Gut Microbiota-Derived Butyrate Induces Epigenetic and Metabolic Reprogramming in Myeloid-Derived Suppressor Cells to Alleviate Primary Biliary Cholangitis.

BACKGROUND & AIMS: Gut dysbiosis and myeloid-derived suppressor cells (MDSCs) are implicated in primary biliary cholangitis (PBC) pathogenesis. However, it remains unknown whether gut microbiota or their metabolites can modulate MDSCs homeostasis to rectify immune dysregulation in PBC. METHODS: We measured fecal short-chain fatty acids levels using targeted gas chromatography-mass spectrometry and analyzed circulating MDSCs using flow cytometry in 2 independent PBC cohorts. Human and murine MDSCs were differentiated in vitro in the presence of butyrate, followed by transcriptomic, epigenetic (CUT&Tag-seq and chromatin immunoprecipitation-quantitative polymerase chain reaction), and metabolic (untargeted liquid chromatography-mass spectrometry, mitochondrial stress test, and isotope tracing) analyses. The in vivo role of butyrate-MDSCs was evaluated in a 2-octynoic acid-bovine serum albumin-induced cholangitis murine model. RESULTS: Decreased butyrate levels and defective MDSC function were found in patients with incomplete response to ursodeoxycholic acid, compared with those with adequate response. Butyrate induced expansion and suppressive activity of MDSCs in a manner dependent on PPARD-driven fatty acid ß-oxidation (FAO). Pharmaceutical inhibition or genetic knockdown of the FAO rate-limiting gene CPT1A abolished the effect of butyrate. Furthermore, butyrate inhibited HDAC3 function, leading to enhanced acetylation of lysine 27 on histone H3 at promoter regions of PPARD and FAO genes in MDSCs. Therapeutically, butyrate administration alleviated immune-mediated cholangitis in mice via MDSCs, and adoptive transfer of butyrate-treated MDSCs also displayed protective efficacy. Importantly, reduced expression of FAO genes and impaired mitochondrial physiology were detected in MDSCs from ursodeoxycholic acid nonresponders, and their impaired suppressive function was restored by butyrate. CONCLUSIONS: We identify a critical role for butyrate in modulation of MDSC homeostasis by orchestrating epigenetic and metabolic crosstalk, proposing a novel therapeutic strategy for treating PBC.

Effects of Sophora flavescens dietary supplementation on the growth performance, haematological indices, and intestinal bacterial community of Oreochromis niloticus.

Sophora flavescens is considered to be of various medicinal and economic importance. Previous studies have shown that it has antibacterial, antioxidant, and immune-enhancing functions. To explore the full potential of S. flavescens in fish feed development, we investigated the effects of different levels of S. flavescens added to the diet on the growth performance, haematological indices, and the intestinal bacterial community of Nile tilapia (Oreochromis niloticus). The feeding trial lasted for 56 days, and the initial weight of the fish was 40.00 ± 5.00 g. Nile tilapia were randomly divided into six groups: a control group (CN) and five S. flavescens supplementation groups (0.02%, 0.04%, 0.08%, 0.16%, and 0.3% [w/w] of S. flavescens in diet). The growth performance of fish increased first and then decreased with the increase of S. flavescens supplemental level. Compared with other experimental groups, the growth performance of fish supplemented with 0.08% S. flavescens was significantly improved (p < 0.05). Haematological indices exhibited that erythrocyte (RBC), along with leucocyte (WBC) indices, exhibited a secondary trend of increasing and then decreasing with the increase of S. flavescens, reaching the highest level at 0.08% (p < 0.05). However, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), and mean corpuscular haemoglobin concentration (MCHC) exhibited a secondary trend of first decreasing and then increasing with the increase of S. flavescens and reached the lowest value at 0.08% (p < 0.05). Compared with the CN, alkaline phosphatase (AKP) significantly decreased and changed when the additional amount of S. flavescens was 0.04% in each treatment group (p < 0.05). In another way, the gut microbial profiles revealed that Bacteroides dominated the gut communities, and compared with the control group, two uncultured bacteria were suppressed. In addition, when the supplemental level of S. flavescens was more significant than 0.04%, the proliferation of Arcobacter cryaerophilus, Solibacillus silvestris, and Escherichia sp. in the gut of Nile tilapia was promoted. The results revealed that S. flavescens, as an additive to the Nile tilapia diet with levels ranging from 0.04% to 0.08%, can enhance the growth performance and immunity and promote the proliferation of intestinal beneficial bacteria of Nile tilapia.

