Phenomic landscape and pharmacogenomic implications for HLA region in a Taiwan Han Chinese population.

BACKGROUND: The human leukocyte antigen (HLA) genes, exhibiting significant genetic diversity, are associated with susceptibility to various clinical diseases and diverse in drug responses. High costs of HLA sequencing and the population-specific architecture of this genetic region necessitate the establishment of a population-specific HLA imputation reference panel. Moreover, there is a lack of understanding about the genetic and phenotypic landscape of HLA variations within the Taiwanese population. METHODS: We created models for a Taiwanese-specific HLA imputation reference panel. These models were trained with the array genotype data and HLA sequencing data from 845 Taiwanese subjects. HLA imputation was applied for 59,448 Taiwanese subjects to characterize the HLA allele and haplotype frequencies. Additionally, a phenome-wide association study (PheWAS) was conducted to identify the phenotypes associated with HLA variations. The association of the biallelic HLA variants with the binary and quantitative traits were evaluated with additive logistic and linear regression models, respectively. Furthermore, an omnibus test with likelihood-ratio test was applied for each HLA amino acid position in the multiallelic HLA amino acid polymorphisms to compare the difference between a fitted model and a null model following a χ2 distribution of n-1 degree of freedom at a position with n residues. Finally, we estimated the prevalence of adverse drug reactions (ADR)-related HLA alleles in the Taiwanese population. RESULTS: In this study, the reference panel models displayed remarkable accuracy, with averages of 99.3%, 98.9%, and 99.1% for 2-, 4-, 6-digit alleles of the eight classical HLA genes, respectively. For PheWAS, a total of 18,136 significant associations with HLA variants across 26 phenotypes are identified (p < 5×10-8), highlighting the pleiotropy feature of the HLA region. Among the independent signals, 15 are novel, including the association of HLA-B pos 138 variation with ankylosing spondylitis (AS), and rs9266290 and rs9266292 with allergy. Through an analysis spanning the entire HLA region, we identified clusters of phenotype correlations. Finally, the carriers of pharmacogenomic related HLA alleles, including HLA-C*01:02 (35.86%), HLA-B*58:01 (20.9%), and HLA-B*15:02 (8.38%), were characterized in the Taiwanese general population. CONCLUSIONS: We successfully delivered the HLA imputation for 59,448 Taiwanese subjects and characterized the genetic and phenotypic landscapes of the HLA variations. In addition, we quantified the estimated prevalence of the ADR-related HLA alleles in the Taiwanese population. The developed HLA imputation reference panel could be used for estimation of population HLA allele frequencies, which can facilitate further studies in the role of HLA variants in a wider range of phenotypes in the population.

Ophiocordyceps sinensis preparations combined with the renin-angiotensin system inhibitor for diabetic kidney disease treatment: an umbrella review of systematic reviews and network meta-analysis.

Aims: This study aimed to synthesize the evidence of the comparative effectiveness and safety of Ophiocordyceps sinensis (OS) preparations combined with renin-angiotensin system inhibitors (RASi) for diabetic kidney disease (DKD). Methods: Eight databases were searched from their inception to May 2023. Systematic reviews (SRs) of OS preparations combined with RASi for DKD were identified. Randomized controlled trials (RCTs) from the included SRs and additional searching were performed for data pooling. Cochrane risk-of-bias 2 (RoB 2) tool and AMSTAR 2 were used to evaluate the methodological quality of RCTs and SRs, respectively. A Bayesian network meta-analysis was performed to compare the add-on effect and safety of OS preparations for DKD. The certainty of evidence was graded using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Results: Fourteen SRs were included, whose methodological quality was assessed as high (1/14) or critically low (13/14). After combining additional searching, 157 RCTs were included, involving 13,143 participants. The quality of the RCTs showed some concerns (155/157) or high risk (2/157). Jinshuibao capsules and tablets, Bailing capsules and tablets, and Zhiling capsules were evaluated. Compared to RASi, adding either of the OS capsular preparations resulted in a decreased 24-h urinary total protein levels. OS preparations ranked differently in each outcome. Jinshuibao capsules plus RASi were beneficial in reducing urinary protein, serum creatinine, serum urea nitrogen, and blood glucose levels, with moderate-certainty evidence. No serious adverse events were observed after adding OS to RASi. Conclusion: Combining OS capsular preparations with RASi appeared to be associated with decreased urinary total protein levels in DKD patients. Further high-quality studies are needed to confirm. Systematic Review Registration: INPASY202350066.

