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Abstract Juvenile myelomonocytic leukemia (JMML) is caused by constitutively activated RAS signaling and characterized by increased proliferation and predominant myelomonocytic differentiation of hematopoietic cells. Using MxCre;Ptpn11 D61Y/+ mice, which model human JMML, we show that RAS pathway activation affects apoptosis signaling through cell type-dependent regulation of BCL-2 family members. Apoptosis resistance observed in monocytes and granulocytes was mediated by overexpression of the anti-apoptotic and down-regulation of the pro-apoptotic members of the BCL-2 family. Two anti-apoptotic proteins, BCL-XL and MCL-1, were directly regulated by the oncogenic RAS signaling but, in addition, were influenced by microenvironmental signals. While BCL-XL and BCL-2 were required for the survival of monocytes, MCL-1 was essential for neutrophils. Interestingly, stem and progenitor cells expressing the oncogenic PTPN11 mutant showed no increased apoptosis resistance. BCL-XL inhibition was the most effective in killing myeloid cells in vitro but was insufficient to completely resolve myeloproliferation in vivo.

Flaviviruses are zoonotic pathogens transmitted by infected mosquitoes and ticks, posing a persistent threat to global health. These infections lead to a diverse spectrum of diseases, broadly classified into two phenotypes: systemic hemorrhagic conditions, such as dengue and yellow fever, and neurological complications, exemplified by West Nile virus (WNV) and Zika virus (ZIKV) infections. The interactions between flaviviruses and human host cells are pivotal to the viral lifecycle and the activation of host immunity. Investigating the molecular mechanisms of flavivirus-host interactions is essential for understanding viral pathogenesis, managing epidemics, optimizing therapeutic strategies, and enhancing public health security. Flaviviruses utilize various strategies to evade the host immune system, and understanding these mechanisms is critical for the development of antiviral therapeutics. This study employs bibliometric methods, leveraging CiteSpace and VOSviewer software, to analyze literature on flavivirus-host interactions and the associated immune responses. By examining developmental trends and pivotal research areas, this analysis provides insights and guidance for future studies in this field.

Abstract Objective To compare the efficacy of femtosecond laser-assisted cataract surgery (FLACS) and conventional phacoemulsification surgery (CPS) in treating postvitrectomy cataracts. Methods Prospective randomized controlled study. Patients who underwent cataract surgery after pars plana vitrectomy (PPV) were randomly divided into the FLACS group and the CPS group. Preoperative data of all patients were collected to compare intraoperative complications, average phacoemulsification energy (AVE), effective phacoemulsification time (EPT), postoperative intraocular pressure, corneal endothelial cell density (ECD), and best corrected visual acuity (BCVA). Results A total of 92 eyes were included in the analysis, with 47 eyes in the FLACS group and 45 eyes in the CPS group. The intraoperative AVEs and EPTs in the FLACS group were both lower than those in the CPS group (P 0.05). Postoperatively, intraocular pressure (IOP) was lower in both groups than preoperatively, and there was no statistically significant difference in intraocular pressure between the two groups at three months postsurgery (P > 0.05). Three months postoperatively, the ECD in the FLACS group was greater than that in the CPS group, with less average endothelial cell loss (ECL) than that in the CPS group (P 0.05). Conclusion FLACS is safe and effective for treating post-PPV cataracts and, compared with CPS, facilitates early postoperative recovery with no difference in final visual acuity. Residual silicone oil in the anterior chamber post-PPV may lead to certain specific outcomes for FLACS. Although it may not affect surgical results, it is still noteworthy.

Abstract Background Gestational diabetes mellitus is hyperglycemia in special populations (pregnant women), however gestational diabetes mellitus (GDM) not only affects maternal health, but also has profound effects on offspring health. The prevalence of gestational diabetes in my country is gradually increasing. Objective To study the application effect of self-transcendence nursing model in GDM patients. Methods One hundred fourteen GDM patients undergoing prenatal examination in Hai'an People’s Hospital from January 2019 to November 2021 were selected and divided into two groups of 57 cases respectively according to the principle of random single blind. The patients in the control group should receive pregnancy health care under the routine nursing mode, while those in the observation group should receive pregnancy health care under the self-transcendence nursing mode. Then, we would compare the insulin utilization rate, admission before delivery, gestational weeks, delivery outcome and neonatal conditions between the two groups, examine the changes of blood glucose related indexes in the two groups and evaluate the differences between the two groups' Diabetes Distress Scale (DDS) scores and Chinese Versions of Diabetes Management Self-efficacy Scale (C-DMSES) scores. Results The number of hospital admissions (1.12 ± 0.31) and the hospital stay (7.54 ± 1.45) days in the observation group were less than those in the control group (1.56 ± 0.42) and (10.23 ± 2.32) days. There was no difference between the two groups after statistical analysis of gestational weeks and insulin utilization rate (P > 0.05). After the intervention, the total DDS score and emotional burden, doctor/life law/interpersonal relationship related distress score of GDM in the two groups were lower than those before the intervention, while the scores of healthy diet, regular exercise, regular monitoring of blood glucose and medication compliance in C-DMSES were higher than those before the intervention. In addition, the improvements of overall DDS scores and C-DMSES scores of GDM in the observation group were significantly better than those in the control group, so there was statistical significance (P 0.05) in other aspects of pregnancy outcomes and neonatal conditions. Conclusion Self-transcendence nursing mode intervention can improve blood sugar, reduce psychological distress, and improve self-efficacy in GDM patients, thereby reducing the rate of pregnancy-induced hypertension and premature birth.

Abstract Chemiluminescence (CL) is a self-illuminating phenomenon fueled by chemical energy instead of extra excited light, which features superiority in sensitivity, signal-to-background ratios, and imaging depth. Strategies to synthesize a CL emission unimolecular skeleton in the second near-infrared window (NIR-II) and a unimolecular probe with direct duplex NIR-II [CL/fluorescence (FL)] emission are lacking. Here, we employ modular synthesis routes to construct a series of directly activated NIR-II CL emission unimolecular probes with a maximum emission wavelength of up to 1060 nm, and use them for real-time and continuous detection of the superoxide anion generated in acetaminophen induced liver injury in a female mice model under both NIR-II CL and NIR-II FL imaging channels. Thus, this study establishes a directly activatable NIR-II CL emission unimolecular skeleton, validating the scalability of this duplex NIR-II CL/FL imaging platform in bioactive molecule detection and disease diagnosis.

Objective: This study aimed to design and fabricate a probiotic Weizmannia coagulans BC99 (W. coagulans BC99) emergency energy bar with high nutrition, high energy, and anti-fatigue properties. Methods: Taking sensory evaluation as the response value, the formulation of energy bar sandwich was optimized by a Box-Behnken design experiment. The contents of protein, fat, carbohydrate, moisture, ash, dietary fiber, and the composition of amino acid and fatty acid were analyzed. Subsequently, a fatigue mice model was established through three weeks of swimming training to evaluate the anti-fatigue function of the probiotic energy bar. The corresponding exhaustion time, glycogen content, and contents of fatigue factors, inflammatory cytokines, and oxidative stress factors in serum were measured. Results: The optimal conditions of the probiotic energy bar sandwich were as follows: 35 g of nuts, 45 g of oats, 15 g of chia seeds, syrup composite ratio (Wmaltose:Wwhite granulated sugar) of 2.0, and stirring time of 9.0 minutes. Under these conditions, the sensory evaluation of the energy bar sandwich containing W. coagulans BC99 probiotics was 93 score. The coating of the energy bar contained a count of W. coagulans BC99 of 1.43×108 CFU/g, and the nutritional analysis showed abundant essential amino acids and unsaturated fatty acids. The intervention with the W. coagulans BC99 energy bar resulted in significantly increased levels of liver glycogen and muscle glycogen (P

Abstract Background The success of selecting high risk or early-stage Alzheimer’s disease individuals for the delivery of clinical trials depends on the design and the appropriate recruitment of participants. Polygenic risk scores (PRS) show potential for identifying individuals at risk for Alzheimer’s disease (AD). Our study comprehensively examines AD PRS utility using various methods and models. Methods We compared the PRS prediction accuracy in ADNI (N = 568) and BioFINDER (N = 766) cohorts using five disease risk modelling approaches, three PRS derivation methods, two AD genome-wide association study (GWAS) statistics and two sets of SNPs: the whole genome and microglia-selective regions only. Results The best prediction accuracy was achieved when modelling genetic risk by using two predictors: APOE and remaining PRS (AUC = 0.72–0.76). Microglial PRS showed comparable accuracy to the whole genome (AUC = 0.71–0.74). The individuals’ risk scores differed substantially, with the largest discrepancies (up to 70%) attributable to the GWAS statistics used. Conclusions Our work benchmarks the best PRS derivation and modelling strategies for AD genetic prediction.

