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Abstract Background Nonalcoholic fatty liver disease (NAFLD) is a globally increasing health epidemic. Lifestyle intervention is recommended as the main therapy for NAFLD. However, the optimal approach is still unclear. This study aimed to evaluate the effects of a comprehensive approach of intensive lifestyle intervention (ILI) concerning enhanced control of calorie-restricted diet (CRD), exercise, and personalized nutrition counseling on liver steatosis and extrahepatic metabolic status in Chinese overweight and obese patients with NAFLD. Methods This study was a multicenter randomized controlled trial (RCT) conducted across seven hospitals in China. It involved 226 participants with a body mass index (BMI) above 25. These participants were randomly assigned to two groups: the ILI group, which followed a low carbohydrate, high protein CRD combined with exercise and intensive counseling from a dietitian, and a control group, which adhered to a balanced CRD along with exercise and standard counseling. The main measure of the study was the change in the fat attenuation parameter (FAP) from the start of the study to week 12, analyzed within the per-protocol set. Secondary measures included changes in BMI, liver stiffness measurement (LSM), and the improvement of various metabolic indexes. Additionally, predetermined subgroup analyses of the FAP were conducted based on variables like gender, age, BMI, ethnicity, hyperlipidemia, and hypertension. Results A total of 167 participants completed the whole study. Compared to the control group, ILI participants achieved a significant reduction in FAP (LS mean difference, 16.07 [95% CI: 8.90–23.25] dB/m) and BMI (LS mean difference, 1.46 [95% CI: 1.09–1.82] kg/m2) but not in LSM improvement (LS mean difference, 0.20 [95% CI: -0.19–0.59] kPa). The ILI also substantially improved other secondary outcomes (including ALT, AST, GGT, body fat mass, muscle mass and skeletal muscle mass, triglyceride, fasting blood glucose, fasting insulin, HbA1c, HOMA-IR, HOMA-β, blood pressure, and homocysteine). Further subgroup analyses showed that ILI, rather than control intervention, led to more significant FAP reduction, especially in patients with concurrent hypertension (p

Abstract Methylation-based liquid biopsies show promises in detecting cancer using circulating cell-free DNA; however, current limitations impede clinical application. Most assays necessitate substantial DNA inputs, posing challenges. Additionally, underrepresented tumor DNA fragments may go undetected during exponential amplification steps of traditional sequencing methods. Here, we report linear amplification-based bisulfite sequencing (LABS), enabling linear amplification of bisulfite-treated DNA fragments in a genome-wide, unbiased fashion, detecting cancer abnormalities with sub-nanogram inputs. Applying LABS to 100 patient samples revealed cancer-specific patterns, copy number alterations, and enhanced cancer detection accuracy by identifying tissue-of-origin and immune cell composition.

Abstract Background Grade 4 glioma is the most aggressive and currently incurable brain tumor with a median survival of one year in adult patients. Elucidating novel transcriptomic and epigenetic contributors to the molecular heterogeneity underlying its aggressiveness may lead to improved clinical outcomes. Methods To identify grade 4 glioma -associated 5-hydroxymethylcytosine (5hmC) and transcriptomic features as well as their cross-talks, genome-wide 5hmC and transcriptomic profiles of tissue samples from 61 patients with grade 4 gliomas and 9 normal controls were obtained for differential and co-regulation/co-modification analyses. Prognostic models on overall survival based on transcriptomic features and the 5hmC modifications summarized over genic regions (promoters, gene bodies) and brain-derived histone marks were developed using machine learning algorithms. Results Despite global reduction, the majority of differential 5hmC features showed higher modification levels in grade 4 gliomas as compared to normal controls. In addition, the bi-directional correlations between 5hmC modifications over promoter regions or gene bodies and gene expression were greatly disturbed in grade 4 gliomas regardless of IDH1 mutation status. Phenotype-associated co-regulated 5hmC–5hmC modules and 5hmC–mRNA modules not only are enriched with different molecular pathways that are indicative of the pathogenesis of grade 4 gliomas, but also are of prognostic significance comparable to IDH1 mutation status. Lastly, the best-performing 5hmC model can predict patient survival at a much higher accuracy (c-index = 74%) when compared to conventional prognostic factor IDH1 (c-index = 57%), capturing the molecular characteristics of tumors that are independent of IDH1 mutation status and gene expression-based molecular subtypes. Conclusions The 5hmC-based prognostic model could offer a robust tool to predict survival in patients with grade 4 gliomas, potentially outperforming existing prognostic factors such as IDH1 mutations. The crosstalk between 5hmC and gene expression revealed another layer of complexity underlying the molecular heterogeneity in grade 4 gliomas, offering opportunities for identifying novel therapeutic targets.