Seroprevalence of SARS-CoV-2 in self-reported COVID-19-free children.

INTRODUCTION: COVID-19 poses risks and leads to complications for vulnerable populations, including children. Unreported cases of COVID-19 among children hinder our understanding of the true disease burden. In this study, we aimed to investigate the proportion of children who report no prior infection to SARS-CoV-2 but who nevertheless exhibit serological evidence of prior infection. METHODS: Between November 2022 and February 2023, we recruited children and adolescents under 19 years of age who lacked a prior history of SARS-CoV-2 infection. Participants underwent SARS-CoV-2 antibody testing to assess the presence of IgG antibodies specific to nucleocapsid (N) and spike (S) proteins. Demographic and contact information were also collected. RESULTS: Among 260 COVID-19-free children, the overall anti-N antibody positivity rate, which varied across age groups (4%-25%), was 9.2% (24/260). Contact with individuals who were positive for COVID-19, particularly the children's mothers, significantly increased the likelihood of antibody positivity. The median age of the 34 children who remained unvaccinated against COVID-19 was lower than that of the children who were vaccinated (6.5 vs. 9 years; p < 0.001). Until January 2024, the overall infection rate was 41.9% (99/236) among children who were negative for anti-N antibodies, irrespective of vaccination status or the presence of chronic disease. CONCLUSION: We discovered previously undisclosed cases of SARS-CoV-2 infection among children. The risk of seropositivity increases substantially with household contact. Regarding children who report no prior exposure to COVID-19, clinicians must remain vigilant, as SARS-CoV-2 remains a concern.

Traditional, complementary and integrative medicine for fatigue post COVID-19 infection: A systematic review of randomized controlled trials.

Background: Chronic fatigue is a predominant symptom of post COVID-19 condition, or long COVID. We aimed to evaluate the efficacy and safety of Traditional, Complementary and Integrative Medicine (TCIM) for fatigue post COVID-19 infection. Methods: Ten English and Chinese language databases and grey literature were searched up to 12 April 2023 for randomized controlled trials (RCTs). Cochrane "Risk of bias" (RoB) tool was applied. Evidence certainty was assessed using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Effect estimates were presented as risk ratio (RR) or mean difference (MD) with 95% confidence interval (CI). Results: Thirteen RCTs with 1632 participants were included. One RCT showed that Bufei Huoxue herbal capsules reduced fatigue (n=129, MD -14.90, 95%CI -24.53 to -5.27), one RCT reported that Ludangshen herbal liquid lowered fatigue (n=184, MD -1.90, 95%CI -2.38 to -1.42), and the other one RCT shown that fatigue disappearance rate was higher with Ludangshen herbal liquid (n=184, RR 4.19, 95%CI 2.06 to 8.53). Compared to traditional Chinese medicine rehabilitation (TCM-rahab) alone, one RCT showed that fatigue symptoms were lower following Qingjin Yiqi granules plus TCM-rehab (n=388, MD -0.48, 95%CI -0.50 to -0.46). Due to concerns with RoB and/or imprecision, the certainty in this evidence was low to very low. No serious adverse events was reported. Conclusions: Limited evidence suggests that various TCIM interventions might reduce post COVID-19 fatigue. Larger, high quality RCTs of longer duration are required to confirm these preliminary findings. Study Registration: The protocol of this review has been registered at PROSPERO: CRD42022384136.

Signal enhancement ratio of multi-phase contrast-enhanced MRI: an imaging biomarker for survival in pancreatic adenocarcinoma.