Abstract Liver fibrosis is a critical liver disease that can progress to more severe manifestations, such as cirrhosis, yet no effective targeted therapies are available. Here, we identify that ATF4, a master transcription factor in ER stress response, promotes liver fibrosis by facilitating a stress response-independent epigenetic program in hepatic stellate cells (HSCs). Unlike its canonical role in regulating UPR genes during ER stress, ATF4 activates epithelial-mesenchymal transition (EMT) gene transcription under fibrogenic conditions. HSC-specific depletion of ATF4 suppresses liver fibrosis in vivo. Mechanistically, TGFβ resets ATF4 to orchestrate a unique enhancer program for the transcriptional activation of pro-fibrotic EMT genes. Analysis of human data confirms a strong correlation between HSC ATF4 expression and liver fibrosis progression. Importantly, a small molecule inhibitor targeting ATF4 translation effectively mitigates liver fibrosis. Together, our findings identify a mechanism promoting liver fibrosis and reveal new opportunities for treating this otherwise non-targetable disease.

Abstract Background Formerly known as non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated steatotic liver disease (MASLD) has now become the most widespread chronic liver disease worldwide. The primary goal of this study is to assess the ability of different indexes (including VAI, TyG, HOMA-IR, BMI, LAP, WHtR, TyG-BMI, TyG-WC, and TyG-WHtR) to predict MASLD in individuals diagnosed with type 2 diabetes mellitus (T2DM), particularly within the Chinese population. Methods This cross-sectional study involved 1,742 patients with T2DM, recruited from the Metabolic Management Centers (MMC) at Suzhou Municipal Hospital. Abdominal ultrasonography was employed for MASLD diagnosis in patients with T2DM. The predictive accuracy of various screening indexes for MASLD in the Chinese T2DM population was evaluated using logistic regression and receiver operating characteristic (ROC) curve analyses. Results Among the 1,742 participants, 996 were diagnosed with MASLD. After adjusting for potential confounding factors, positive associations with the risk of MASLD were found for all the nine indexes. The lipid accumulation product (LAP) exhibited the greatest predictive value for detecting MASLD, with an area under the curve (AUC) of 0.786(95%CI 0.764,0.807), followed by BMI(AUC = 0.785), VAI(AUC = 0.744), TyG(AUC = 0.720), WHtR(AUC = 0.710) and HOMA-IR(AUC = 0.676). The composite Indexes (TyG-BMI, TyG-WC, TyG-WHtR) also showed considerable predictive ability with AUCs of 0.765, 0.752 and 0.748, respectively. Conclusion Our results indicated that all nine indexes have favorable correlations with the risk of MASLD, and most of them have a good performance in predicting MASLD. According to our study, LAP was a reliable index for predicting MASLD among Chinese T2DM patients. The exploration of non-invasive screenings will provide significant support for the early detection and diagnosis of MASLD.

Abstract In herpesvirus, the terminase subunit pUL15 is involved in cleavage of the viral genome concatemers in the nucleus. Previous studies have shown that herpes simplex virus 1 (HSV-1) pUL15 can enter the nucleus without other viral proteins and help other terminase subunits enter the nucleus. However, this study revealed that duck plague virus (DPV) pUL15 cannot localize independently to the nucleus and can only be localized in the nucleus in the presence of pUL28 and pUL33. However, the data suggested the presence of a potential nuclear localization signal (NLS) in DPV pUL15, which is important for the localization of the terminase subunits. Subsequently, several single-point mutants were constructed to identify the vital amino acids within the NLS. The conserved amino acids K187, R188, and K190 are critical for the nuclear localization of pUL15, pUL28, and pUL33 but not for their interaction. Furthermore, corresponding recombinant viruses were constructed. The results revealed that the mutations rUL15K187Q, rUL15K188Q and rUL15K190Q had an obvious influence on concatemeric genome cleavage, but only K190Q significantly affected the production of progeny virions. These findings indicate that the NLS is important for the functions of DPV pUL15. Overall, a potential NLS and the key amino acids in DPV pUL15 were identified. Mutations in K187, K188 and K190 affected the cleavage of the concatemeric genome, but only mutations in K190 had an obvious effect on viral proliferation.

Abstract We propose and demonstrate a data-driven plasmonic metascreen that efficiently absorbs incident light over a wide spectral range in an ultra-thin silicon film. By embedding a double-nanoring silver array within a 20 nm ultrathin amorphous silicon (a-Si) layer, we achieve a significant enhancement of light absorption. This enhancement arises from the interaction between the resonant cavity modes and localized plasmonic modes, requiring precise tuning of plasmon resonances to match the absorption region of the silicon active layer. To facilitate the device design and improve light absorption without increasing the thickness of the active layer, we develop a deep learning framework, which learns to map from the absorption spectra to the design space. This inverse design strategy helps to tune the absorption for selective spectral functionalities. Our optimized design surpasses the bare silicon planar device, exhibiting a remarkable enhancement of over 100%. Experimental validation confirms the broadband enhancement of light absorption in the proposed configuration. The proposed metascreen absorber holds great potential for light harvesting applications and may be leveraged to improve the light conversion efficiency of ultra-thin silicon solar cells, photodetectors, and optical filters.

Abstract This research demonstrates that DCC-2036 (Rebastinib), a potent third-generation tyrosine kinase inhibitor (TKI), effectively suppresses tumor growth in colorectal cancer (CRC) models with functional immune systems. The findings underscore the capacity of DCC-2036 to enhance both the activation and cytotoxic functionality of CD8+ T cells, which are crucial for facilitating anti-tumor immune responses. Through comprehensive multi-omics investigations, significant shifts in both gene and protein expression profiles were detected, notably a marked decrease in DKK1 levels. This reduction in DKK1 was linked to diminished CD8+ T cell effectiveness, correlating with decreased FGR expression. Moreover, our findings identify FGR as a pivotal modulator that influences DKK1 expression via the PI3K-AKT-SP1 signaling cascade. Correlative analysis of clinical specimens supports the experimental data, showing that increased levels of FGR and DKK1 in CRC tissues are associated with inferior clinical outcomes and reduced efficacy of immunotherapeutic interventions. Consequently, targeting the FGR-AKT-SP1-DKK1 pathway with DCC-2036 could potentiate immunotherapy by enhancing CD8+ T cell functionality and their tumor infiltration. This strategy may contribute significantly to the refinement of therapeutic approaches for CRC, potentially improving patient prognoses.

Background: Neuroimaging studies have revealed aberrant network functional connectivity in postherpetic neuralgia (PHN) patients. However, there is a lack of knowledge regarding the relationship between the brain network connectivity during the acute period and disease prognosis. Objective: The purpose of this study was to detect characteristic network connectivity in the process of herpes zoster (HZ) pain chronification and to identify whether abnormal network connectivity in the acute period can predict the outcome of patients with HZ. Methods: In this cross-sectional study, 31 patients with PHN, 33 with recuperation from herpes zoster (RHZ), and 28 with acute herpes zoster (AHZ) were recruited and underwent resting-state functional magnetic resonance imaging (fMRI). We investigated the differences in the connectivity of four resting-state networks (RSN) among the three groups. Receiver operating characteristic (ROC) curve analysis was performed to identify whether abnormal network connectivity in the acute period could predict the outcome of patients with HZ. Results: First, we found within-basal ganglia network (BGN) and default mode network (DMN)-BGN connectivity differences, with PHN patients showing increased DMN-BGN connectivity compared to AHZ and RHZ patients, while RHZ patients showing increased within-BGN connectivity compared to AHZ and PHN patients. Moreover, DMN-BGN connectivity was associated with the ID pain score in patients with AHZ. Finally, the DMN-BGN connectivity of AHZ patients could predict the outcome of HZ patients with sensitivity and specificity of 77.8 % and 63.2 %, respectively. Conclusions: Our results provide evidence that DMN-BGN connectivity during the acute period confers a risk for the development of chronic pain and can act as a neuroimaging biomarker to predict the outcome of patients with HZ.