Abstract The Illumina EPIC array is widely used for high-throughput profiling of DNA cytosine modifications in human samples, covering more than 850,000 modification sites across various genomic features. The application of this platform is expected to provide novel insights into the epigenetic contribution to human complex traits and diseases. Considering the diverse inter-population genetic and epigenetic variation, it will benefit the research community with a comprehensive characterization of this platform for its applicability to major global populations. Specifically, we mapped 866,836 CpG probes from the EPIC array to the human genome reference. We detected 91,034 CpG probes that did not align reliably to the human genome reference. In addition, 21,256 CpG probes were found to ambiguously map to multiple loci in the human genome, and 448 probes showing inaccurate genomic information from the original Illumina annotations. We further characterized those uniquely mapped CpG probes in terms of whether they contained common genetic variants, i.e., single nucleotide polymorphisms (SNPs), in major global populations, by utilizing the 1000 Genomes Project data. A list of optimal CpG probes on the EPIC array was generated for major global populations, with the aim of providing a resource to facilitate future studies of diverse human populations. In conclusion, our analysis indicated that studies of diverse human populations using the EPIC array would be benefited by taking into account of the technical features of this platform.

ObjectiveTo investigate the relationship between single nucleotide polymorphisms (SNPs) related to vitamin D (VitD) metabolism and post-stroke depression (PSD) in patients with ischemic stroke.MethodsA total of 210 patients with ischemic stroke were enrolled at the Department of Neurology in Xiangya Hospital, Central South University, from July 2019 to August 2021. SNPs in the VitD metabolic pathway (VDR, CYP2R1, CYP24A1, and CYP27B1) were genotyped using the SNPscan™ multiplex SNP typing kit. Demographic and clinical data were collected using a standardized questionnaire. Multiple genetic models including dominant, recessive, and over-dominant models were utilized to analyze the associations between SNPs and PSD.ResultsIn the dominant, recessive, and over-dominant models, no significant association was observed between the selected SNPs in the CYP24A1 and CYP2R1 genes and PSD. However, univariate and multivariate logistic regression analysis revealed that the CYP27B1 rs10877012 G/G genotype was associated with a decreased risk of PSD (OR: 0.41, 95% CI: 0.18–0.92, p = 0.030 and OR: 0.42, 95% CI: 0.18–0.98, p = 0.040, respectively). Furthermore, haplotype association analysis indicated that rs11568820-rs1544410-rs2228570-rs7975232-rs731236 CCGAA haplotype in the VDR gene was associated with a reduced risk of PSD (OR: 0.14, 95% CI: 0.03–0.65, p = 0.010), whereas no significant association was observed between haplotypes in the CYP2R1 and CYP24A1 genes and PSD.ConclusionOur findings suggest that the polymorphisms of VitD metabolic pathway genes VDR and CYP27B1 may be associated with PSD in patients with ischemic stroke.

CRISPR/Cas9 has been proposed as a treatment for genetically inherited skin disorders. Here we report that CRISPR transfection activates STING-dependent antiviral responses in keratinocytes, resulting in heightened endogenous interferon (IFN) responses through induction of IFN-κ, leading to decreased plasmid stability secondary to induction of the cytidine deaminase gene APOBEC3G. Notably, CRISPR-generated KO keratinocytes had permanent suppression of IFN-κ and IFN-stimulated gene (ISG) expression, secondary to hypermethylation of the IFNK promoter region by the DNA methyltransferase DNMT3B. JAK inhibition via baricitinib prior to CRISPR transfection increased transfection efficiency, prevented IFNK promoter hypermethylation, and restored normal IFN-κ activity and ISG responses. This work shows that CRISPR-mediated gene correction alters antiviral responses in keratinocytes, has implications for future gene therapies for inherited skin diseases using CRISPR technology, and suggests pharmacologic JAK inhibition as a tool for facilitating and attenuating inadvertent selection effects in CRISPR/Cas9 therapeutic approaches.

ABSTRACT: Objective: To differentiate diagnostic and prognostic factors from the clinical material of patients with cerebral sparganosis in central South China. Methods: Consecutive patients with cerebral sparganosis from our hospital between 2010 and 2018 were retrospectively enrolled. The clinical manifestations, radiographic features, treatment, and outcomes of these patients were analyzed. Results: Thirty patients with cerebral sparganosis were included, and foci migration on magnetic resonance imaging was detected in 22 patients, from whom we observed 4 migration modes: interlobar migration (50.0%, 11/22); transmidline migration (27.3%, 6/22); transventricular migration (13.6%, 3/22); and cerebellum-brainstem migration (9.1%, 2/22). The percentage of good outcomes was higher in patients with live worm capture than in those without live worm capture (75.0%, 12/16 vs 33.3%, 2/6). Exposure to preoperative antiparasitic medication was associated with worm migration toward the cortical surface, which led to a higher probability of live worm capture. Conclusions: We propose 4 modes of sparganosis migration that are correlated with worm capture and neurologic prognosis. We found that exposure to antiparasitic medication was associated with worm migration toward the cortical surface, leading to a higher probability of live worm capture. These observations suggest a novel significance for preoperative medication of cerebral sparganosis.