A+T rich interaction domain protein 3a (Arid3a) impairs Mertk-mediated efferocytosis in cholestasis.

BACKGROUND & AIMS: Macrophages are key elements in the pathogenesis of cholestatic liver diseases. Arid3a plays a prominent role in the biologic properties of hematopoietic stem cells, B lymphocytes and tumor cells, but its ability to modulate macrophage function during cholestasis remains unknown. METHODS: Gene and protein expression and cellular localization were assessed by q-PCR, immunohistochemistry, immunofluorescence staining and flow cytometry. We generated myeloid-specific Arid3a knockout mice and established three cholestatic murine models. The transcriptome was analyzed by RNA-seq. A specific inhibitor of the Mertk receptor was used in vitro and in vivo. Promoter activity was determined by chromatin immunoprecipitation-seq against Arid3a and a luciferase reporter assay. RESULTS: In cholestatic murine models, myeloid-specific deletion of Arid3a alleviated cholestatic liver injury (accompanied by decreased accumulation of macrophages). Arid3a-deficient macrophages manifested a more reparative phenotype, which was eliminated by in vitro treatment with UNC2025, a specific inhibitor of the efferocytosis receptor Mertk. Efferocytosis of apoptotic cholangiocytes was enhanced in Arid3a-deficient macrophages via upregulation of Mertk. Arid3a negatively regulated Mertk transcription by directly binding to its promoter. Targeting Mertk in vivo effectively reversed the protective phenotype of Arid3a deficiency in macrophages. Arid3a was upregulated in hepatic macrophages and circulating monocytes in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Mertk was correspondingly upregulated and negatively correlated with Arid3a expression in PBC and PSC. Mertk+ cells were located in close proximity to cholangiocytes, while Arid3a+ cells were scattered among immune cells with greater spatial distances to hyperplastic cholangiocytes in PBC and PSC. CONCLUSIONS: Arid3a promotes cholestatic liver injury by impairing Mertk-mediated efferocytosis of apoptotic cholangiocytes by macrophages during cholestasis. The Arid3a-Mertk axis is a promising novel therapeutic target for cholestatic liver diseases. IMPACT AND IMPLICATIONS: Macrophages play an important role in the pathogenesis of cholestatic liver diseases. This study reveals that macrophages with Arid3a upregulation manifest a pro-inflammatory phenotype and promote cholestatic liver injury by impairing Mertk-mediated efferocytosis of apoptotic cholangiocytes during cholestasis. Although we now offer a new paradigm to explain how efferocytosis is regulated in a myeloid cell autonomous manner, the regulatory effects of Arid3a on chronic liver diseases remain to be further elucidated.

Bioinformatics analysis based on high-throughput sequencing data to identify hub genes related to different clinical types of COVID-19.

This article aims to explore hub genes related to different clinical types of cases with COVID-19 and predict the therapeutic drugs related to severe cases. The expression profile of GSE166424 was divided into four data sets according to different clinical types of COVID-19 and then calculated the differential expression genes (DEGs). The specific genes of four clinical types of COVID-19 were obtained by Venn diagram and conducted enrichment analysis, protein-protein interaction (PPI) networks analysis, screening hub genes, and ROC curve analysis. The hub genes related to severe cases were verified in GSE171110, their RNA-specific expression tissues were obtained from the HPA database, and potential therapeutic drugs were predicted through the DGIdb database. There were 536, 266, 944, and 506 specific genes related to asymptomatic infections, mild, moderate, and severe cases, respectively. The hub genes of severe specific genes were AURKB, BRCA1, BUB1, CCNB1, CCNB2, CDC20, CDC6, KIF11, TOP2A, UBE2C, and RPL11, and also differentially expressed in GSE171110 (P < 0.05), and their AUC values were greater than 0.955. The RNA tissue specificity of AURKB, CDC6, KIF11, UBE2C, CCNB2, CDC20, TOP2A, BUB1, and CCNB1 specifically enhanced on lymphoid tissue; CCNB2, CDC20, TOP2A, and BUB1 specifically expressed on the testis. Finally, 55 drugs related to severe COVID-19 were obtained from the DGIdb database. Summary, AURKB, BRCA1, BUB1, CCNB1, CCNB2, CDC20, CDC6, KIF11, TOP2A, UBE2C, and RPL11 may be potential diagnostic biomarkers for severe COVID-19, which may affect immune and male reproductive systems. 55 drugs may be potential therapeutic drugs for severe COVID-19.