Abstract Sepsis, characterized as life-threatening organ dysfunction resulting from dysregulated host responses to infection, remains a significant challenge in clinical practice. Despite advancements in understanding host-bacterial interactions, molecular responses, and therapeutic approaches, the mortality rate associated with sepsis has consistently ranged between 10 and 16%. This elevated mortality highlights critical gaps in our comprehension of sepsis etiology. Traditionally linked to bacterial and fungal pathogens, recent outbreaks of acute viral infections, including Middle East respiratory syndrome coronavirus (MERS-CoV), influenza virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), among other regional epidemics, have underscored the role of viral pathogenesis in sepsis, particularly when critically ill patients exhibit classic symptoms indicative of sepsis. However, many cases of viral-induced sepsis are frequently underdiagnosed because standard evaluations typically exclude viral panels. Moreover, these viruses not only activate conventional pattern recognition receptors (PRRs) and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) but also initiate primary antiviral pathways such as cyclic guanosine monophosphate adenosine monophosphate (GMP-AMP) synthase (cGAS)-stimulator of interferon genes (STING) signaling and interferon response mechanisms. Such activations lead to cellular stress, metabolic disturbances, and extensive cell damage that exacerbate tissue injury while leading to a spectrum of clinical manifestations. This complexity poses substantial challenges for the clinical management of affected cases. In this review, we elucidate the definition and diagnosis criteria for viral sepsis while synthesizing current knowledge regarding its etiology, epidemiology, and pathophysiology, molecular mechanisms involved therein as well as their impact on immune-mediated organ damage. Additionally, we discuss clinical considerations related to both existing therapies and advanced treatment interventions, aiming to enhance the comprehensive understanding surrounding viral sepsis.

Abstract Reports on the application of metagenomic next-generation sequencing (mNGS) in adult patients with severe pneumonia after cardiac surgery remain limited. This study aimed to evaluate the clinical outcomes of mNGS analysis of bronchoalveolar lavage fluid (BALF) in such patients.A retrospective cohort study was conducted on adult patients with severe pneumonia after cardiac surgery. Samples were collected from patients in the surgical intensive care unit (SICU) of Sichuan Provincial People’s Hospital between January 2019 and March 2024. Upon diagnosis of severe pneumonia, bronchoalveolar lavage fluid was obtained via bronchoscopy within 24 h. The mNGS group was composed of patients tested using mNGS and conventional microbiological tests. BALF was detected only by the conventional microbiological test (CMT) method in the CMT group, which involved examining bacterial and fungal smears and cultures at least. We reviewed a total of 4,064 cardiac surgeries, and based on the inclusion criteria, a total of 113 adult patients with severe pneumonia after cardiac surgery were included in this study. The overall positive rate detected by mNGS was significantly higher than that of the culture method (98% vs. 58%, P

Background: Evidence has demonstrated that visceral fat area (VFA) and subcutaneous fat area (SFA) have different influences on cardiovascular disease (CVD) risk in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the relationship between the visceral fat area (VFA), the subcutaneous fat area (SFA) ratio (V/S), and carotid atherosclerosis (CAS) in patients with T2DM. Methods: From January 2018 to May 2023, 1838 patients with T2DM admitted to the National Metabolic Management Centre in our hospital were assigned to two groups based on comorbid CAS. Dual bioelectrical impedance analysis was used to measure the VAF and SFA, and the V/S was calculated. Patient characteristics and serum biochemical indices were compared between groups. Factors influencing comorbid CAS were determined, and correlations between V/S and other clinical indices were analyzed. Results: The group with comorbid CAS included 858 individuals and 980 without comorbid CAS. Those with comorbid CAS were older and had a longer disease duration, more significant systolic blood pressure, and greater V/S. The proportions of patients with comorbid hypertension increased significantly with the V/S ratio. The V/S ratio positively correlated with triglyceride (TG), low-density lipoprotein cholesterol levels, and waist circumference. According to binary logistic regression analysis, V/S was an independent risk factor for CAS. Conclusion: Elevated V/S is an independent risk factor for CAS in patients with T2DM.

Abstract The efficacy and safety of venetoclax in newly diagnosed pediatric acute myeloid leukemia (AML) are not well-established as they are in adults. Children newly diagnosed with AML were recommended for induction therapy with venetoclax and chemotherapy or hypomethylating agents (HMAs) as per for the ChiCTR1900027146 trial. Venetoclax was administered at a consistent dose of 200 mg/m2/day for 28 days, with adjustments when used concurrently with azoles. The study measured both the remission rates and the safety assessments of venetoclax. We enrolled 45 newly diagnosed pediatric patients with AML. The complete remission rates were 94.7% in the low/middle-risk group and 80.8% in the high-risk group; MRD-negative rates were 52.6% and 38.5% in the low/middle-risk group and high-risk group, respectively. Venetoclax based combination therapy was well tolerated by the majority of patients. The median duration of venetoclax dosing was 18 days (range 9–28), with hematological toxicity and infection being the most common adverse events. Venetoclax-based induction regimens demonstrated a high response rate and safety profile in newly diagnosed pediatric AML cases. This underscores the significance of venetoclax as a viable treatment option for untreated AML, extending beyond its role as salvage therapy for refractory/relapsed AML.

Objective We assessed the contributions of B cell and T cell subsets to the disparate clinical outcomes in NZM.Baff−/− and NZM.Br3−/− mice. Methods We assessed in NZM wild‐type, NZM.Baff−/−, and NZM.Br3−/− mice numbers and percentages of B cells and subsets, T cells and subsets, and in vivo proliferation and survival of forkhead box P3 (Foxp3)+ cells by fluorescence‐activated cell sorting. Relationships between percentages of Foxp3+ cells and numbers of CD19+ and CD4+ cells were assessed by linear regressions. Results In each age and sex cohort, percentages and numbers of CD19+ cells were similar in NZM.Baff−/− and NZM.Br3−/− mice. Percentages of CD3+ and CD4+ cells were greater in NZM.Br3−/− than in NZM.Baff−/− mice, with the CD4 to CD3 cell ratios being greater in NZM.Br3−/− than in NZM.Baff−/− mice and percentages of Foxp3+ cells in NZM.Br3−/− mice being lower than in NZM.Baff−/− mice. Percentages of Foxp3+ cells correlated positively with CD19+ cells in NZM.Baff−/− mice but negatively in NZM.Br3−/− mice. In vivo proliferation and survival of Foxp3+ cells were lower in NZM.Baff−/− mice than in NZM.Br3−/− mice. Conclusion Differences between NZM.Baff−/− and NZM.Br3−/− mice in Foxp3+ cells and their relationships with CD19+ cells may have more to do with their divergent clinical outcomes than do differences in numbers of B cells. These unexpected findings suggest that B cell activating factor (BAFF)–B cell maturation antigen (BCMA) or BAFF–Transmembrane activator and calcium‐modulator and cyclophilin ligand interactor (TACI) interactions may help drive development of clinical systemic lupus erythematosus (SLE) even under conditions of considerable B cell depletion. Insufficient blocking of BAFF–BCMA and BAFF–TACI interactions may lie at the heart of incomplete clinical response to BAFF‐targeting agents in human SLE.