BackgroundThe immune-inflammatory response has been widely considered to be involved in the pathogenesis of post-stroke depression (PSD), but there is ambiguity about the mechanism underlying such association.MethodsAccording to Diagnostic and Statistical Manual of Mental Disorders (5th edition), depressive symptoms were assessed at 2 weeks after stroke onset. 15 single nucleotide polymorphisms (SNPs) in genes of indoleamine 2,3-dioxygenase (IDO, including IDO1 and IDO2) and its inducers (including pro-inflammatory cytokines interferon [IFN]-γ, tumor necrosis factor [TNF]-α, interleukin [IL]-1β, IL-2 and IL-6) were genotyped using SNPscan™ technology, and serum IDO1 levels were detected by double-antibody sandwich enzyme-linked immune-sorbent assay.ResultsFifty-nine patients (31.72%) were diagnosed with depression at 2 weeks after stroke onset (early-onset PSD). The IDO1 rs9657182 T/T genotype was independently associated with early-onset PSD (adjusted odds ratio [OR] = 3.008, 95% confidence interval [CI] 1.157-7.822, p = 0.024) and the frequency of rs9657182 T allele was significantly higher in patients with PSD than that in patients with non-PSD (χ2 = 4.355, p = 0.037), but these results did not reach the Bonferroni significance threshold (p > 0.003). Serum IDO1 levels were also independently linked to early-onset PSD (adjusted OR = 1.071, 95% CI 1.002-1.145, p = 0.044) and patients with PSD had higher serum IDO1 levels than patients with non-PSD in the presence of the rs9657182 T allele but not homozygous C allele (t = -2.046, p = 0.043). Stroke patients with the TNF-α rs361525 G/G genotype had higher serum IDO1 levels compared to those with the G/A genotype (Z = -2.451, p = 0.014).ConclusionsOur findings provided evidence that IDO1 gene polymorphisms and protein levels were involved in the development of early-onset PSD and TNF-α polymorphism was associated with IDO1 levels, supporting that IDO1 which underlie strongly regulation by cytokines may be a specific pathway for the involvement of immune-inflammatory mechanism in the pathophysiology of PSD.

Abstract Novel coronavirus 19 (COVID‐19) is the latest and most intense epidemic, which is caused by the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). In addition to causing respiratory symptoms, SARS‐CoV‐2 can have severe effects on the nervous system. Clinically, COVID‐19 patients have been reported ranging from mild hypogeusia and hyposmia to severe neurological disorders, such as encephalopathy, encephalitis, strokes, and seizures syndrome. However, the pathological mechanisms of this SARS‐CoV‐2 neuro aggressiveness remain unclear, so it is of great significance to explore the neurological effects of SARS‐CoV‐2 infection. To facilitate clinicians to timely recognize the manifestations of COVID‐19 patients with neurological injury and timely treatment, the author hereby reviews the latest research progress in the possible pathways, clinical manifestations, and pathogenesis of COVID‐19 patients with nerve injury.

BackgroundHomocysteine (Hcy) has been indicated to be involved in pathophysiology of post stroke depression (PSD). There is a lack of research to study the relationship between Hcy metabolism genes and PSD. Our study aims to investigate the relationship among Hcy metabolism genes, Hcy, and early-onset PSD.Materials and methodsWe recruited 212 patients with stroke and collected their peripheral blood sample, clinical data, and laboratory test on admission. 12 single nucleotide polymorphisms (SNPs) in methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), and methionine synthase (MTR) genes were genotyped by high-resolution melt analysis. PSD was diagnosed by DSM-V at 2 weeks after stroke. Binary logistic regression and haplotype analysis were used to examine the association between Hcy metabolism genes and PSD. Mediation analysis was performed to clarify whether the SNPs exerted their effect on PSD by affecting the Hcy level.Results81 patients were diagnosed with PSD, and the incidence rate was 38.2%. Hcy level in PSD group was significantly higher than it in non-PSD group (p = 0.019). MTHFR rs1801133 AA genotype an A allele were associated with an elevated risk of PSD after adjustment for some confounding factors (OR = 4.021, 95% CI: 1.459∼11.080, p = 0.007 for AA genotype; OR = 1.808, 95% CI: 1.172∼2.788, p = 0.007 for A allele). Furthermore, the effect of MTHFR rs1801133 AA genotype on PSD was mediated by Hcy (OR = 1.569, 95% CI: 0.013∼3.350, p < 0.05).ConclusionMTHFR rs1801133 and Hcy were associated with PSD, and MTHFR rs1801133 may exert an effect on PSD via mediating Hcy level. This offers a new perspective for treating PSD and understanding the mechanism of PSD.