Ultrastable Graphite-Potassium Anode through Binder Chemistry.

Graphite with abundant reserves has attracted enormous research interest as an anode of potassium-ion batteries (PIBs) owing to its high plateau capacity of 279 mAh g-1 at ≈0.2 V in conventional carbonate electrolytes. Unfortunately, it suffers from fast capacity decay during K+ storage. Herein, an ultrastable graphite-potassium anode is developed through binder chemistry. Polyvinyl alcohol (PVA) is utilized as a water-soluble binder to generate a uniform and robust KF-rich SEI film on the graphite surface, which can not only inhibit the electrolyte decomposition, but also withstand large volume expansion during K+ -insertion. Compared to the PVDF as binder, PVA-based graphite anode can operate for over 2000 cycles (running time of 406 days at C/3) with 97% capacity retention in KPF6 -based electrolytes. The initial Coulombic efficiency (ICE) of graphite anode is as high as 81.6% using PVA as the binder, higher than that of PVDF (40.1%). Benefiting from the strong adhesion ability of PVA, a graphite||fluorophosphate K-ion full battery is further built through 3D printing, which achieves a record-high areal energy of 8.9 mWh cm-2 at a total mass loading of 38 mg cm-2 . These results demonstrate the important role of binder in developing high-performance PIBs.

A Potential Immune-Related miRNAs Regulatory Network and Corresponding Diagnostic Efficacy in Schizophrenia.

PURPOSE: Immune-related pathways actively participate in the progression of schizophrenia (SCZ), however, roles of immune-related miRNAs in SCZ are still unclear. METHODS: A microarray expression study was conducted to explored roles of immune-related genes in SCZ. Functional enrichment analysis by using "clusterProfiler" was used to identify molecular alterations of SCZ. Protein-protein interaction (PPI) network was constructed and helped core molecular factors identification. Based on The Cancer Genome Atlas (TCGA) database, clinical significances of hub immune-related genes in cancers were also been explored. Then, correlation analyses were used to determine immune-related miRNAs. We further validated that hsa-miR-1299 could be an effective diagnostic biomarker for SCZ via analyzing multi-cohorts' data and quantitative real-time PCR (qRT-PCR). RESULTS: A total of 455 mRNAs and 70 miRNAs that were differentially expressed between SCZ and control samples. Functional enrichment analysis based on differentially expressed genes (DEGs) hinted that immune-related pathways were significantly correlated with SCZ. Furthermore, a total of 35 immune-related genes that involved in disease onset and showed significant co-expressed relationships. Hub immune-related gene CCL4 and CCL22 are valuable in tumor diagnosis and survival prediction. Furthermore, we also identified 22 immune-related miRNAs that play important roles in this disease. An immune-related miRNAs-mRNAs regulatory network was constructed to provide miRNAs regulatory roles in SCZ. Core miRNAs expression status of hsa-miR-1299 were also validated in another cohort, which suggested its diagnostic performance for SCZ. CONCLUSIONS: Our study reports the downregulation of some miRNAs in the process of SCZ are important. Shared genomics characteristics between SCZ and cancers also provide novel insights for cancers. A significant alteration of hsa-miR-1299 expression is effective as biomarker for the diagnosis of SCZ, suggesting that this miRNA could be a specific biomarker.

Phylogeny, Morphology, Distribution, and Pathogenicity of Seven Calonectria Species from Leaf-Blighted Eucalyptus in HaiNan Island, China.