OBJECTIVES: To evaluate signal enhancement ratio (SER) for tissue characterization and prognosis stratification in pancreatic adenocarcinoma (PDAC), with quantitative histopathological analysis (QHA) as the reference standard. METHODS: This retrospective study included 277 PDAC patients who underwent multi-phase contrast-enhanced (CE) MRI and whole-slide imaging (WSI) from three centers (2015-2021). SER is defined as (SIlt - SIpre)/(SIea - SIpre), where SIpre, SIea, and SIlt represent the signal intensity of the tumor in pre-contrast, early-, and late post-contrast images, respectively. Deep-learning algorithms were implemented to quantify the stroma, epithelium, and lumen of PDAC on WSIs. Correlation, regression, and Bland-Altman analyses were utilized to investigate the associations between SER and QHA. The prognostic significance of SER on overall survival (OS) was evaluated using Cox regression analysis and Kaplan-Meier curves. RESULTS: The internal dataset comprised 159 patients, which was further divided into training, validation, and internal test datasets (n = 60, 41, and 58, respectively). Sixty-five and 53 patients were included in two external test datasets. Excluding lumen, SER demonstrated significant correlations with stroma (r = 0.29-0.74, all p < 0.001) and epithelium (r = -0.23 to -0.71, all p < 0.001) across a wide post-injection time window (range, 25-300 s). Bland-Altman analysis revealed a small bias between SER and QHA for quantifying stroma/epithelium in individual training, validation (all within ± 2%), and three test datasets (all within ± 4%). Moreover, SER-predicted low stromal proportion was independently associated with worse OS (HR = 1.84 (1.17-2.91), p = 0.009) in training and validation datasets, which remained significant across three combined test datasets (HR = 1.73 (1.25-2.41), p = 0.001). CONCLUSION: SER of multi-phase CE-MRI allows for tissue characterization and prognosis stratification in PDAC. CLINICAL RELEVANCE STATEMENT: The signal enhancement ratio of multi-phase CE-MRI can serve as a novel imaging biomarker for characterizing tissue composition and holds the potential for improving patient stratification and therapy in PDAC. KEY POINTS: Imaging biomarkers are needed to better characterize tumor tissue in pancreatic adenocarcinoma. Signal enhancement ratio (SER)-predicted stromal/epithelial proportion showed good agreement with histopathology measurements across three distinct centers. Signal enhancement ratio (SER)-predicted stromal proportion was demonstrated to be an independent prognostic factor for OS in PDAC.

Baicalin nanodelivery system based on functionalized metal-organic framework for targeted therapy of osteoarthritis by modulating macrophage polarization.

Intra-articular drugs used to treat osteoarthritis (OA) often suffer from poor pharmacokinetics and stability. Nano-platforms as drug delivery systems for drug delivery are promising for OA therapy. In this study, we reported an M1 macrophage-targeted delivery system Bai@FA-UIO-66-NH2 based on folic acid (FA) -modified metal-organic framework (MOF) loaded with baicalin (Bai) as antioxidant agent for OA therapy. With outstanding biocompatibility and high drug loading efficiency, Bai@FA-UIO-66-NH2 could be specifically uptaken by LPS-induced macrophages to serve as a potent ROS scavenger, gradually releasing Bai at the subcellular level to reduce ROS production, modulate macrophage polarization to M2, leading to alleviation of synovial inflammation in OA joints. The synergistic effect of Bai@FA-UIO-66-NH2 on macrophage polarization and ROS scavenging significantly improved the therapeutic efficacy of OA, which may provide a new insight into the design of OA precision therapy.

The safety and feasibility Assessment of Overlap Esophagojejunostomy with Self-pulling and Latter Transection Technique in Totally Laparoscopic Total Gastrectomy.

BACKGROUND: This study presents an innovative technique in totally laparoscopic total gastrectomy (TLTG) for Overlap esophagojejunostomy, termed self-pulling and latter transection (Overlap SPLT). It evaluates the effectiveness and short-term outcomes of this novel method through a comparative analysis with the established functional end-to-end esophagojejunostomy incorporating self-pulling and latter transection (FETE SPLT). METHODS: From September 2018 to September 2023, this study enrolled 68 gastric cancer patients who underwent totally laparoscopic total gastrectomy (TLTG) with Overlap SPLT anastomosis and 120 patients who underwent TLTG with FETE SPLT anastomosis. Clinicopathological characteristics, surgical and postoperative outcomes data for Overlap SPLT cases were gathered and retrospectively compared with those from FETE SPLT TLTG to evaluate the effectiveness and clinical safety. RESULTS: The duration of anastomosis for Overlap SPLT was 25.3 ± 7.4minutes, significantly longer than that for the FETE SPLT (18.1 ± 4.0minutes, P = 0.031). Perioperatively, one anastomosis-related complication occurred in each group, but this did not constitute a statistically significant difference (P = 0.682). No statistically significant differences were found between the two groups in terms of operative time, postoperative hospital stay, operative cost, surgical margins, or number of lymph nodes removed. Postoperative morbidity rates were similar between the groups (4.4% vs. 5.8%, P = 0.676). CONCLUSION: The Overlap SPLT technique is regarded as a safe and feasible method for anastomosis. There were no apparent differences in complications between Overlap SPLT and FETE SPLT, but Overlap SPLT costed one additional stapler cartridge and required a longer duration.