This study reports the development and evaluation of yttrium-90 (90Y) radiolabeled silica-coated iron oxide (SiO2-Fe3O4) resin microspheres for potential theranostic application in cancer radiation therapy. Iron oxide nanoparticles of average diameter 29.7 nm were synthesized via optimized co-precipitation and displayed superparamagnetic behavior ideal for MRI. Aminosilane surface functionalization enabled covalent conjugation of 1 mmol/g DTPA/DOTA chelators for labeling 2 mCi 90Y per 150 μg nanoparticles with 92 % efficiency when incubated for 45 mins at pH 5.5 and 50°C. In vitro stability assays in buffers and human serum showed excellent 90Y retention (>95 %) up to 48 hours. In vivo biodistribution in Wistar rats revealed extended nanoparticle circulation half-life of 5.2 hours and peak exposure of 22.4 %ID/g compared to rapid clearance of unconjugated 90Y chloride within 1 hour. Complete renal recovery by 72 hours and minimal bone accumulation (

Abstract This study aimed to evaluate the safety profile and beneficial effects of Heyndrickxia coagulans strain BC99 (BC99) for potential use in functional foods and pharmaceuticals. We began with whole genome sequencing of BC99, followed by a comprehensive safety assessment comprising genome analysis, hemolysis, cytotoxicity, antibiotic susceptibility tests, and cell adhesion and tolerance studies, along with acute and subacute oral toxicity studies in animal models. BC99 was isolated from a well-characterized collection originating from the feces of a healthy infant. Our results indicated no hemolytic activity on Columbia blood agar plates and broad antibiotic sensitivity, including to gentamicin, ampicillin, chloramphenicol, ciprofloxacin, and others. Cytotoxicity testing confirmed no adverse effects on HT-29 cells and significant adhesive properties to intestinal epithelial cells. Tolerance tests demonstrated over 90% viability of BC99 under simulated gastrointestinal conditions. In vivo studies in mice and rats confirmed the absence of adverse effects following oral administration. Collectively, these findings support BC99’s robust tolerance to gastrointestinal environments, strong adhesion capabilities, and a broad spectrum of antibiotic resistance, underlining its potential as a safe and effective agent for gut microbiota modulation and host health enhancement.

Abstract Flaviviruses strategically utilize the endoplasmic reticulum (ER) in their replication cycles. However, the role of ER autophagy (ER-phagy) in viral replication process remains poorly understood. Here, we reveal that prolonged Zika virus (ZIKV) infection results from the degradation of ER-phagy receptor FAM134B, facilitated by viral NS2A protein. Mechanistically, ER-localized NS2A undergoes K48-linked polyubiquitination at lysine (K) 56 by E3 ligase AMFR. Ubiquitinated NS2A binds to FAM134B and AMFR orchestrates the degradation of NS2A-FAM134B complexes. AMFR-catalyzed NS2A ubiquitination not only targets FAM134B degradation but also hinders the FAM134B-AMFR axis. Notably, a recombinant ZIKV mutant (ZIKV-NS2AK56R), lacking ubiquitination and ER-phagy inhibition, exhibits attenuation in ZIKV-induced microcephalic phenotypes in human brain organoids and replicates less efficiently, resulting in weakened pathogenesis in mouse models. In this work, our mechanistic insights propose that flaviviruses manipulate ER-phagy to modulate ER turnover, driving viral infection. Furthermore, AMFR-mediated flavivirus NS2A ubiquitination emerges as a potential determinant of viral pathogenecity.

Abstract Spatial transcriptomics technologies have been widely applied to decode cellular distribution by resolving gene expression profiles in tissue. However, sequencing techniques still limit the ability to create a fine-resolved spatial cell-type map. To this end, we develop a novel deep-learning-based approach, STASCAN, to predict the spatial cellular distribution of captured or uncharted areas where only histology images are available by cell feature learning integrating gene expression profiles and histology images. STASCAN is successfully applied across diverse datasets from different spatial transcriptomics technologies and displays significant advantages in deciphering higher-resolution cellular distribution and resolving enhanced organizational structures.

Abstract Duck plague virus (DPV) causes the highly pathogenic duck plague, and the envelope glycoprotein I (gI), as one of the key virulence genes, has not yet had its critical virulence sites identified through screening. This study used reverse genetics technology to target the gI, specifically within the DPV genome. Four DPV mutants with gI N-glycosylation site mutations were designed and constructed, and these mutant strains were successfully rescued. Our results confirmed that three asparagine residues of gI (N69, N78, and N265) are N-glycosylation sites, and western blot analysis substantiated that glycosylation at each predicted N-glycosylation site was compromised. The deglycosylation of gI leads to the protein misfolding and subsequent retention in the endoplasmic reticulum (ER). The subsequent deglycosylated gI is carried into the Golgi apparatus (GM130) in the interaction of gE. Compared to the parental virus, the mutated virus shows a 66.3% reduction in intercellular transmission capability. In ducks, the deglycosylation of gI significantly reduces DPV replication in vivo, thereby weakening the virulence of DPV. This study represents the first successful creation of a weak DPV virus strain by specific mutation at the N-glycosylation site. The findings provide a foundational understanding of DPV pathogenesis and form the basis for developing live attenuated vaccines against the disease.

Abstract Small single-stranded DNA phages of the Microviridae family are diverse and prevalent in oceans. Our understanding of Microviridae phages that infect the ecologically important marine Roseobacter is currently limited, comprising few isolates. Here, we report six roseophages that infect Roseobacter RCA strains. Genomic and phylogenetic analyses revealed that they were new members of the previously identified subfamily Occultatumvirinae. Additionally, 232 marine uncultivated virus genomes (UViGs) affiliated to Occultatumvirinae were obtained from environmental genome datasets. Phylogenomic analysis revealed that marine Occultatumvirinae phages could be further grouped into 11 subgroups. Moreover, meta-omics based read-mapping analysis showed that Occultatumvirinae phages were globally distributed, with two low G + C subgroups showing the most prevalent distribution. Furthermore, one phage in subgroup 2 was found to be extremely ubiquitous. Overall, this study expands our understanding of the diversity and ecology of the Occultatumvirinae microviruses in the ocean and highlights their ecological impacts.

With the increase of energy demand, the accompanying environmental problems are also increasing. The CO2 generated by combustion is the direct source of greenhouse gases, and coal-fired power plants are the main source of carbon emissions, and a lot of waste heat is generated in the production process. The decarbonization system of coal-fired power plant and the cogeneration system have similar heat source temperature requirements. Therefore, the waste heat generated in the process can be recycled while controlling the carbon emissions of the coal-fired power plant, and the heating capacity of the system can be improved. Based on the power generation system of coal-fired power plant, solid amine absorbent decarbonization system and primary/secondary heating system, an integrated coupling system of power generation, decarbonization and heating is proposed innovatively. The back-pressure heating steam turbine and back-pressure decarburization steam turbine are introduced to replace the low-pressure steam turbine, and the exhaust steam of the back-pressure heating steam turbine and the back-pressure decarburization steam turbine provide heat sources for the heating process and the decarburization process respectively. On the premise of ensuring decarbonization capacity, the power generation capacity loss of the coupled system is significantly reduced. In order to further improve the thermal performance of the coupling system, the absorption heat transfer technology is used to recover the low-temperature waste heat released by the decarbonization system and improve the heating capacity of the coupling system. The calculation results show that more than 90% of the low-temperature waste heat released by the system is recovered by the new power-decarbonization and heat-supply coupling system. The heating capacity of the system is increased from 785.06 MW to 1 288.94 MW, and the heating capacity is increased by 65%.

Abstract Cancer cells present sialylated glycoconjugates that modulate the activity of various immune cells within the tumor microenvironment through trans interaction with immunosuppressive Siglec receptors. Identifying counter receptors for Siglecs can provide valuable targets for cancer immunotherapy, but it presents significant challenges. Here, the identification of DSG2 (Desmoglein 2) as a dominant counter receptor of Siglec‐9 in melanoma cells is reported, using a workflow that combines the strength of proximity labeling and the advantage of CRISPR knockout screening. It is further demonstrated that the interaction between DSG2 and Siglec‐9 is mainly dependent on sialic acid‐bearing N‐glycans on DSG2. Importantly, blocking trans interaction between DSG2 and Siglec‐9 significantly enhances macrophage phagocytosis of melanoma cells and, to a lesser extent, other cancer cells. The work thus suggests sialylated DSG2 as a potential “don't eat me” signal molecule with therapeutic potentials in cancer immunotherapy.