With the rapid development of electric vehicles, people have higher requirement for the energy density and lifespan of power batteries. The cycle performance and rate performance of lithium-ion batteries can be effectively improved through the modification of the positive and negative active materials, the application of new conductive agents and binders, and the optimized design of the electrode group distribution ratio. However, the problems caused by the preparation process of the traditional electrode and the characteristics of the single-layer electrode structure put a limit on the further improvement of the performance of the lithium-ion battery. Therefore, solving the problems of the traditional single-layer electrode structure itself is an important direction of lithium-ion battery research. Three solutions to solve the problems of the single-layer electrode structure by analyzing the related research on the multilayer composite electrode structure were summarized in this paper which are increasing the stability of the electrode surface, increasing the conductivity of the electrode surface and adjusting the internal component distribution of the electrode, and they have their own advantages.By analyzing the characteristics and limitations of different schemes and preparation processes, new directions and ideas for electrode design and engineering application of lithium-ion batteries and other battery systems were proposed in this paper. Finally, the current research status of the multilayer composite electrode structure was summarized in this paper.

Lithium-rich manganese-based cathode material is a promising next-generation lithium-ion battery cathode material, however, it exhibits significant differences in electrochemical performance at different temperatures, which severely limits the application in practical environments. A variety of electrochemical measures were used to characterize the difference in electrochemical performance of lithium-rich material within the temperature range of 5-45℃. The influencing factors of material properties and temperature dependence were analyzed from the perspective of polarization. The results show that the charge/discharge capacity of lithium-rich material decreases with decreasing temperature, which is mainly due to the significant increase in the polarization of the oxygen/manganese ion reaction in the high-voltage and low-voltage ranges with decreasing temperature, resulting in a severe decrease in its capacity contribution.The significantly increased polarization is mainly caused by the poor intrinsic kinetic performance of oxygen/manganese ions, which leading to high apparent activation energy of the charge transfer process. In addition, the participation of oxygen and manganese ions in the charge compensation reaction changes the structure of the material seriously.It induces changes in the composition of the interface film, which increases the apparent activation energy of lithium ion transmission at the interface in the low voltage interval. Moreover, it causes bulk diffusion of lithium ions at the end of the charge and discharge process having higher apparent activation energy. Therefore, improving the oxygen/manganese ion reaction kinetics of lithium-rich material is the main method to enhance its environmental adaptability.

Summary: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death among patients with epilepsy. However, the underlying mechanism of SUDEP remains elusive. Previous studies showed seizure-induced respiratory arrest (S-IRA) is the main factor in SUDEP, and that enhancement of serotonin (5-HT) function in the dorsal raphe nucleus (DR) can significantly reduce the incidence of S-IRA in the DBA/1 mouse model of SUDEP. The pre-Bötzinger complex (PBC), known for its role in regulating respiratory rhythm, can express the 5-HT2A receptor (5-HT2AR). Here, using the pharmacological and optogenetic methods, respectively, we observed that the serotonergic neural circuit between DR and PBC was involved in S-IRA evoked by either acoustic stimulation or pentylenetetrazole (PTZ) injection in the DBA/1 mice, and found 5-HT2AR located in PBC plays an important role in it. Our findings will further significantly improve our understanding of SUDEP and provide a promising therapeutic target for SUDEP prevention.

Abstract The 5-methylcytosines (5mC) have been implicated in the pathogenesis of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the role of 5-hydroxymethylcytosines (5hmC) that are generated from 5mC through active demethylation, in lymphomagenesis is unknown. We profiled genome-wide 5hmC in circulating cell-free DNA (cfDNA) from 73 newly diagnosed patients with DLBCL and FL. We identified 294 differentially modified genes between DLBCL and FL. The differential 5hmC in the DLBCL/FL-differentiating genes co-localized with enhancer marks H3K4me1 and H3K27ac. A four-gene panel (CNN2, HMG20B, ACRBP, IZUMO1) robustly represented the overall 5hmC modification pattern that distinguished FL from DLBCL with an area under curve of 88.5% in the testing set. The median 5hmC modification levels in signature genes showed potential for separating patients for risk of all-cause mortality. This study provides evidence that genome-wide 5hmC profiles in cfDNA differ between DLBCL and FL and could be exploited as a non-invasive approach.