Pirin Promotes the Progression of Non-Small-Cell Lung Cancer by Increasing ODC1 to Suppress Autophagy.

Non-small-cell lung cancer (NSCLC), a common malignant tumor, requires deeper pathogenesis investigation. Autophagy is an evolutionarily conserved lysosomal degradation process that is frequently blocked during cancer progression. It is an urgent need to determine the novel autophagy-associated regulators in NSCLC. Here, we found that pirin was upregulated in NSCLC, and its expression was positively correlated with poor prognosis. Overexpression of pirin inhibited autophagy and promoted NSCLC proliferation. We then performed data-independent acquisition-based quantitative proteomics to identify the differentially expressed proteins (DEPs) in pirin-overexpression (OE) or pirin-knockdown (KD) cells. Among the pirin-regulated DEPs, ornithine decarboxylase 1 (ODC1) was downregulated in pirin-KD cells while upregulated along with pirin overexpression. ODC1 depletion reversed the pirin-induced autophagy inhibition and pro-proliferation effect in A549 and H460 cells. Immunohistochemistry showed that ODC1 was highly expressed in NSCLC cancer tissues and positively related with pirin. Notably, NSCLC patients with pirinhigh/ODC1high had a higher risk in terms of overall survival. In summary, we identified pirin and ODC1 as a novel cluster of prognostic biomarkers for NSCLC and highlighted the potential oncogenic role of the pirin/ODC1/autophagy axis in this cancer type. Targeting this pathway represents a possible therapeutic approach to treat NSCLC.

Altered microbiome of serum exosomes in patients with acute and chronic cholecystitis.

BACKGROUND: This study aimed to investigate the differences in the microbiota composition of serum exosomes from patients with acute and chronic cholecystitis. METHOD: Exosomes were isolated from the serum of cholecystitis patients through centrifugation and identified and characterized using transmission electron microscopy and nano-flow cytometry. Microbiota analysis was performed using 16S rRNA sequencing. RESULTS: Compared to patients with chronic cholecystitis, those with acute cholecystitis exhibited lower richness and diversity. Beta diversity analysis revealed significant differences in the microbiota composition between patients with acute and chronic cholecystitis. The relative abundance of Proteobacteria was significantly higher in exosomes from patients with acute cholecystitis, whereas Actinobacteria, Bacteroidetes, and Firmicutes were significantly more abundant in exosomes from patients with chronic cholecystitis. Furthermore, functional predictions of microbial communities using Tax4Fun analysis revealed significant differences in metabolic pathways such as amino acid metabolism, carbohydrate metabolism, and membrane transport between the two patient groups. CONCLUSIONS: This study confirmed the differences in the microbiota composition within serum exosomes of patients with acute and chronic cholecystitis. Serum exosomes could serve as diagnostic indicators for distinguishing acute and chronic cholecystitis.

Clinical characteristics and genetic HLA marker for patients with oxaliplatin-induced adverse drug reactions.