Ascosphaera apis, a specialized fungal pathogen, causes lethal infection in honeybee larvae. miRNA-like small RNAs (milRNAs) are fungal small non-coding RNAs similar to miRNAs, which have been shown to regulate fungal hyphal growth, spore formation, and pathogenesis. Based on the transcriptome data, differentially expressed miRNA-like RNAs (DEmilRNAs) in A. apis infecting the Apis cerana cerana worker 4-, 5-, and 6-day-old larvae (Aa-4, Aa-5, and Aa-6) were screened and subjected to trend analysis, followed by target prediction and annotation as well as investigation of regulatory networks, with a focus on sub-networks relative to MAPK signaling pathway, glycerolipid metabolism, superoxide dismutase, and enzymes related to chitin synthesis and degradation. A total of 606 milRNAs, with a length distribution ranging from 18 nt to 25 nt, were identified. The first nucleotide of these milRNAs presented a bias toward U, and the bias patterns across bases of milRNAs were similar in the aforementioned three groups. There were 253 milRNAs, of which 68 up-and 54 down-regulated milRNAs shared by these groups. Additionally, the expression and sequences of three milRNAs were validated by stem-loop RT-PCR and Sanger sequencing. Trend analysis indicated that 79 DEmilRNAs were classified into three significant profiles (Profile4, Profile6, and Profile7). Target mRNAs of DEmilRNAs in these three significant profiles were engaged in 42 GO terms such as localization, antioxidant activity, and nucleoid. These targets were also involved in 120 KEGG pathways including lysine biosynthesis, pyruvate metabolism, and biosynthesis of antibiotics. Further investigation suggested that DEmilRNA-targeted mRNAs were associated with the MAPK signaling pathway, glycerolipid metabolism, superoxide dismutase, and enzymes related to chitin synthesis and degradation. Moreover, the binding relationships between aap-milR10516-x and ChsD as well as between aap-milR-2478-y and mkh1 were confirmed utilizing a combination of dual-luciferase reporter gene assay and RT-qPCR. Our data not only provide new insights into the A. apis proliferation and invasion, but also lay a basis for illustrating the DEmilRNA-modulated mechanisms underlying the A. apis infection.

BackgroundHepatic arterial infusion chemotherapy (HAIC) has emerged as a promising treatment for unresectable hepatocellular carcinoma (HCC). However, the safety profiles of HAIC and its various combination therapies remain to be systematically evaluated.MethodsWe systematically searched PubMed, Embase, Cochrane Library, and Web of Science databases from inception to November 2024. Studies reporting adverse events (AEs) of HAIC monotherapy or combination therapies in HCC were included. The severity and frequency of AEs were analyzed according to different treatment protocols.ResultsA total of 58 studies (11 prospective, 47 retrospective) were included. HAIC monotherapy demonstrated relatively mild toxicity, primarily affecting hepatobiliary (transaminase elevation 53.2%, hypoalbuminemia 57.2%) and hematological systems (anemia 43.0%, thrombocytopenia 35.2%). HAIC with targeted therapy showed increased adverse events, including characteristic reactions like hand-foot syndrome (48.0%) and hypertension (49.9%). HAIC combined with targeted, and immunotherapy exhibited the highest adverse reaction rates (neutropenia 82.9%, transaminase elevation 97.1%), while HAIC with anti-angiogenic and immunotherapy showed a relatively favorable safety profile. Prospective studies consistently reported higher incidence rates than retrospective studies, suggesting potential underreporting in clinical practice.ConclusionsDifferent HAIC-based regimens exhibit distinct safety profiles requiring individualized management approaches. We propose a comprehensive framework for patient selection, monitoring strategies, and AE management. These recommendations aim to optimize treatment outcomes while minimizing adverse impacts on patient quality of life.

BackgroundPostherpetic neuralgia (PHN) is a debilitating condition resulting from herpes zoster infection, characterized by persistent pain that significantly impacts quality of life. This study aimed to investigate the white matter microstructural alterations associated with PHN and to assess the relationship between diffusion metrics and clinical symptoms.MethodsA total of 29 patients with PHN, 28 patients recovering from herpes zoster (RHZ), and 27 healthy controls (HC) were recruited, and clinical assessments were obtained to evaluate pain intensity and psychological distress. Diffusion tensor imaging (DTI) data was collected, followed by analysis of diffusion and neurite orientation dispersion and density imaging (NODDI) metrics. Statistical analyses included ANOVA to compare groups and Pearson correlation coefficients to assess relationships between imaging metrics and clinical outcomes.ResultsPHN patients exhibited significantly altered white matter integrity, specifically in neurite density index (NDI) and orientation dispersion index, compared to both RHZ patients and HC. Significant correlations were also found between altered imaging metrics and clinical assessments of pain and emotional distress, with lower fractional anisotropy (FA) and NDI associated with higher pain scores and psychological symptoms.ConclusionOur study highlights significant microstructural changes in white matter tracts in patients with PHN, indicating compromised neural integrity that correlates with increased pain perception and emotional distress. NODDI demonstrated superior sensitivity in detecting these alterations compared to traditional DTI metrics, underscoring its potential for enhancing diagnostic and therapeutic approaches in managing chronic pain conditions like PHN.

BackgroundThe prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has increased worldwide. In recent years, fecal microbiota transplantation (FMT) has become an important promising method for the treatment of MASLD. However, the mechanism remains unclear.MethodsThe animal model with C57BL/6 male mice induced by high-fat diet (HFD) for 12 weeks has been introduced. Fecal microbiota and indole-3-carbinol (I3C) was given by oral gavage.ResultsOur study demonstrated that a 6-week healthy gut microbiota transplantation tended to ameliorate hepatic steatosis and reverse the decreased liver ILC1 induced by HFD. Interestingly, there was also a negative correlation between liver ILC1 and liver TG, TC level. Furthermore, the protective effect was associated with the elevated levels of serum indole-3-carbinol (I3C). Also, a I3C administration for 6 weeks improved liver steatosis and increased the frequency of liver ILC1 induced by HFD through aryl hydrocarbon receptor (AhR) activation. Moreover, I3C binds to the residues of ALA349, PHE348, LEU309, TYR316, PHE318 on AhR through hydrogen bonds, Π bonds, hydrophobic bonds which was proved by molecular docking.ConclusionTo conclude, our data demonstrated that FMT improved liver steatosis induced by HFD associated with liver ILC1 regulation and indole-3-carbinol level. The study highlighted the potential treatment value of FMT and microbiota-derived I3C in the MASLD treatment and regulation of liver ILC1 function.

Avian reovirus (ARV), a double-stranded RNA virus, frequently induces immunosuppression in poultry, leading to symptoms such as irregular bleeding and spleen necrosis in infected ducks. Since 2017, the morbidity and mortality rates associated with ARV infection in poultry have been on the rise, progressively emerging as a significant viral disease impacting the duck farming industry in China. In our study, we collected duck embryo fibroblasts 18 h post-infection with ARV and conducted transcriptome sequencing analysis. The analysis revealed that 3,818 mRNA expressions were up-regulated, 4,573 mRNA expressions were down-regulated, 472 long noncoding RNAs (LncRNAs) were up-regulated, and 345 lncRNAs were down-regulated. We employed qRT-PCR to validate the sequencing results, confirming their accuracy. The transcriptome data indicated significant upregulation of the PARP9, TLR7, TRIM33, and ATG5 genes, suggesting their potential involvement in ARV infection. Notably, our study identified a novel functional lncRNA, MSTRG.9284.1 (It was named linc000889 in the present study), which inhibits the replication of ARV at the transcriptional, translational levels and viral titer. Overall, this study has identified numerous ARV-induced differentially expressed mRNAs and lncRNAs, including the functional lncRNA linc000889 that inhibits ARV replication. This discovery provides new insights into the mechanisms of ARV infection and may contribute to the development of new prevention and treatment strategies.