Leaf blight caused by Calonectria species constrains Eucalyptus trees in China. Calonectria leaf disease on Eucalyptus in China was first reported in HaiNan Island in 1985. No systematic investigation of Calonectria species associated with diseased Eucalyptus in HaiNan has been performed. To understand the species diversity, distribution, and pathogenicity of these Calonectria, 400 Calonectria isolates were obtained from 278 diseased Eucalyptus planted in 17 sites in five regions. All 400 isolates were identified by DNA sequences of translation elongation factor 1-alpha, ß-tubulin, calmodulin, and histone H3 gene regions and on morphology. Seven species, C. acaciicola (198 isolates), C. pseudoreteaudii (161 isolates), C. reteaudii (29 isolates), C. hawksworthii (6 isolates), C. hongkongensis (4 isolates), C. auriculiformis (1 isolate), and C. chinensis (1 isolate), were identified. This is the first report of C. acaciicola in China. C. acaciicola, C. pseudoreteaudii, and C. reteaudii belong to the C. reteaudii species complex and accounted for 97% of all isolates. The three species overlapped in vesicle shape, macroconidia size, and macroconidia septa number. Region significantly influenced C. acaciicola and C. pseudoreteaudii distribution. Representative isolates of C. acaciicola, C. pseudoreteaudii, C. reteaudii, and C. hawksworthii producing abundant macroconidia were used in conidial suspension inoculation on Eucalyptus seedlings; all were highly pathogenic to the two tested genotypes. The tolerances of two Eucalyptus genotypes were significantly different. This first systematic investigation of Calonectria species associated with Eucalyptus leaf blight in HaiNan will aid selection of disease-resistant genotypes for managing Eucalyptus leaf blight caused by Calonectria species in China.

A novel approach for the forensic diagnosis of drowning by microbiological analysis with next-generation sequencing and unweighted UniFrac-based PCoA.

The diagnosis of drowning is one of the major challenges in forensic practice, especially when the corpse is in a state of decomposition. Novel indicators of drowning are desired in the field of forensic medicine. In the past decade, aquatic bacteria have attracted great attention from forensic experts because they can easily enter the blood circulation with drowning medium, and some of them can proliferate in the corpse. Recently, the advent of next-generation sequencing (NGS) has created new opportunities to efficiently analyze whole microbial communities and has catalyzed the development of forensic microbiology. We presumed that NGS could be a potential method for diagnosing drowning. In the present study, we verified this hypothesis by fundamental experiments in drowned and postmortem-submersed rat models. Our study revealed that detecting the bacterial communities with NGS and processing the data in a transparent way with unweighted UniFrac-based principal coordinates analysis (PCoA) could clearly discriminate the skin, lung, blood, and liver specimens of the drowning group and postmortem submersion group. Furthermore, the acquired information could be used to identify new cases. Taken together, these results suggest that we could build a microbial database of drowned and postmortem-submersed victims by NGS and subsequently use a bioinformatic method to diagnose drowning in future forensic practice.

MGAT5/TMEM163 variant is associated with prognosis in ursodeoxycholic acid-treated patients with primary biliary cholangitis.

BACKGROUND: Primary biliary cholangitis (PBC) is a chronic immune-mediated liver disease. Previous genome-wide meta-analysis has identified the association between variants in TMEM163 with PBC. Here we aimed to evaluate the association between variants near the reported risk loci of TMEM163 at 2q21.3 and prognosis of PBC patients. METHODS: We performed a retrospective analysis of 347 PBC patients treated with ursodeoxycholic acid (UDCA) for at least 1 year. We collected clinical data at diagnosis and 1 year after UDCA treatment. SNPs within 200 kb upstream and downstream of the lead variant were genotyped and screened. RESULTS: We identified that rs661899 near MGAT5 and TMEM163 showed the strongest association with prognosis in PBC patients. Patients carrying the rs661899 T allele tended to respond incompletely to UDCA treatment and had worse performances in laboratory values including aspartate aminotransferase (53.5 vs 32 vs 28.5 U/L, p = 0.001), alkaline phosphate (157.25 vs 125 vs 113 U/L, p = 0.001), albumin (41.5 vs 42.3 vs 43.7 g/L, p = 0.008) and bilirubin (19.2 vs 14.9 vs 12.85 µmol/L, p = 0.001). GLOBE scores (p = 4.8 × 10-5) and UK-PBC risk scores (p = 4.6 × 10-4) were strongly correlated with rs661899 genotype. Patients with TT genotype had a higher risk for adverse events compared with CC genotype (p = 0.039) during the 1-year follow-up. Results were also verified in an independent cohort. CONCLUSIONS: PBC patients carrying the rs661899 T allele are associated with poor prognosis and adverse outcomes after 1-year UDCA therapy.