BACKGROUND: Oxaliplatin is commonly used to treat gastrointestinal malignancies. However, its applications are limited due to potential adverse drug reactions (ADRs), particularly severe anaphylactic shock. There is no method to predict or prevent ADRs caused by oxaliplatin. Therefore, we aimed to investigate the genetic HLA predisposition and immune mechanism of oxaliplatin-induced ADRs. METHODS: A retrospective review was performed for 154 patients with ADRs induced by oxaliplatin during 2016-2021 recorded in our ADR notification system. HLA genotyping was conducted for 47 patients with oxaliplatin-induced ADRs, 1100 general population controls, and 34 oxaliplatin-tolerant controls in 2019-2023. The in vitro basophil activation test (BAT) was performed and oxaliplatin-specific IgE levels were determined. RESULTS: The incidence of oxaliplatin-induced ADRs and anaphylactic shock in our cohort was 7.1% and 0.15%, respectively. Of the 154 patients, 67.5% suffered rash/eruption; 26.0% of the patients who could not undergo oxaliplatin rechallenge were considered to show oxaliplatin-induced immune-mediated hypersensitivity reactions (HRs). The genetic study found that the HLA-DRB∗12:01 allele was associated with oxaliplatin-induced HRs compared to the general population controls (sensitivity = 42.9%; odds ratio [OR] = 3.4; 95% CI = 1.4-8.2; P = 0.008) and tolerant controls (OR = 12; 95% CI = 2.3-63.7; P = 0.001). The in vitro BAT showed higher activation of CD63+ basophils in patients with oxaliplatin-induced HRs compared to the tolerant controls (P < 0.05). Only four patients (8.5%) with oxaliplatin-induced ADRs were positive for oxaliplatin-specific IgE. CONCLUSIONS: This study found that 26.0% of patients with oxaliplatin-induced ADRs could not undergo oxaliplatin rechallenge. HLA-DRB∗12:01 is regarded as a genetic marker for oxaliplatin-induced hypersensitivity.

Cell-based tissue engineered flexor tendon allograft: A canine in vivo study.

This study aimed to compare the clinically established autologous extrasynovial tendon graft to a newly developed tissue-engineered allograft (Eng-allograft) in terms of functional outcomes following flexor tendon reconstruction in a canine model. The second and fifth flexor digitorum profundus (FDP) tendons from 16 dogs were transected and repaired in Zone II. After 6 weeks of cage activity, the repaired tendons were intentionally ruptured, creating a clinically relevant model for reconstruction. The re-ruptured FDP tendons were then reconstructed using either the clinically standard autologous extrasynovial tendon graft or the Eng-allograft, which had been revitalized with autologous bone marrow-derived mesenchymal stem cells (BMSCs) and synovialized using carbodiimide derivatized synovial fluid (cd-SYN). Following 12 weeks of postoperative rehabilitation, the functional outcomes of the surgical digits were evaluated. The Eng-allograft group exhibited improved digital function, including lower digit work of flexion and reduced adhesion status, while maintaining similar tendon gliding resistance compared to the autograft group. However, the failure load of both the distal and proximal host/graft conjunctions in the Eng-allograft group was significantly lower than that of the autograft group with higher graft rupture at the host-graft junction. In conclusion, the decellularized allogenic intrasynovial tendon, when revitalized BMSCs and synovialized with cd-SYN, demonstrates positive effects on digital function improvement and adhesion reduction. However, the healing at both proximal and distal graft/host junctions is far lower than the autograft. Further research is needed to enhance the healing capacity of allograft conjunctions, aiming to achieve a comparable level of healing seen with autografts.

High incidence of cerebrovascular lesions on magnetic resonance imaging in pediatric COVID-19 during omicron outbreak - A retrospective case series.

BACKGROUND: The incidence of pediatric hospitalizations has significantly increased since the spread of the omicron variant of COVID-19. Changes of characteristics in respiratory and neurological symptoms have been reported. We performed a retrospective, cross-sectional study to characterize the MRI change in children with an emphasis on the change of cerebral vasculatures. METHODS: We retrospectively collected clinical and MRI data of 31 pediatric patients with neurological symptoms during the acute infection and abnormalities on MRI during the outbreak of omicron variant from April 2022 to June 2022 in Taiwan. The clinical manifestations and MRI abnormalities were collected and proportion of patients with vascular abnormalities was calculated. RESULTS: Among 31 pediatric patients with post-COVID-19 neurological symptoms, MRI abnormalities were observed in 15 (48.4%), predominantly encephalitis/encephalopathy (73.3%). Notable MRI findings included focal diffusion-weighted imaging (DWI) hyperintensity in cerebral cortex and thalamus, diffuse cortical T2/DWI hyperintensity, and lesions in the medulla, pons, cerebellum, and splenium of corpus callosum. Vascular abnormalities were seen in 12 (80%) patients with MRI abnormalities, mainly affecting the middle cerebral arteries. The spectrum of neurological manifestations ranged from seizures to Alice in Wonderland syndrome, underscoring the diverse impact of COVID-19 on pediatric patients. CONCLUSION: A high proportion of vascular abnormalities was observed in pediatric patients with neurological involvements, suggesting that vascular involvement is an important mechanism of neurological manifestations in omicron variant infection.