During viral infection, the transport of various proteins between the nucleus and cytoplasm plays an important role in the viral lifecycle. Shuttling proteins are key factors in the transmission of nucleocytoplasmic information within cells and usually contain nuclear localization signals and nuclear export signals to mediate correct positioning for themselves and other proteins. The nucleocytoplasmic transport process is carried out through the nuclear pore complex on the nuclear envelope and is mediated by specific protein carriers. The viral proteins that function through nucleocytoplasmic shuttling in herpesviruses have gradually been identified as research advances. This article provides an overview of how shuttling proteins utilize nucleocytoplasmic shuttling signals and nuclear transport receptors for nucleocytoplasmic transport, as well as discusses how herpesvirus shuttling proteins enhance the effective infection of viruses by affecting their lifecycle and participating in innate immunity, this review provides a reference for understanding the pathogenesis of herpesvirus infection and determining new antiviral strategies.

Background: The intricate interactions between malignant cells and endothelial cells (ECs) are crucial in the progress of colorectal cancer (CRC). Identifying molecular signatures associated with this interaction could yield critical prognostic insights and inform personalized therapeutic approaches. Methods: We conducted an in silico study integrating single-cell RNA sequencing and bulk transcriptome data to characterize the cellular heterogeneity of CRC. Through computational cell interaction analysis facilitated the elucidation of signaling dynamics among cell subpopulations linked to CRC prognosis. Prognostic signatures were developed using various machine learning algorithms based on marker genes linked to the identified cell subpopulations. Immune cell infiltration assessment and gene enrichment analysis were performed to characterize CRC patients stratified by the signature. Results: Our analysis revealed two distinct cell subgroups, Malignant Cluster01 tumor cells, and Tip-like endothelial cells, showing significant interaction and closely associated with colorectal cancer prognosis. Specifically, Malignant Cluster01 subpopulations primarily served as signal senders, while Tip-like endothelial cells acted as receivers in PARs signaling. The Malignant Cluster01 and Tip-like endothelial cells related machine learning-derived prognostic signature (MTMLDPS), demonstrated potent prognostic capability, effectively predicting colorectal cancer patient outcomes across diverse databases. The colorectal cancer group with a high Malignant Cluster01 and Tip-like endothelial cells related machine learning-derived prognostic signature score exhibited significant associations with invasion, epithelial-mesenchymal transition, and angiogenesis pathways, along with immune cell infiltration. Conclusion: The Malignant Cluster01 and Tip-like endothelial cells related machine learning-derived prognostic signature holds promise for improving prognostic precision and guiding individual therapeutic strategies in colorectal cancer patients. Moreover, our findings emphasize the importance of considering tumor-endothelial cell interactions in cancer prognosis, providing insights for future therapeutic interventions targeting these interactions.

Probiotics interventions may contribute to eradicate Helicobacter pylori infection and reduce gastrointestinal symptom, but their mechanisms require more research. This study involved 100H. pylori-positive adults, randomly assigned to either Weizmannia coagulans BC99 group or Placebo group. Both groups were received bismuth quadruple therapy for 4 weeks and took either BC99 or placebo for 6 weeks. After 6 weeks, BC99 significantly reduced eradication rate and happening of adverse events. BC99 reduced GSRS score, particularly the severity of stomach-abdominal pain during hunger symptoms. Additionally, BC99 reduced the disruption of bismuth quadruple therapy on the gut microbiota, particularly significantly increasing the abundance of Prevotella, Bacillus, Candidatus_Saccharimonas and reducing the abundance of Lachnoclostridium, Intestinibacter, Holdemania, Desulfovibrio. These findings supported the use of W. coagulans BC99 in combination with BQT in the clinical management of patients with H. pylori infection.

Enterocytes are a necessary portal for fecal-oral transmission of viruses, including duck hepatitis A virus (DHAV), that act on the absorption of amino acids (AAs). We note that the rapid death of ducklings caused by DHAV is likely due to its rapid release from enterocytes. However, the underlying mechanism driving the release of DHAV remains poorly understood. Compared to infected fibroblasts, we found that DHAV-infected enterocytes triggered much more rapid viral release and induced swift and diverse remodeling of the mature tRNAome. Surprisingly, we found that tRNA-Ser-UGA in enterocytes was rapidly and specifically upregulated by DHAV infection and was highly correlated with serine decoding of DHAV, which is enriched with UCA codons. Overexpression of tRNA-Ser-UGA in enterocytes promoted rapid DHAV release, whereas overexpression of the cognate tRNA-Ser-GCU in enterocytes or the same tRNA in fibroblasts did not. In enterocytes, inhibition of serine charging of tRNA-Ser-UGA, transfection of a tRNAm-Ala-UGA backbone mutant or a tRNAm-Ser-UGA>CGA anticodon mutant decreased DHAV release. This finding suggests that tRNA-Ser-UGA plays a prominent role in DHAV release in infected enterocytes, which should be supported by efficient protein translation of the virus. Similarly, tRNA-Ser-UGA potently enhances DHAV protein synthesis, and the inhibition of charging of this tRNA or the transfection of the two mutants decreases DHAV protein synthesis. Phenotypically, the overexpression of tRNA-Ser-UGA in enterocytes further accelerates the spread of DHAV to hepatocytes. In conclusion, we revealed a novel tRNA-Ser-UGA that efficiently promotes the rapid release of DHAV by increasing serine decoding in infected enterocytes, thereby promoting remote cell-to-cell dissemination.

Riemerella anatipestifer (R. anatipestifer, RA) is the etiological agent of duck serositis, an acute multisystemic disease in ducks that is globally distributed and causes serious economic losses in the duck industry. Despite exhibiting multidrug resistance, the transmission mechanism of its antibiotic resistance genes (ARGs) remains incompletely identified. To contribute to addressing this gap, in this study, outer membrane vesicles (OMVs) from the RA strain CH-1 were isolated and characterized to investigate their involvement in ARG transfer in RA. Sequencing and data analysis revealed that RA CH-1 OMVs had ∼2.04 Mb genomic size, representing 88.3 % of the RA CH-1 genomic length. Proteomic analysis showed that OMVs contained 577 proteins, representing 27.2 % of the bacterial proteins. Subsequent investigations demonstrated that OMVs from antibiotic-resistant strains transferred ARG fragments and plasmids to the sensitive strain RA ATCC11845, relying on the natural transformation system, and the transformants exhibited corresponding resistance. Overall, OMV-mediated horizontal transfer of ARGs serving as a significant mechanism for acquiring multiple resistance genes in R. anatipestifer.

Balance is crucial for various athletic tasks, and accurately assessing balance ability among elite athletes using simple and accessible measurement methods is a significant challenge in sports science. A common approach to balance assessment involves recording center of pressure (CoP) displacements using force platforms, with various indicators proposed to distinguish subtle balance differences. However, these indicators have not reached a consensus, and it remains unclear whether these analyses alone can fully explain the complex interactions of postural control. In this study, we investigated four parameters related to balance control-anterior-posterior (AP) displacement, medial-lateral (ML) displacement, length, and tilt angle-in 13 elite athletes and 12 freestyle skiing aerial expert athletes. Data were recorded during 30-second trials on both soft and hard support surfaces, with eyes open and closed. We calculated the CMCI and used four machine learning algorithms-Logistic Regression, Support Vector Machine(SVM), Naive Bayes, and Ranking Forest-to combine these features and assess each participant's balance ability. A classic train-test split method was applied, and the performance of different classifiers was evaluated using Receiver Operating Characteristic(ROC) analysis. The ROC results showed that traditional time-domain features were insufficient for accurately distinguishing athletes' balance abilities, whereas CMCI performed the best overall. Among all classifiers, the combination of CMCI and Ranking Forest yielded the best performance, with a sensitivity of 0.95 and specificity of 0.35. This nonlinear, multidimensional approach appears to be highly suitable for assessing the complexity of postural control.