Integrating commercial graphite with network-like carbon fibers for high-rate and long-term cycling K+-storage.

K can reversibly intercalate into graphite by forming KC8 (279 mA h g-1, ≈0.2 V) in conventional carbonate electrolytes, but the large ionic radius of K+ (1.38 Å) easily results in structural degradation and rapid capacity decay. Here, commercial graphite particles are directly electrospun into network-like carbon fibers, thus forming a flexible Gr@CNF membrane. This hybrid electrode configuration can efficiently withstand the volume expansion during K+ insertion. K||Gr@CNF half-cells can stably operate for over 800 cycles (running time of 170 days at C/3) and achieve fast K+-intercalation kinetics at 5C. The fabricated Gr@CNF||AC K-ion hybrid capacitor delivers a high energy density of 119.3 W h kg-1 at 2717.82 W kg-1, corresponding to a fast-charge time of 3.2 min.

A prospective cohort study on the effect of lipid accumulation product index on the incidence of cardiovascular diseases.

BACKGROUND: Cardiovascular disease (CVD) is a chronic disease with a serious prognosis, and obesity is a risk factor for CVD. Lipid accumulation product index (LAP) is a new indicator of obesity, waist circumference, and triglycerides were included in the formula, but its association with CVD is inconsistent. Therefore, this study researched the effect of LAP levels on CVD. METHODS: This prospective cohort study was based on the Kailuan cohort. A total of 95,981 participants who completed the first physical examination in 2006 and had no history of CVD or LAP absence were included. The participants were divided into four groups according to the LAP quartile (Q1 - Q4). Up until December 31, 2022, incidence density was calculated for each group. The hazard ratio (HR) and 95% confidence interval (CI) of CVD in each group were calculated by the Cox proportional hazards model. RESULTS: During a median follow-up period of 15.95 years, 9925 incident CVD events occurred (2123 myocardial infarction and 8096 stroke). There were differences in potential confounders among the four groups (P < 0.001). The incidence density and 95% CI of CVD in Q1-Q4 groups were 4.76(4.54, 5.00), 6 0.50(6.24, 6.77), 8.13(7.84, 8.44) and 9.34(9.02, 9.67), respectively. There were significant differences in the survival curves among the four groups by log-rank test (P < 0.001). After adjusting for potential confounders, Cox proportional hazards model results showed that compared with the Q1 group, the HR and 95% CI of CVD in the Q2, Q3, and Q4 groups were1.15(1.08, 1.23), 1.29(1.21, 1.38) and 1.39(1.30, 1.49), respectively. The HR and 95%CI of myocardial infarction were 1.28(1.10, 1.49), 1.71(1.47, 1.98) and 1.92(1.64, 2.23), respectively. The HR and 95%CI of stroke were 1.11 (1.03, 1.19), 1.20 (1.12, 1.29) and 1.28 (1.19, 1.38), respectively. After subgroup analysis by gender, there was no significant interaction (P = 0.169), and the relationship between LAP and CVD in different genders was consistent with the main results. After subgroup analysis by age, there was a significant interaction (P = 0.007), and the association between LAP and CVD in different age groups was consistent with the main results. After subgroup analysis by BMI, there was no significant interaction (P = 0.506), and the association between LAP and CVD in different BMI groups was consistent with the main results. The results remained robust after sensitivity analyses. For each unit increase in ln(LAP), the HR and 95%CI of CVD were 4.07 (3.92, 4.23). CONCLUSION: This study demonstrated that the risk of CVD increased with the increase of LAP level. The risk of CVD in group Q2 - Q4 was 1.15, 1.29, and 1.39 times higher than that in group Q1, respectively. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR2000029767.

Synthesis of N-(acyloxy)-N-alkynylamides via generation of "C2" from hypervalent alkynyliodane and a weak base.

The first synthesis of N-(acyloxy)ynamides was realized through the coupling of N-(acyloxy)amides and hypervalent alkynyliodane under mild conditions. This reaction probably involves biradical species ("C2") generation and radical processes. Furthermore, we also demonstrated that N-(acyloxy)ynamide could be transformed into a N-sulfonylimidate derivative by a copper catalyst. This study provides new building blocks for synthetic organic chemistry reactions and improves understanding of the chemical reactivity of "C2".