Background & Aims: CD4+ T cells are regulated by activating and inhibitory cues, and dysregulation of these proper regulatory inputs predisposes these cells to aberrant inflammation and exacerbation of disease. We investigated the role of the inhibitory receptor paired immunoglobulin-like receptor B (PIR-B) in the regulation of the CD4+ T-cell inflammatory response and exacerbation of the colitic phenotype. Methods: We used Il10-/- spontaneous and CD4+CD45RBhi T-cell transfer models of colitis with PIR-B-deficient (Pirb-/-) mice. Flow cytometry, Western blot, and RNA sequencing analysis was performed on wild-type and Pirb-/- CD4+ T cells. In silico analyses were performed on RNA sequencing data set of ileal biopsy samples from pediatric CD and non–inflammatory bowel disease patients and sorted human memory CD4+ T cells. Results: We identified PIR-B expression on memory CD4+ interleukin (IL)17a+ cells. We show that PIR-B regulates CD4+ T-helper 17 cell (Th17)-dependent chronic intestinal inflammatory responses and the development of colitis. Mechanistically, we show that the PIR-B– Src-homology region 2 domain-containing phosphatase-1/2 axis tempers mammalian target of rapamycin complex 1 signaling and mammalian target of rapamycin complex 1–dependent caspase-3/7 apoptosis, resulting in CD4+ IL17a+ cell survival. In silico analyses showed enrichment of transcriptional signatures for Th17 cells (RORC, RORA, and IL17A) and tissue resident memory (HOBIT, IL7R, and BLIMP1) networks in PIR-B+ murine CD4+ T cells and human CD4+ T cells that express the human homologue leukocyte immunoglobulin-like receptor subfamily B member 3 (LILRB3). High levels of LILRB3 expression were associated strongly with mucosal injury and a proinflammatory Th17 signature, and this signature was restricted to a treatment-naïve, severe pediatric CD population. Conclusions: Our findings show an intrinsic role for PIR-B/LILRB3 in the regulation of CD4+ IL17a+ T-cell pathogenic memory responses.

Background: Long-term effects of Coronavirus Disease 2019 (COVID-19) on infants born to infected mothers are not clear. Fine motor skills are crucial for the development of infant emotional regulation, learning ability and social skills.Methods: Clinical information of 100 infants born to 98 mothers (COVID-19 n = 31, non-COVID-19 n = 67) were collected. Infants were follow-up up to 9 months post-partum. The placental tissues were examined for SARS-CoV-2 infection, pathological changes, cytokines, and mtDNA content.Results: Decreased placental oxygen and nutrient transport capacity were found in infected pregnant women. Increased IL-2, IL-6, TNF-α, and IFN-γ were detected in trophoblast cells and maternal blood of COVID-19 placentas. Elevated early fine motor abnormal-ities and increased serum TNI (troponin I) levels at delivery were observed in infants born to mothers with COVID-19. Increased abnormal mitochondria and elevated mtDNA content were found in the placentas from infected mothers. The placental mtDNA content of three infants with abnormal DDST were increased by 4, 7, and 10%, respectively, compared to the mean of the COVID-19 group. The Maternal Vascular Malperfusion (MVM), elevated cytokines and increased placental mtDNA content in mothers with COVID-19 might be associated with transient early fine motor abnormalities in infants. These abnormalities are only temporary, and they could be corrected by daily training.Conclusions: Babies born to COVID-19 mothers with mild symptoms appeared to have little or no excess long-term risks of abnormal physical and neurobehavioral development as compared with the infants delivered by non-COVID-19 mothers.

Background and Aims: Central 5-hydroxytryptamine (5-HT) defects are responsible for the occurrence of sudden unexpected death in epilepsy (SUDEP). The DBA/1 mouse is an animal model of SUDEP since the mouse exhibits audiogenic seizure-induced respiratory arrest (S-IRA). The synthesis of central 5-HT is closely related to the gut microbiota. Moreover, emerging studies suggest a possible role for the microbiota in mitigating seizure likelihood. Based on this, we aimed to explore the effect of a high-tryptophan diet (HTD) on SUDEP as well as the synthesis and metabolism of central 5-HT. Furthermore, we investigated the involvement of the gut microbiota in this process.Methods: All DBA/1 mice were subjected to acoustic stimulation to induce seizures. Only those mice that exhibited S-IRA were randomly assigned to the normal diet (ND) group (n = 39) or HTD group (n = 53). After 1 month of dietary intervention, (1) S-IRA rates were evaluated, (2) the concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the plasma and brain were determined by ultra-high-pressure liquid chromatography, and (3) the fecal flora biodiversity and species composition were analyzed by 16S rDNA microbiota profiling.Results: The S-IRA rate in DBA/1 mice was significantly reduced in the HTD group compared with that in the control group. HTD increased the levels of 5-HT and 5-HIAA in both the telencephalon and midbrain. HTD significantly elevated the species richness and diversity of the gut microbiota. Moreover, there was a significant difference in the gut microbiota composition between the two groups, and the intestinal flora was dominated by Proteobacteria and Actinobacteria after HTD.Conclusions: HTD is efficient in lowering S-IRA rates and elevating the central 5-HT level in DBA/1 mice. The gut microbiota was altered after HTD intervention. The significant increase in Proteobacteria and Actinobacteria may be related to the SUDEP-protective effect of HTD. Our findings shed light on a candidate choice of dietary prevention for SUDEP.