Objectives: Inflammasomes are associated with various autoimmune diseases. Herein, we aimed to study the occurrence of inflammasomes in peripheral blood mononuclear cells (PBMCs) from patients with autoimmune thyroiditis (AIT), and the relationship between their abundance and the inflammatory response index of AIT. Furthermore, we examined the effect of iodine on inflammasomes containing NLR family pyrin domain-containing 3 (NLRP3) and inflammasome activation of helper T (Th) cell differentiation regulation in cultured PBMCs. Methods: We collected PBMCs and serum samples from 50 patients with AIT with normal thyroid function and 50 controls matched for age and sex. In PBMCs, the mRNA and protein expressions of certain inflammasome constituents (e.g., NLRP1, NLRP3, absent in melanoma 2 (AIM2) and caspase-1), interleukin (IL)-1β and IL-18 were assessed using qRT-PCR and western blotting. Enzyme-linked immunosorbent assays (ELISAs) assessed the serum levels of IL-1β and IL-18. Flow cytometry was employed to examine NLRP3 expression on CD14+ monocytes and Th1 and Th17 cell percentages in the groups. AIT- or healthy control-derived PBMCs were stimulated using sodium iodide, with or without lipopolysaccharide (LPS) for 72 h. Results: PBMCs from patients with AIT had significantly higher levels of pro-IL-18, pro-IL-1β and NLRP3 than did the PBMCs from the healthy controls (P < 0.05). Compared with those from the controls, AIT-derived PBMCs had enhanced levels of active IL-18 and active caspase-1 p20 (P < 0.05), whereas their abundance of active IL-1β was similar (P > 0.05). In serum, the AIT group had enhanced levels of IL-18 compared with the healthy controls (P < 0.05) but had similar levels of IL-1β (P > 0.05). NLRP3 expression on CD14+ monocytes from AIT patients was significantly augmented compared with the healthy controls (P< 0.01). Significantly increased percentages of Th1 and Th17 cells were detected in AIT patients compared with those in the healthy participants (P < 0.001). Sodium iodide treatment upregulated NLRP3 expression in PBMCs during 72 h of culture (P < 0.001). The percentage of Th1 and Th17 cells in AIT patients increased in an iodine-dependent manner (P < 0.01). Iodine had no significant effect on the number of these cells in the healthy control group (P > 0.05). Conclusion: AIT-derived PBMC NLRP3 activity and expression increased. Iodine might regulate the immune and inflammatory response of patients with AIT by activating NLRP3 and promoting Th1 and Th17 cell differentiation.

Daqu, a starter culture rich in microorganisms like bacteria and fungi, is central to vinification and liquor brewing, yet fungal contributions are often understudied. In this study, we used Illumina MiSeq sequencing to investigate the succession of fungal community during Chinese strong-flavor liquor fermentation. The results showed that the alpha and beta diversity of fungal community were significantly different during Daqu fermentation. The dominant phyla and genera are Ascomycota and Saccharomycopsis, respectively. Co-occurrence network analysis identified 10 keystone species during Daqu fermentation, displaying that the positive correlations (99.64%) dominated the fungal network. The redundancy analysis showed that moisture has the most significant influence on the Daqu fungal community. Concurrently, a robust association was observed between 10 keystone fungal genera and environmental parameters such as acidity and moisture. These findings not only elucidated the intricate dynamics of the fungal community succession and the interplays among fungi but also pinpointed the primary drivers of the fungal community and its keystone species during the Daqu fermentation process. Ultimately, this research presented novel perspectives for enhancing the quality and precision of liquor production by shedding light on the central role of keystone species in maintaining community stability and their adaptive responses to environmental stimuli.

ObjectiveThis study aimed to assess the impact of Lactiplantibacillus plantarum Lp05 (Lp05) on the gastrointestinal microbiome and pathophysiological status of mice infected with Helicobacter pylori (H. pylori), exploring its potential as a probiotic treatment for H. pylori infections.MethodsIn vitro, the interaction between Lp05 and H. pylori was analyzed using laser confocal and scanning electron microscopy. In vivo, C57BL/6 mice infected with H. pylori were treated with Lp05 and divided into six groups: control, model, quadruple therapy, and three dosage levels of Lp05 (2×107, 2×108, 2×109 CFU/mouse/day). Over six weeks, the impact of Lp05 on the gastrointestinal microbiome and physiological markers was assessed. Measurements included digestive enzymes (α-amylase, pepsin, cellulase), inflammatory markers (interleukin-17A, interleukin-23, interleukin-10, interferon-β, interferon-γ, FoxP3, endothelin, IP-10, TGF-β1), oxidative stress markers (catalase, malondialdehyde, superoxide dismutase, myeloperoxidase), and tissue pathology (via modified Warthin-Starry silver and H&E staining). Microbial community structure in the stomach and intestines was evaluated through 16S rRNA gene sequencing.ResultsIn vitro studies showed Lp05 and H. pylori formed co-aggregates, with Lp05 potentially disrupting H. pylori cell structure, reducing its stomach colonization. In vivo, Lp05 significantly lowered gastric mucosal urease activity and serum H. pylori-IgG antibody levels in infected mice (p < 0.01). It also mitigated pathological changes in the stomach and duodenum, decreased inflammatory responses (ET, IL-17A, IL-23, TGF-beta1, and IP-10, p < 0.01 for all), and enhanced antioxidant enzyme activities (CAT and SOD, p < 0.01) while reducing MDA and MPO levels (p < 0.01), combating oxidative stress from H. pylori infection. Lp05 treatment significantly modified the intestinal and gastric microbiota, increasing beneficial bacteria like Lactobacillus and Ligilactobacillus, and decreasing harmful bacteria such as Olsenella, linked to pathological conditions.ConclusionLp05 effectively modulates the gastrointestinal microbiome, reduces inflammation and oxidative stress, and suppresses H. pylori, promising for probiotic therapies with further research needed to refine its clinical use.

BackgroundHypocretin-1 is a vital neurotransmitter in regulating the sleep–wake cycle and provides neuroprotection against cerebral ischemia. We aims to develop a poor sleep quality predictive model for elderly population with acute ischemic stroke.MethodsA total of 183 consecutively elderly patients were included in the prospective cohort study. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). Cerebrospinal fluid samples were taken within 24 h of acute ischemic stroke onset. After selecting optimal predictors via univariate analysis and bootstrapped stepwise logistic regression, the predictive model was developed. The models were internally validated and evaluated comprehensively via discrimination, calibration, and clinical utility.ResultsThe prevalence of poor sleep (PSQI >7) was 64.5% among elderly individuals experiencing acute ischemic stroke. The study developed a predictive model using hypocretin-1, hypertension, stroke history, the National Institutes of Health Stroke score, and depression. Adding hypocretin-1 (as continuous variable) significantly improved the model performance greatly, as the area under the receiver operating characteristic curve increased from 0.799 to 0.845 (p

Duck plague (DP), which is caused by duck plague virus (DPV), is an infectious disease that severely harms the waterfowl breeding industry. The UL14 protein (pUL14) is a tegument protein encoded by the UL14 gene, which is located in the unique long (UL) region of the DPV genome. DPV pUL14 plays a crucial role in viral replication, likely by interacting with host and viral proteins that have yet to be identified. In this study, glutathione-S-transferase (GST) pull-down combined with liquid chromatography-mass spectrometry (LC-MS/MS) was employed to identify pUL14-interacting proteins in DPV-infected cells. A total of 281 host proteins and 58 viral proteins that interacted with pUL14 were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed that the identified proteins could be assigned to several different subcellular locations and functional classes. These proteins are associated mainly with the regulation of biological processes, RNA biosynthetic processes, and nuclear export. In addition, four viral proteins of interest, the α-gene transducing factor (α-TIF) pUL48, the nuclear egress complex (NEC) proteins pUL31/34, and pUL51, a protein involved in secondary envelopment, were validated by coimmunoprecipitation (co-IP) to interact with DPV pUL14. Additionally, the nuclear export signal (NES) was identified in a leucine-rich region at aa 77-87 (77VQTKIEEQLAI87) of DPV pUL14. The interactome data between DPV pUL14 and host/viral proteins contribute to understanding the role of DPV pUL14 in the replication of DPV.