CircFOXP1 alleviates brain injury after acute ischemic stroke by regulating STAT3/apoptotic signaling.

According to previous studies, circular RNAs (circRNAs) are involved in multiple pathological processes of acute ischemic stroke (AIS). However, the relationship between circFOXP1 and IS has not yet been reported. Here, we found that circFOXP1 expression was significantly decreased in the peripheral blood of AIS patients compared to controls and was associated with the severity and prognosis of AIS. Functionally, knockdown and overexpression of circFOXP1 promoted and inhibited apoptotic signaling, respectively, following oxygen-glucose deprivation/reperfusion (OGD/R) treatment in vitro. Adeno-associated virus (AAV)-mediated circFOXP1 overexpression attenuated neurological deficits and improved functional recovery after transient middle cerebral artery occlusion (tMCAO) treatment in vivo. Mechanistically, decreased QKI expression inhibited circFOXP1 biogenesis under hypoxic conditions. Decreased circFOXP1 expression accelerated signal transducer and activator of transcription 3 (STAT3) protein degradation by binding to and increasing STAT3 protein ubiquitination, ultimately aggravating brain injury after cerebral ischemia by activating apoptotic signaling. In summary, our study is the first to reveal that circFOXP1 alleviates brain injury after cerebral ischemia by regulating STAT3/apoptotic signaling, which provides a potentially novel therapeutic target for AIS.

A regulatory variant at 19p13.3 is associated with primary biliary cholangitis risk and ARID3A expression.

Genome-wide association studies have identified 19p13.3 locus associated with primary biliary cholangitis (PBC). Here we aim to identify causative variant(s) and initiate efforts to define the mechanism by which the 19p13.3 locus variant(s) contributes to the pathogenesis of PBC. A genome-wide meta-analysis of 1931 PBC subjects and 7852 controls in two Han Chinese cohorts confirms the strong association between 19p13.3 locus and PBC. By integrating functional annotations, luciferase reporter assay and allele-specific chromatin immunoprecipitation, we prioritize rs2238574, an AT-Rich Interaction Domain 3A (ARID3A) intronic variant, as a potential causal variant at 19p13.3 locus. The risk allele of rs2238574 shows higher binding affinity of transcription factors, leading to an increased enhancer activity in myeloid cells. Genome-editing demonstrates the regulatory effect of rs2238574 on ARID3A expression through allele-specific enhancer activity. Furthermore, knock-down of ARID3A inhibits myeloid differentiation and activation pathway, and overexpression of the gene has the opposite effect. Finally, we find ARID3A expression and rs2238574 genotypes linked to disease severity in PBC. Our work provides several lines of evidence that a non-coding variant regulates ARID3A expression, presenting a mechanistic basis for association of 19p13.3 locus with the susceptibility to PBC.

Genetic variants in DNA repair genes and the risk of cutaneous malignant melanoma in melanoma-prone families with/without CDKN2A mutations.

Cutaneous malignant melanoma (CMM) is an etiologically heterogeneous disease with genetic, environmental (sun exposure) and host (pigmentation/nevi) factors and their interactions contributing to risk. Genetic variants in DNA repair genes may be particularly important since their altered function in response to sun exposure-related DNA damage maybe related to risk for CMM. However, systematic evaluations of genetic variants in DNA repair genes are limited, particularly in high-risk families. We comprehensively analyzed DNA repair gene polymorphisms and CMM risk in melanoma-prone families with/without CDKN2A mutations. A total of 586 individuals (183 CMM) from 53 families (23 CDKN2A (+), 30 CDKN2A (-)) were genotyped for 2964 tagSNPs in 131 DNA repair genes. Conditional logistic regression, conditioning on families, was used to estimate trend p-values, odds ratios and 95% confidence intervals for the association between CMM and each SNP separately, adjusted for age and sex. p-Values for SNPs in the same gene were combined to yield gene specific p-values. Two genes, POLN and PRKDC, were significantly associated with melanoma after Bonferroni correction for multiple testing (p = 0.0003 and 0.00035, respectively). DCLRE1B showed suggestive association (p = 0.0006). 28 ∼ 56% of genotyped SNPs in these genes had single SNP p < 0.05. The most significant SNPs in POLN and PRKDC had similar effects in CDKN2A (+) and CDKN2A (-) families. Our finding suggests that polymorphisms in DNA repair genes, POLN and PRKDC, were associated with increased melanoma risk in melanoma families with and without CDKN2A mutations.