The clinical outcomes of hepatocellular carcinoma (HCC) remain dismal. Elucidating the molecular mechanisms for the progression of aggressive HCC holds the promise for developing novel intervention strategies. The transactivation response element RNA-binding protein (TRBP/TARBP2), a key component of microRNA (miRNA) processing and maturation machinery has been shown to play conflicting roles in tumor development and progression. We sought to investigate the expression of TARBP2 in HCC using well-characterized HCC cell lines, patient-derived tissues and blood samples. Additionally, the potential prognostic and diagnostic value of TARBP2 in HCC were analyzed using Kaplan-Meier plots and ROC curve. Cell counting kit‐8 (CCK‐8), wound healing and transwell assays examined the ability of TARBP2 to induce cell proliferation, migration, and invasion in HCC cell lines. RNA sequencing was applied to identify the downstream elements of TARBP2. The interaction of potential targets of TARBP2, miR‐145 and serpin family E member 1 (SERPINE1), was assessed using luciferase reporter assay. TARBP2 expression was down-regulated in HCC cell lines relative to normal hepatocyte cells, with a similar pattern further confirmed in tissue and blood samples. Notably, the loss of TARBP2 was demonstrated to promote proliferation, migration, and invasion in HCC cell lines. Interestingly, the reduction of TARBP2 was shown to result in the upregulation of SERPINE1, also known as plasminogen activator inhibitor (PAI-1), which is a vital gene of the HIF-1 signaling pathway. Knockdown of SERPINE1 rescued the TARBP2-lost phenotype. Moreover, TARBP2 depletion induced the upregulation of SERPINE1 through reducing the processing of miR-145, which directly targets SERPINE1. Finally, overexpression of miR-145 repressed SERPINE1 and rescued the functions in sh-TARBP2 HCC cells. Our findings underscore a linear TARBP2-miR-145-SERPINE1 pathway that drives HCC progression, with the potential as a novel intervention target for aggressive HCC.

Abstract: An elevated level of circulating cell-free DNA (cfDNA) has been associated with tumor bulk and poor prognosis in diffuse large B-cell lymphoma (DLBCL), but the tumor-specific molecular alterations in cfDNA with prognostic significance remain unclear. We investigated the association between 5-hydroxymethylcytosines (5hmC), a mark of active demethylation and gene activation, in cfDNA from blood plasma and prognosis in newly diagnosed DLBCL patients. We used 5hmC-Seal, a highly sensitive chemical labeling technique, to profile genome-wide 5hmC in plasma cfDNA from 48 DLBCL patients at the University of Chicago Medical Center between 2010 and 2013. Patients were followed through 31 December 2017. We found a distinct genomic distribution of 5hmC in cfDNA marking tissue-specific enhancers, consistent with their putative roles in gene regulation. The 5hmC profiles in cfDNA differed by cell of origin and were associated with clinical prognostic factors, including stage and the International Prognostic Index. We developed a 29 gene–based weighted prognostic score (wp-score) for predicting event-free survival (EFS) and overall survival (OS) by applying the elastic net regularization on the Cox proportional-hazards model. The wp-scores outperformed (eg, prognostic accuracy, sensitivity, specificity) established prognostic factors in predicting EFS and OS. In multivariate Cox models, patients with high wp-scores had worse EFS (hazard ratio, 9.17; 95% confidence interval, 2.01-41.89; P = .004) compared with those in the low-risk group. Our findings suggest that the 5hmC signatures in cfDNA at the time of diagnosis are associated with clinical outcomes and may provide a novel minimally invasive prognostic approach for DLBCL.

High voltage Li- and Mn-rich layered oxide (LMRO) electrodes with different amount of conductive carbon black Super P were investigated to explore the effect of carbon black on electrochemical performance of the electrode and scanning electron microscopy (SEM) and electrochemical impedance spectroscopy (EIS) were utilized to study the internal reason why the amount of Super P affects the performance of the electrode. The results show that the performance of cycle stability and high-rate capability of LMRO electrodes exhibit the tendency of increasing first and then decreasing with increase of Super P content, while the optimum performance of electrodes is obtained at 5% (mass fraction,the same below). With the increase of Super P content, electronic contact between LMRO particles and Super P particles can be improved, electrically conductive network can be constructed, resistance between electrode components can be decreased, and electrode polarization can be reduced. However, when the content is higher than 5%, Super P particles are easily agglomerated, which is undesirable for further improving the conductivity of electrode.