Abstract Bridge construction collapse is one of the most common bridge safety accidents. At present, evaluation results are often affected by the ability and experience of the assessor. Therefore, it is difficult to quickly, accurately and effectively evaluate the risk in the process of bridge construction. Moreover, key factors that can prevent accidents can hardly find from the existing bridge construction safety management and evaluation method. This paper analyzes and classifies the artificial and environmental risk factors that affect the bridge construction stage, and establishes 26 risk factors in 5 categories according to the characteristics of bridge construction and the actual situation of the project. Random forest (RF) algorithm is a non-parametric machine learning method based on decision tree, which does not need to be scored by experts in advance and avoids the influence of subjective factors. Compared with other analysis methods, random forest algorithm has the advantages of accurate and robust risk assessment results. Based on the advantages of random forest algorithm and the characteristics of bridge construction risk, this paper uses random forest algorithm to evaluate the bridge construction risk, and ranks the importance of indicators, and identify the index that has a greater influence on the risk. In order to verify the applicability and feasibility of the proposed method, a typical urban complex pedestrian bridge was taken as an example for actual engineering evaluation and verification. The results obtained are basically consistent with the actual risk assessment results of the pedestrian bridge.

Abstract Background Exercise training is fundamental in pulmonary rehabilitation (PR), but patients with chronic obstructive pulmonary disease (COPD) often struggle with exercise intolerance. Respiratory support during exercise in COPD patients may be a beneficial adjunct therapy. In this study, the effect of different respiratory support therapy during pulmonary rehabilitation exercise training in COPD patients was assessed through a network meta-analysis. Methods Five databases were searched to obtain randomized controlled trials involving different respiratory support therapies during PR exercise training in COPD patients. The Cochrane Handbook tool was employed to assess the risk bias of included studies. Network meta-analysis was performed using the STATA software. The study protocol was registered at PROSPERO (CRD42023491139). Results A total of 35 studies involving 1321 patients and 6 different interventions were included. Network meta-analysis showed that noninvasive positive pressure ventilation (NPPV) is superior in improving exercise capacity (6-Minute Walk Test distance, peak work rate, endurance time), dyspnea, and physiological change (peak VO2, tidal volume, minute ventilation and lactate level) in stable COPD patients who were at GOLD stage III or IV during PR exercise training. The final surface under the cumulative ranking curve value indicated that NPPV therapy achieved the best assistive rehabilitation effect. Conclusions The obtained results indicate that NPPV is most powerful in assisting exercise in severe COPD patients under stable condition. Researchers should focus more on the safety, feasibility, and personalization of interventions. Furthermore, there is a need for additional high-quality trials to assess the consistency of evidence across various respiratory support approaches. Trial registration The study was registered at PROSPERO (CRD42023491139).

Abstract Background Submucosal pseudoinvasion and squamous metaplasia (SM) are incidental and special morphological findings in colorectal adenomas, and both can mimic invasive carcinoma. The coexistence of these two findings further increases the risk of misdiagnosis, posing a great diagnostic challenge to pathologists. From 1979 to 2022, only 8 cases have been reported, which was extremely rare. In this report, we presented a case of sigmoid colon adenoma accompanied by pseudoinvasion and SM. Additionally, relevant literature was analyzed to summarize the clinical and pathological characteristics. Case presentation A 51-year-old Chinese male patient presented with fresh blood after defecation. Electronic colonoscopy revealed multiple polyps, which were removed using a snare and subjected to high-frequency electrocoagulation resection. The largest polyp, located in the sigmoid colon, was a thick pedunculated and lobulated polyp with a maximum diameter of 2.8 cm. The surface of the polyp showed slight ruggedness and redness, and it was sent for pathological examination. Grossly, the polyp had a lobulated and slightly rough surface. Microscopically, it showed a tubulovillous adenoma with focal high-grade dysplasia and mucosal muscle hyperplasia. Glandular elements were observed in the submucosal layer, forming a well-defined lobular structure. Some of the glands displayed cystic change, and focal SM could be seen within the adenoma. SM could manifest as discrete solid cell nests of varying sizes or cribriform-morular-like structures. Immunohistochemical staining showed that SM cells were diffusely positive for cytokeratin 5/6 (CK5/6); p40, p63, and cytokeratin 20 (CK20) were negative; while caudal type homeobox 2 (CDX2) was weakly positive. β-catenin showed abnormal nuclear expression, and an extremely low Ki67 proliferation index was observed. Conclusions Coexistence of SM and pseudoinvasion in colorectal adenomas is highly rare. It is more commonly observed in males and tends to occur in the sigmoid colon. It primarily manifests in tubulovillous adenoma and tubular adenoma, with a majority of cases exhibiting a pedicle. Histologically, it is similar to invasive lesions. The cystic dilation of the submucosal glands, hemosiderin deposition, and the presence of a lamina propria around the submucosal glands without adjacent desmoplastic reaction, suggest pseudoinvasion rather than cancer. The bland cytological morphology and Immunohistochemical markers play a crucial role in distinguishing SM from true invasive lesions.

Abstract The ongoing epidemic of flaviviruses worldwide has underscored the importance of studying flavivirus vector competence, considering their close association with mosquito vectors. Tembusu virus is an avian-related mosquito-borne flavivirus that has been an epidemic in China and Southeast Asia since 2010. However, the reason for the outbreak of Tembusu virus in 2010 remains unclear, and it is unknown whether changes in vector transmission played an essential role in this process. To address these questions, we conducted a study using Culex quinquefasciatus as a model for Tembusu virus infection, employing both oral infection and microinjection methods. Our findings confirmed that both vertical and venereal transmission collectively contribute to the cycle of Tembusu virus within the mosquito population, with persistent infections observed. Importantly, our data revealed that the prototypical Tembusu virus MM_1775 strain exhibited significantly greater infectivity and transmission rates in mosquitoes than did the duck Tembusu virus (CQW1 strain). Furthermore, we revealed that the viral E protein and 3′ untranslated region are key elements responsible for these differences. In conclusion, our study sheds light on mosquito transmission of Tembusu virus and provides valuable insights into the factors influencing its infectivity and transmission rates. These findings contribute to a better understanding of Tembusu virus epidemiology and can potentially aid in the development of strategies to control its spread.

Abstract Duck hepatitis A virus type 1 (DHAV-1) is an important member of the Picornaviridae family that causes highly fatal hepatitis in ducklings. Since picornaviruses have small genomes with limited coding capacity, they must utilize host proteins for viral cap-independent translation and RNA replication. Here, we report the role of duck poly(rC)-binding protein 2 (PCBP2) in regulating the replication and translation of DHAV-1. During DHAV-1 infection, PCBP2 expression was upregulated. A biotinylated RNA pull-down assay revealed that PCBP2 positively regulates DHAV-1 translation through specific interactions with structural domains II and III of the DHAV-1 internal ribosome entry site (IRES). Further studies revealed that PCBP2 promotes DHAV-1 replication via an interaction of its KH1 domain (aa 1–92) with DHAV-1 3Dpol. Thus, our studies demonstrated the specific role of PCBP2 in regulating DHAV-1 translation and replication, revealing a novel mechanism by which host‒virus interactions regulate viral translation and replication. These findings contribute to further understanding of the pathogenesis of picornavirus infections.

Abstract DHAV-1 is a highly infectious pathogen that can cause acute hepatitis in ducklings. MicroRNA (miRNA) plays an essential regulatory role in virus response. We characterized and compared miRNA and mRNA expression profiles in duck embryonic fibroblasts (DEF) and the liver of ducklings infected with DHAV-1. DHAV-1 infected DEF was divided into infection group (D group) and blank group (M group), and DHAV-1 infected duckling group was divided into infection group (H group) and blank group (N group). D vs. M have 130 differentially expressed (DE) miRNA (DEM) and 2204 differentially expressed (DE) mRNA (DEG), H vs. N have 72 DEM and 1976 DEG. By the intersection of D vs. M and H vs. N comparisons, 15 upregulated DEM, 5 downregulated DEM, 340 upregulated DEG and 50 downregulated DEG were found with both in vivo and in vitro DHAV-1 infection. In particular, we identified the same DE miRNA target genes and functional annotations of DE mRNA. We enriched with multiple gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, which may have important roles in viral virulence, host immunity, and metabolism. We selected miR-155, which is co-upregulated, and found that miR-155 targets SOCS1 to inhibit DHVA-1 replication.