Exploring biomarkers for ischemic stroke through integrated microarray data analysis.

Stroke is the third leading cause of disability-adjusted life years worldwide, and drugs available for its treatment are limited. This study aimed to explore high-confidence candidate genes associated with ischemic stroke (IS) through bioinformatics analysis and identify potential diagnostic biomarkers and gene-drug interactions. Weighted gene coexpression network analysis (WGCNA) and differentially expressed genes (DEGs) were integrated to identify overlapping genes. Then, high-confidence candidate genes were screened by least absolute shrinkage and selection operator (LASSO) regression. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic value of high-confidence candidate genes as biomarkers for IS. The NetworkAnalyst database was used to construct the TF-gene network and miRNA-TF regulatory network of the high-confidence candidate genes. The DGIdb database was used to identified gene-drug interactions. Through the comprehensive analysis of GSE58294 and GSE16561, 10 high-confidence candidate genes were identified by LASSO regression: ARG1, LY96, ABCA1, SLC22A4, CD163, TPM2, SLC25A42, ID3, FAM102A and CD79B. FAM102A had the highest diagnostic value, and the area under curve (AUC), sensitivity and specificity values were 0.974, 0.919 and 0.936, respectively. The HPA database demonstrated that 10 high-confidence candidate genes were expressed in the brain and blood in normal humans. Finally, DGIdb database analysis identified 8 gene-drug interactions. We identified IS-related diagnostic biomarkers and gene-drug interactions that potentially provide new insights into the diagnosis and treatment of IS.

Intestinal bacterial overgrowth in the early stage of severe acute pancreatitis is associated with acute respiratory distress syndrome.

BACKGROUND: In the early stage of acute pancreatitis (AP), a large number of cytokines induced by local pancreatic inflammation seriously damage the intestinal barrier function, and intestinal bacteria and endotoxins enter the blood, causing inflammatory storm, resulting in multiple organ failure, infectious complications, and other disorders, eventually leading to death. Intestinal failure occurs early in the course of AP, accelerating its development. As an alternative method to detect small intestinal bacterial overgrowth, the hydrogen breath test is safe, noninvasive, and convenient, reflecting the number of intestinal bacteria in AP indirectly. This study aimed to investigate the changes in intestinal bacteria measured using the hydrogen breath test in the early stage of AP to clarify the relationship between intestinal bacteria and acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Early clinical intervention and maintenance of intestinal barrier function would be highly beneficial in controlling the development of severe acute pancreatitis (SAP). AIM: To analyze the relationship between intestinal bacteria change and ALI/ARDS in the early stage of SAP. METHODS: A total of 149 patients with AP admitted to the intensive care unit of the Digestive Department, Xuanwu Hospital, Capital Medical University from 2016 to 2019 were finally enrolled, following compliance with the inclusion and exclusion criteria. The results of the hydrogen breath test within 1 wk of admission were collected, and the hydrogen production rates at admission, 72 h, and 96 h were calculated. The higher the hydrogen production rates the more bacteria in the small intestine. First, according to the improved Marshall scoring system in the 2012 Atlanta Consensus on New Standards for Classification of Acute Pancreatitis, 66 patients with a PaO2/FiO2 score ≤ 1 were included in the mild AP (MAP) group, 18 patients with a PaO2/FiO2 score ≥ 2 and duration < 48 h were included in the moderately SAP (MSAP) group, and 65 patients with a PaO2/FiO2 score ≥ 2 and duration > 48 h were included in the SAP group, to analyze the correlation between intestinal bacterial overgrowth and organ failure in AP. Second, ALI (PaO2/FiO2 = 2) and ARDS (PaO2/FiO2 > 2) were defined according to the simplified diagnostic criteria proposed by the 1994 European Union Conference. The MSAP group was divided into two groups according to the PaO2/FiO2 score: 15 patients with PaO2/FiO2 score = 2 were included in group A, and three patients with score > 2 were included in group B. Similarly, the SAP group was divided into two groups: 28 patients with score = 2 were included in group C, and 37 patients with score > 2 were included in group D, to analyze the correlation between intestinal bacterial overgrowth and ALI/ARDS in AP. RESULTS: A total of 149 patients were included: 66 patients in the MAP group, of whom 53 patients were male (80.3%) and 13 patients were female (19.7%); 18 patients in the MSAP group, of whom 13 patients were male (72.2%) and 5 patients were female (27.8%); 65 patients in the SAP group, of whom 48 patients were male (73.8%) and 17 patients were female (26.2%). There was no significant difference in interleukin-6 and procalcitonin among the MAP, MSAP, and SAP groups (P = 0.445 and P = 0.399, respectively). There was no significant difference in the growth of intestinal bacteria among the MAP, MSAP, and SAP groups (P = 0.649). There was no significant difference in the growth of small intestinal bacteria between group A and group B (P = 0.353). There was a significant difference in the growth of small intestinal bacteria between group C and group D (P = 0.038). CONCLUSION: Intestinal bacterial overgrowth in the early stage of SAP is correlated with ARDS.