Abstract Robust and clinically convenient biomarkers for cancer diagnosis, early detection, and prognosis have great potential to improve patient survival and are the key to precision medicine. The advent of next-generation sequencing technologies enables a more sensitive and comprehensive profiling of genetic and epigenetic information in tumor-derived materials. Researchers are now able to monitor the dynamics of tumorigenesis in new dimensions, such as using circulating cell-free DNA (cfDNA) and tumor DNA (ctDNA). Mutation-based assays in liquid biopsy cannot always provide consistent results across studies due partly to intra- and inter-tumoral heterogeneity as well as technical limitations. In contrast, epigenetic analysis of patient-derived cfDNA is a promising alternative, especially for early detection and disease surveillance, because epigenetic modifications are tissue-specific and reflect the dynamic process of cancer progression. Therefore, cfDNA-based epigenetic assays are emerging to be a highly sensitive, minimally invasive tool for cancer diagnosis and prognosis with great potential in future precise care of cancer patients. The major obstacle for applying epigenetic analysis of cfDNA, however, has been the lack of enabling techniques with high sensitivity and technical robustness. In this review, we summarized the advances in epigenome-wide profiling of 5-hydroxymethylcytosine (5hmC) in cfDNA, focusing on the detection approaches and potential role as biomarkers in different cancer types.

As an attractive candidate for anode materials, silicon has attracted extensive attention. The instability of electrode/electrolyte interphase due to the inherent volume variation upon (de)lithiation is one of the major factors that limit the commercialization of Si materials. The in-depth understanding of the interface reaction of Si is helpful to modify the interface properties of Si, and further improve the electrochemical performance. This review summarizes the research on the interface reaction mechanism of Si during (de)lithiation process, including Li-Si alloying process, the reactions of primary oxide layer and the formation of passivation film on the Si surface. Moreover, the effect of the three processes on the Si electrochemical performance are also discussed.

The skin serves as the primary interface between our body and the external environment and acts as a barrier against entry of physical agents, chemicals, and microbes. Keratinocytes make up the main cellular constitute of the outermost layer of the skin, contributing to the formation of the epidermis, and they are crucial for maintaining the integrity of this barrier. Beyond serving as a physical barrier component, keratinocytes actively participate in maintaining tissue homeostasis, shaping, amplifying, and regulating immune responses in skin. Keratinocytes act as sentinels, continuously monitoring changes in the environment, and, through microbial sensing, stretch, or other physical stimuli, can initiate a broad range of inflammatory responses via secretion of various cytokines, chemokines, and growth factors. This diverse function of keratinocytes contributes to the highly variable clinical manifestation of skin immune responses. In this Review, we highlight the highly diverse functions of epidermal keratinocytes and their contribution to various immune-mediated skin diseases.

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease characterized by chronic abscess formation and development of multiple draining sinus tracts in the groin, axillae, and perineum. Using proteomic and transcriptomic approaches, we characterized the inflammatory responses in HS in depth, revealing immune responses centered on IFN-γ, IL-36, and TNF, with lesser contribution from IL-17A. We further identified B cells and plasma cells, with associated increases in immunoglobulin production and complement activation, as pivotal players in HS pathogenesis, with Bruton’s tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) pathway activation as a central signal transduction network in HS. These data provide preclinical evidence to accelerate the path toward clinical trials targeting BTK and SYK signaling in moderate-to-severe HS.

Betel quid is the fourth most popular psychoactive agent worldwide. Imaging studies have found altered brain structure in prefrontal cortex (PFC) in betel-quid dependent (BQD) chewers. However, the brain function in PFC associated with BQ use still remains unclear. The present study aimed to examine brain functional activity in PFC in individuals with BQD. This study recruited 48 participants with BQD and 22 normal controls (NCs). Both BQ-specific cue reactivity and Go/NoGo tasks were administered with functional magnetic resonance imaging (fMRI). Behavioral results showed a deficit in the choice reaction time task in BQD group. The fMRI results of the cue reactivity task suggested that, individuals with BQD exhibited responses in right ventromedial PFC, left posterior cingulate cortex (PCC), left lateral parietal lobe (LPL), left middle temporal gyrus and left visual cortex, when seeing BQ images compared with control images. In the Go/NoGo task, relative to NCs group, individuals with BQD showed higher activity in right dorsolateral PFC, right PCC and bilateral LPL between NoGo and Go trials. Across these two tasks, we consistently found disrupted function in PFC in individuals with BQD, which might lead to impaired craving and response inhibition in BQ addiction. Results of current study might shed light on the neural mechanisms involved in BQ use, which could be used as potential guidelines for diagnosis and treatment of BQ dependence.

