessed in open field test, novel object recognition test, Y-maze test, and Morris water maze test. We showed that FX5 administration significantly ameliorated the cognitive impairments in both type 1 and 2 diabetic mice. Similar cognitive improvement was observed in diabetic mice following brain GR-specific knockdown by injecting AAV-si-GR. Moreover, AAV-si-GR injection occluded the cognition-improving effects of FX5, suggesting that FX5 functioning as a non-steroidal GR antagonist. In PA-treated primary neurons (as DCI model in vitro), we demonstrated that FX5 (2, 5, 10 µM) dose-dependently ameliorated synaptic impairment via upregulating GR/BDNF/TrkB/CREB pathway, protected against neuronal apoptosis through repressing GR/PI3K/AKT/GSK3ß-mediated tauopathy and subsequent endoplasmic reticulum stress. In LPS-treated primary microglia, FX5 dose-dependently inhibited inflammation through GR/NF-κB/NLRP3/ASC/Caspase-1 pathway. These beneficial effects were also observed in the hippocampus of diabetic mice following FX5 administration. Collectively, we have elucidated the mechanisms underlying the beneficial effects of non-steroidal GR antagonist FX5 on DCI and highlighted the potential of FX5 in the treatment of the disease.

Update: Innate Lymphoid Cells in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic and nonspecific intestinal inflammatory condition with high relapse rate. Its pathogenesis has been linked to dysbacteriosis, genetic and environmental factors. In recent years, a new type of lymphocytes, termed innate lymphoid cells, has been described and classified into three subtypes of innate lymphoid cells-group 1, group 2 and group 3. An imbalance among these subsets' interaction with gut microbiome, and other immune cells affects intestinal mucosal homeostasis. Understanding the role of innate lymphoid cells may provide ideas for developing novel and targeted approaches for treatment of IBD.

Methodology in phenome-wide association studies: a systematic review.

Phenome-wide association study (PheWAS) has been increasingly used to identify novel genetic associations across a wide spectrum of phenotypes. This systematic review aims to summarise the PheWAS methodology, discuss the advantages and challenges of PheWAS, and provide potential implications for future PheWAS studies. Medical Literature Analysis and Retrieval System Online (MEDLINE) and Excerpta Medica Database (EMBASE) databases were searched to identify all published PheWAS studies up until 24 April 2021. The PheWAS methodology incorporating how to perform PheWAS analysis and which software/tool could be used, were summarised based on the extracted information. A total of 1035 studies were identified and 195 eligible articles were finally included. Among them, 137 (77.0%) contained 10 000 or more study participants, 164 (92.1%) defined the phenome based on electronic medical records data, 140 (78.7%) used genetic variants as predictors, and 73 (41.0%) conducted replication analysis to validate PheWAS findings and almost all of them (94.5%) received consistent results. The methodology applied in these PheWAS studies was dissected into several critical steps, including quality control of the phenome, selecting predictors, phenotyping, statistical analysis, interpretation and visualisation of PheWAS results, and the workflow for performing a PheWAS was established with detailed instructions on each step. This study provides a comprehensive overview of PheWAS methodology to help practitioners achieve a better understanding of the PheWAS design, to detect understudied or overstudied outcomes, and to direct their research by applying the most appropriate software and online tools for their study data structure.

Gas Concentration Prediction Based on IWOA-LSTM-CEEMDAN Residual Correction Model.

In this study, to further improve the prediction accuracy of coal mine gas concentration and thereby preventing gas accidents and improving coal mine safety management, the standard whale optimisation algorithm's (WOA) susceptibility to falling into local optima, slow convergence speed, and low prediction accuracy of the single-factor long short-term memory (LSTM) neural network residual correction model are addressed. A new IWOA-LSTM-CEEMDAN model is constructed based on the improved whale optimisation algorithm (IWOA) to improve the IWOA-LSTM one-factor residual correction model through the use of the complete ensemble empirical model decomposition with adaptive noise (CEEMDAN) method. The population diversity of the WOA is enhanced through multiple strategies and its ability to exit local optima and perform global search is improved. In addition, the optimal weight combination model for subsequence is determined by analysing the prediction error of the intrinsic mode function (IMF) of the residual sequence. The experimental results show that the prediction accuracy of the IWOA-LSTM-CEEMDAN model is higher than that of the BP neural network and the GRU, LSTM, WOA-LSTM, and IWOA-LSTM residual correction models by 47.48%, 36.48%, 30.71%, 27.38%, and 12.96%, respectively. The IWOA-LSTM-CEEMDAN model also achieves the highest prediction accuracy in multi-step prediction.