A late eating midpoint is associated with increased risk of diabetic kidney disease: a cross-sectional study based on NHANES 2013-2020.

BACKGROUND: Modifying diet is crucial for diabetes and complication management. Numerous studies have shown that adjusting eating habits to align with the circadian rhythm may positively affect metabolic health. However, eating midpoint, eating duration, and their associations with diabetic kidney disease (DKD) are poorly understood. METHODS: The National Health and Nutrition Examination Survey (2013-2020) was examined for information on diabetes and dietary habits. From the beginning and ending times of each meal, we calculated the eating midpoint and eating duration. Urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg/g and/or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 were the specific diagnostic criteria for DKD. RESULTS: In total, details of 2194 subjects with diabetes were collected for analysis. The overall population were divided into four subgroups based on the eating midpoint quartiles. The prevalence of DKD varied noticeably (P = 0.037) across the four categories. When comparing subjects in the second and fourth quartiles of eating midpoint to those in the first one, the odds ratios (ORs) of DKD were 1.31 (95% CI, 1.03 to 1.67) and 1.33 (95% CI, 1.05 to 1.70), respectively. And after controlling for potential confounders, the corresponding ORs of DKD in the second and fourth quartiles were 1.42 (95% CI, 1.07 to 1.90) and 1.39 (95% CI, 1.04 to 1.85), respectively. CONCLUSIONS: A strong correlation was found between an earlier eating midpoint and a reduced incidence of DKD. Eating early in the day may potentially improve renal outcomes in patients with diabetes.

CDDO regulates central and peripheral sensitization to attenuate post-herpetic neuralgia by targeting TRPV1/PKC-δ/p-Akt signals.

Postherpetic neuralgia (PHN) is a notorious neuropathic pain featuring persistent profound mechanical hyperalgesia with significant negative impact on patients' life quality. CDDO can regulate inflammatory response and programmed cell death. Its derivative also protects neurons from damages by modulating microglia activities. As a consequence of central and peripheral sensitization, applying neural blocks may benefit to minimize the risk of PHN. This study aimed to explore whether CDDO could generate analgesic action in a PHN-rats' model. The behavioural test was determined by calibrated forceps testing. The number of apoptotic neurons and degree of glial cell reaction were assessed by immunofluorescence assay. Activation of PKC-δ and the phosphorylation of Akt were measured by western blots. CDDO improved PHN by decreasing TRPV1-positive nociceptive neurons, the apoptotic neurons, and reversed glial cell reaction in adult rats. It also suppressed the enhanced PKC-δ and p-Akt signalling in the sciatic nerve, dorsal root ganglia (DRG) and spinal dorsal horn. Our research is the promising report demonstrating the analgesic and neuroprotective action of CDDO in a PHN-rat's model by regulating central and peripheral sensitization targeting TRPV1, PKC-δ and p-Akt. It also is the first study to elucidate the role of oligodendrocyte in PHN.

Long-term analysis of humoral responses and spike-specific T cell memory to Omicron variants after different COVID-19 vaccine regimens.