In vitro Studies and Clinical Observations Imply a Synergistic Effect Between Epstein-Barr Virus and Dengue Virus Infection.

Dengue virus (DENV) infection can lead to a complex spectrum of clinical outcomes, ranging from asymptomatic infection to life-threatening severe dengue. The reasons for thus drastically varying manifestations of the disease remain an enigma. Herein, we reported an original discovery of the synergistic effect between preexisting Epstein-Barr virus (EBV) infection and DENV superinfection in vitro and of a strong correlation of these two viruses in the clinical samples from dengue patients. We showed that (I) DENV-2 infection of an EBV-positive cell line (EBV + Akata cell) reactivated EBV, and it could be blocked by wortmannin treatment. (II) Examination of human peripheral blood mononuclear cell (PBMC) samples from dengue patients revealed significantly elevated cell-associated EBV DNA copy number at the time of hospitalization vs. at the time of disease recovery in most individuals. (III) EBV infection promoted DENV propagation in both EBV-hosting B cells and indirectly in THP-1 cells, supported by the following evidence: (A) EBV + Akata cells were more permissive to DENV-2 infection compared with Akata cells harboring no EBV virus (EBV- Akata cells). (B) Low-molecular weight fraction secreted from EBV + Akata cells could enhance DENV-2 propagation in monocytic THP-1 cells. (C) While reactivation of EBV in EBV + Akata cells further increased DENV-2 yield from this cell line, pharmacological inhibition of EBV replication by acyclovir had the opposite effect. To our knowledge, this is the first investigation demonstrating a positive correlation between EBV and DENV in vitro and in human biospecimens.

The challenge of detecting epistasis (G x G interactions): Genetic Analysis Workshop 16.

Interest is increasing in epistasis as a possible source of the unexplained variance missed by genome-wide association studies. The Genetic Analysis Workshop 16 Group 9 participants evaluated a wide variety of classical and novel analytical methods for detecting epistasis, in both the statistical and machine learning paradigms, applied to both real and simulated data. Because the magnitude of epistasis is clearly relative to scale of penetrance, and therefore to some extent, to the choice of model framework, it is not surprising that strong interactions under one model might be minimized or even disappear entirely under a different modeling framework.

Histone deacetylase gene PtHDT902 modifies adventitious root formation and negatively regulates salt stress tolerance in poplar.

Histone deacetylases (HDACs) regulate gene transcription, and play a critical role in plant growth, development and stress responses. HD2 proteins are plant specific histone deacetylases. In woody plants, functions of HD2s are not known. In this study, we cloned an HD2 gene PtHDT902 from Populus trichocarpa and investigated its sequence, expression, subcellular localization, and functions in root development and salt stress responses. Our findings indicated that PtHDT902 was a nuclear protein and its expression was regulated by abiotic stresses. The over-expression of PtHDT902 in both Arabidopsis and poplar increased the expression levels of gibberellin (GA) biosynthetic genes. The expression of PtHDT902 in Arabidopsis enhanced primary root growth, and its over-expression in poplar inhibited adventitious root formation. These phenotypes resulted from over-expression of PtHDT902 were consistent with the GA-overproduction phenotypes. In addition, the poplar plants over-expressing PtHDT902 exhibited lower tolerance to salt than non-transgenic plants. These findings indicated that PtHDT902 worked as an important regulator in adventitious root formation and salt stress tolerance in poplar.