Mullerian adenosarcoma (MAS) is a biphasic tumor with malignant stroma. It is most commonly of endometrial origin but occasionally originates in the cervix, ovary, or other pelvic/peritoneal sites. The typical MAS is low grade with an indolent clinical course; however, tumors with sarcomatous overgrowth (SO) or a high-grade sarcoma tend to be aggressive. Tumor etiology is largely unknown. To better understand the global genome alterations and gene mutations in MAS, whole-genome sequencing (WGS) and target validation analysis were performed. MAS showed remarkable chromosome (chr) copy number variation (CNV), specifically, gains in chr 1q, 5p, 12p, 12q, and 17q and losses in chr 3p, 3q, 9p, and 11q. Gain of chr 12q13-15 was present in 50% of cases. The selected gene products in gain regions were upregulated as measured by immunohistochemistry. HMGA2 overexpression was significantly correlated with SO. While the structural variation (SV) rate was relatively low overall, a disproportionally high rate of break-ends at chr 7 was noted involving 6 in-frame rearrangement fusion genes. Among 40 frequently mutated genes detected by WGS and validated in 29 MAS by next generation sequencing (NGS), KMT2C, and BCOR were frequently seen in MAS both with and without SO, while MAGEC1 and KDM6B were strongly associated with SO. Overall, a higher rate of frequently mutated genes was found in MAS with SO (33%) than MAS without (11%). This study uncovers the complex and specific genetic alterations in this malignancy. The findings provide a tool for future investigation of these molecular changes in tumorigenesis and target therapies.

Sudden unexpected death in epilepsy (SUDEP) is a devastating epilepsy complication. Seizure-induced respiratory arrest (S-IRA) occurs in many witnessed SUDEP patients and animal models as an initiating event leading to death. Thus, understanding the mechanisms underlying S-IRA will advance the development of preventive strategies against SUDEP. Serotonin (5-HT) is an important modulator for many vital functions, including respiration and arousal, and a deficiency of 5-HT signaling is strongly implicated in S-IRA in animal models, including the DBA/1 mouse. However, the brain structures that contribute to S-IRA remain elusive. We hypothesized that the dorsal raphe (DR), which sends 5-HT projections to the forebrain, is implicated in S-IRA. The present study used optogenetics in the DBA/1 mouse model of SUDEP to selectively activate 5-HT neurons in the DR. Photostimulation of DR 5-HT neurons significantly and reversibly reduced the incidence of S-IRA evoked by acoustic stimulation. Activation of 5-HT neurons in the DR suppressed tonic seizures in most DBA/1 mice without altering the seizure latency and duration of wild running and clonic seizures evoked by acoustic stimulation. This suppressant effect of photostimulation on S-IRA is independent of seizure models, as optogenetic stimulation of DR also reduced S-IRA induced by pentylenetetrazole, a proconvulsant widely used to model human generalized seizures. The S-IRA-suppressing effect of photostimulation was increased by 5-hydroxytryptophan, a chemical precursor for 5-HT synthesis, and was reversed by ondansetron, a specific 5-HT3 receptor antagonist, indicating that reduction of S-IRA by photostimulation of the DR is specifically mediated by enhanced 5-HT neurotransmission. Our findings suggest that deficits in 5-HT neurotransmission in the DR are implicated in S-IRA in DBA/1 mice, and that targeted intervention in the DR is potentially useful for prevention of SUDEP.

The clinical outcomes of pancreatic ductal adenocarcinoma (PDAC) remain dismal, with an estimated five-year survival rate of less than 5%. Early detection and prognostic approaches, including robust biomarkers for PDAC, are critical for improving patient survival. Our goal was to explore the biomarker potential of 5-hydroxymethylcytosines (5hmC), an emerging epigenetic marker with a distinct role in cancer pathobiology, yet under-investigated, due largely to technical constraints relating to PDAC. The TET-assisted bisulfite (TAB)-Array assay represents state-of-the-art technology and was used to directly profile 5hmC at single-base resolution with the Illumina EPIC array (~850,000 cytosine modification sites) in 17 pairs of tumor/adjacent tissue samples from US patients collected at the University of Chicago Medical Center. The TAB-Array data were analyzed to explore the genomic distribution of 5hmC and evaluate whether 5hmC markers were differentially modified between tumors and adjacent tissues. We demonstrated distinctive distribution patterns of 5hmC in tissue samples from PDAC patients relative to cis-regulatory elements (e.g., histone modification marks for enhancers), indicating their potential gene regulatory relevance. Substantial differences in 5hmC-modified CpG sites were detected between tumors and adjacent tissues in genes related to cancer pathobiology. The detected 5hmC-contaning marker genes also showed prognostic value for overall survival in the US patients with PDAC from the Cancer Genome Atlas Project. This study demonstrated the technical feasibility of the TAB-Array approach in cancer biomarker discovery and the biomarker potential of 5hmC for PDAC. Future studies using tissues and/or liquid biopsies may include 5hmC as a potential epigenetic biomarker target for PDAC.