Background: The emergence of SARS-CoV-2 variants has raised concerns about the sustainability of vaccine-induced immunity. Little is known about the long-term humoral responses and spike-specific T cell memory to Omicron variants, with specific attention to BA.4/5, BQ.1.1, and XBB.1. Methods: We assessed immune responses in 50 uninfected individuals who received varying three-dose vaccination combinations (2X AstraZeneca + 1X Moderna, 1X AstraZeneca + 2X Moderna, and 3X Moderna) against wild-type (WT) and Omicron variants at eight months post-vaccination. The serum antibody titers were analyzed by enzyme-linked immunosorbent assays (ELISA), and neutralizing activities were examined by pseudovirus and infectious SARS-CoV-2 neutralization assays. T cell reactivities and their memory phenotypes were determined by flow cytometry. Results: We found that RBD-specific antibody titers, neutralizing activities, and CD4+ T cell reactivities were reduced against Omicron variants compared to WT. In contrast, CD8+ T cell responses, central memory, effector memory, and CD45RA+ effector memory T cells remained unaffected upon stimulation with the Omicron peptide pool. Notably, CD4+ effector memory T cells even exhibited a higher proportion of reactivity against Omicron variants. Furthermore, participants who received three doses of the Moderna showed a more robust response regarding neutralization and CD8+ T cell reactions than other three-dose vaccination groups. Conclusion: Reduction of humoral and CD4+ T cell responses against Omicron variants in vaccinees suggested that vaccine effectiveness after eight months may not have sufficient protection against the new emerging variants, which provides valuable information for future vaccination strategies such as receiving BA.4/5 or XBB.1-based bivalent vaccines.

The bidirectional associations between sarcopenia-related traits and cognitive performance.

While many studies have sought to explore the degree to which sarcopenia-related traits are associated with cognitive performance, these studies have yielded contradictory results without any clear indication of the causality of such relationships. In efforts to better understand associations between sarcopenia-related traits and cognitive ability, a series of multivariate linear regression assessments were carried out upon datasets derived through the National Health and Nutrition Examination Survey (NHANES). Of these, cognitive performance was assessed by the Digit Symbol Substitution Test (DDST), the Consortium to Establish a Registry for Alzheimer's Disease Immediate Recall Test (CERAD-IR), Delayed Recall Test (CERAD-DR) and Animal Fluency Test (AFT). Causal relationships between the two were further inferred via a two-sample Mendelian randomization (MR) analysis approach. Sarcopenia-related traits considered in these assessments included walking speed, appendicular skeletal muscle mass (ASM), and hand grip strength (HGS). Walking speed, ASM, and HGS were all significantly independently related to cognitive scores following adjustment for covariates. MR assessments also identified that each 1-SD higher walking speed and appendicular lean mass were causally and respectively associated with a 0.34 [standard error (SE) = 0.09; p < 0.001)] standardized score higher and a 0.07 (SE = 0.01; p < 0.001) standardized score higher cognitive score, whereas a higher hand grip strength was positively associated with a better cognitive performance. Reverse MR assessments also yielded similar findings. These data suggest that lower walking speed, muscle strength, and muscle mass were all closely related to lower cognitive performance irrespective of gender, and that there may be a mutually reinforcing relationship among these variables.

Superstructured Optoionic Heterojunctions for Promoting Ion Pumping Inspired by Photoreceptor Cells.

Photoreceptor cells of vertebrates feature ultrastructural membranes interspersed with abundant photosensitive ion pumps to boost signal generation and realize high gain in dim light. In light of this, superstructured optoionic heterojunctions (SSOHs) with cation-selective nanochannels are developed for manipulating photo-driven ion pumping. A template-directed bottom-up strategy is adopted to sequentially assemble graphene oxide (GO) and PEDOT:PSS into heterogeneous membranes with sculptured superstructures, which feature programmable variation in membrane topography and contain a donor-acceptor interface capable of maintaining electron-hole separation upon photoillumination. Such elaborate design endows SSOHs with a much higher magnitude of photo-driven ion flux against a concentration gradient in contrast to conventional optoionic membranes with planar configuration. This can be ascribed to the buildup of an enhanced transmembrane potential owing to the effective separation of photogenerated carriers at the heterojunction interface and the increase of energy input from photoillumination due to a synergistic effect of reflection reduction, broad-angle absorption, and wide-waveband absorption. This work unlocks the significance of membrane topographies in photo-driven transmembrane transportation and proposes such a universal prototype that could be extended to other optoionic membranes to develop high-performance artificial ion pumps for energy conversion and sensing.

KSHV vIL-6 promotes SIRT3-induced deacetylation of SERBP1 to inhibit ferroptosis and enhance cellular transformation by inducing lipoyltransferase 2 mRNA degradation.

Ferroptosis, a defensive strategy commonly employed by the host cells to restrict pathogenic infections, has been implicated in the development and therapeutic responses of various types of cancer. However, the role of ferroptosis in oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV)-induced cancers remains elusive. While a growing number of non-histone proteins have been identified as acetylation targets, the functions of these modifications have yet to be revealed. Here, we show KSHV reprogramming of host acetylation proteomics following cellular transformation of rat primary mesenchymal precursor. Among them, SERPINE1 mRNA binding protein 1 (SERBP1) deacetylation is increased and required for KSHV-induced cellular transformation. Mechanistically, KSHV-encoded viral interleukin-6 (vIL-6) promotes SIRT3 deacetylation of SERBP1, preventing its binding to and protection of lipoyltransferase 2 (Lipt2) mRNA from mRNA degradation resulting in ferroptosis. Consequently, a SIRT3-specific inhibitor, 3-TYP, suppresses KSHV-induced cellular transformation by inducing ferroptosis. Our findings unveil novel roles of vIL-6 and SERBP1 deacetylation in regulating ferroptosis and KSHV-induced cellular transformation, and establish the vIL-6-SIRT3-SERBP1-ferroptosis pathways as a potential new therapeutic target for KSHV-associated cancers.

Long-range connections damage in white matter hyperintensities affects information processing speed.

White matter hyperintensities, one of the major markers of cerebral small vessel disease, disrupt the integrity of neuronal networks and ultimately contribute to cognitive dysfunction. However, a deeper understanding of how white matter hyperintensities related to the connectivity patterns of brain hubs at the neural network level could provide valuable insights into the relationship between white matter hyperintensities and cognitive dysfunction. A total of 36 patients with moderate to severe white matter hyperintensities (Fazekas score ≥ 3) and 34 healthy controls underwent comprehensive neuropsychological assessments and resting-state functional MRI scans. The voxel-based graph-theory approach-functional connectivity strength was employed to systematically investigate the topological organization of the whole-brain networks. The white matter hyperintensities patients performed significantly worse than the healthy controls in episodic memory, executive function and information processing speed. Additionally, we found that white matter hyperintensities selectively affected highly connected hub regions, predominantly involving the medial and lateral prefrontal, precuneus, inferior parietal lobule, insula and thalamus. Intriguingly, this impairment was connectivity distance-dependent, with the most prominent disruptions observed in long-range connections (e.g. 100-150 mm). Finally, these disruptions of hub connectivity (e.g. the long-range functional connectivity strength in the left dorsolateral prefrontal cortex) positively correlated with the cognitive performance in white matter hyperintensities patients. Our findings emphasize that the disrupted hub connectivity patterns in white matter hyperintensities are dependent on connection distance, especially longer-distance connections, which in turn predispose white matter hyperintensities patients to worse cognitive function.

Clonorchis sinensis on the prognosis of patients with spontaneous rupture of Hepatocellular Carcinoma: An inverse probability of treatment weighting analysis.

BACKGROUND: We examined the impact of the Clonorchis sinensis (C. sinensis) infection on the survival outcomes of spontaneous rupture Hepatocellular Carcinoma (srHCC) patients undergoing hepatectomy. METHODS: Between May 2013 and December 2021, 157 consecutive srHCC patients who underwent hepatectomy were divided into an no C. sinensis group (n = 126) and C. sinensis group (n = 31). To adjust for differences in preoperative characteristics an inverse probability of treatment weighting (IPTW) analysis was done, using propensity scores. Overall survival (OS) and recurrence-free survival (RFS) were compared before and after IPTW. Multivariate Cox regression analysis was performed to determine whether the C. sinensis infection was an independent prognostic factor after IPTW. RESULTS: In original cohort, the no C. sinensis group did not show a survival advantage over the C. sinensis group. After IPTW adjustment, the median OS for the C. sinensis group was 9 months, compared to 29 months for the no C. sinensis group. C. sinensis group have worse OS than no C. sinensis group (p = 0.024), while it did not differ in RFS(p = 0.065). The multivariate Cox regression analysis showed that C. sinensis infection and lower age were associated with worse OS. CONCLUSIONS: The C. sinensis infection has an adverse impact on os in srHCC patients who underwent hepatectomy.