Downregulation of mesenteric afferent sensitivity following long-term systemic treatment of vincristine in mice.

AIMS: Gastrointestinal paresthesia and dysmotility are common side effects of vincristine (VCR) chemotherapy, which have become one of the factors for dose reduction, therapy delay or discontinuation. However, the mechanism is not entirely clear, whether it is related to autonomic nerves injury remains unknown. Therefore, we aimed to study whether VCR-induced gastrointestinal toxicity is related to changes in mesenteric afferent activity. METHODS: The effects of a single VCR stimulation and long-term systemic VCR treatment on mesenteric afferent activity were investigated by directly recording mesenteric afferent discharge in vitro. RESULTS: Our results showed that a single VCR (0.001-1 µmol/L) stimulation obviously increased the spontaneous, chemically evoked and mechanically evoked discharge of jejunal and colonic mesenteric afferents. This kind of hypersensitivity of VCR could be blocked by capsazepine, a transient receptor potential vanilloid 1 (TRPV1) antagonist. For the mice treated with VCR (0.1 mg/kg/d, i.p.) for 14 days, the abdominal withdrawal reflex and writhing response scores were reduced. Meanwhile, the spontaneous discharge of colonic mesenteric afferents and the afferent response to VCR was downregulated, and the afferent sensitivity to chemical and mechanical stimulation was reduced. Moreover, the expression of TRPV1 in colon was decreased. CONCLUSIONS: These results suggest that the direct stimulation by VCR increases the mesenteric afferent sensitivity by activating TRPV1, which may be the reason of VCR-induced abdominal pain; the long-term systemic treatment of VCR decreases mesenteric afferent sensitivity by reducing TRPV1, which may be the reason of VCR-induced constipation.

Ba6RE2Ti4O17 (RE = Nd, Sm, Gd, Dy-Yb): A Family of Rare-Earth-Based Layered Triangular Lattice Magnets.

The exploration of new rare-earth (RE)-based triangular-lattice materials plays a significant role in motivating the discovery of exotic magnetic states. Herein, we report a family of hexagonal perovskite compounds Ba6RE2Ti4O17 (RE = Nd, Sm, Gd, Dy-Yb) with a space group of P63/mmc, where magnetic RE3+ ions are distributed on the parallel triangular-lattice layers within the ab-plane and stacked in an 'AA'-type fashion along the c-axis. The low-temperature magnetic characterizations indicate that all synthesized Ba6RE2Ti4O17 compounds exhibit dominant antiferromagnetic (AFM) interactions and the absence of magnetic order down to 1.8 K. The isothermal magnetization and electron spin resonance results reveal the distinct magnetic anisotropy for the compounds with different RE ions. Moreover, the as-grown Ba6Nd2Ti4O17 single crystals exhibit Ising-like magnetic anisotropy with a magnetic easy-axis perpendicular to the triangle-lattice plane and no long-range magnetic order down to 80 mK, as the quantum spin liquid candidate with dominant Ising-type interactions.

Single-sEV profiling identifies the TACSTD2 + sEV subpopulation as a factor of tumor susceptibility in the elderly.

BACKGROUND: Aging is a very complex physiological phenomenon, and sEVs are involved in the regulation of this mechanism. Serum samples from healthy individuals under 30 and over 60 years of age were collected to analyze differences in sEVs proteomics. RESULTS: Based on PBA analysis, we found that sEVs from the serum of elderly individuals highly express TACSTD2 and identified a subpopulation marked by TACSTD2. Using ELISA, we verified the upregulation of TACSTD2 in serum from elderly human and aged mouse. In addition, we discovered that TACSTD2 was significantly increased in samples from tumor patients and had better diagnostic value than CEA. Specifically, 9 of the 13 tumor groups exhibited elevated TACSTD2, particularly for cervical cancer, colon cancer, esophageal carcinoma, liver cancer and thyroid carcinoma. Moreover, we found that serum sEVs from the elderly (especially those with high TACSTD2 levels) promoted tumor cell (SW480, HuCCT1 and HeLa) proliferation and migration. CONCLUSION: TACSTD2 was upregulated in the serum of elderly individuals and patients with tumors, and could serve as a dual biomarker for aging and tumors.

Association of accommodation and convergence with axial length elongation in children with basic intermittent exotropia: a 12-month observational study.

INTRODUCTION: To investigate the association of parameters related to accommodation and convergence and axial elongation in basic intermittent exotropia (IXT) patients and the potential clinical predictors of axial length (AL) growth. METHODS: A total of 140 basic IXT patients were recruited in this study. The medians of AL growth in different age brackets were chosen to divide the subjects into Group A (slower axial elongation group, n=69) and Group B (faster axial elongation group, n=71). Parameters of dominant and nondominant eyes were compared and analyzed during the 12-month follow-up period. The parameters, including baseline refraction, angle of deviation, Newcastle score (NCS), accommodative amplitude (AMP), accommodative facility (AMF), accommodative response, positive or negative relative accommodation (PRA/NRA), and near point of convergence (NPC), were analyzed via univariate and multivariate regression. RESULTS: Subjects in faster axial elongation group tended to have more myopic spherical equivalents (t=3.956, P<.001), greater accommodative amplitudes of dominant eyes (t=-2.238, P=.027) and less near points of convergence (t=2.347, P=.020) than in slower axial elongation group. For dominant eyes, logistic and linear regression analysis revealed that more negative spherical equivalents (OR=0.603, P<.001; ß=-0.045, P<.001), greater accommodative amplitudes (OR=1.201, P=.027; ß=0.023, P=.010) and less near points of convergence (OR=0.883, P=.021; ß=-0.012, P=.019) were correlated with the faster axial elongation. For nondominant eyes, more myopic spherical equivalent (OR=0.682; P=.001; ß=-0.029, P=.005) was the only parameter correlated with faster axial elongation through regression analysis. CONCLUSION: In children with basic intermittent exotropia, faster axial elongation in the dominant eyes were associated with more myopic spherical equivalents, greater accommodative amplitudes, and lower near points of convergence. These accommodative parameters can serve as potential clinical indicators for monitoring myopia progression in addition to axial length.

Comparison of the quadrant method measuring four points and bernard method in femoral tunnel position evaluation on 3-dimensional reconstructed computed tomography after anatomical single-bundle anterior cruciate ligament reconstruction.

PURPOSE: This prospective study aimed to compare the postoperative evaluation of the quadrant method measuring four points and Bernard method in femoral tunnel position evaluation on 3-Dimensional (3D) reconstructed computed tomography (CT) following the arthroscopic single-bundle anterior cruciate ligament (ACL) reconstruction. METHODS: Thirty-eight patients with ACL tears that were reconstructed using single-bundle ACL reconstruction between May 2021 and March 2023 were included in this study. Postoperative 3D CT images were obtained after the operation. The femoral tunnel position was measured by use of the quadrant method measuring four points and Bernard method. RESULTS: Average mean position of the femoral tunnel insertion center on the 3D CT image was at 26.16 ± 6.27% in the x-coordinate and at 24.36 ± 5.52% in the y-coordinate according to the Bernard method. Meanwhile, the position of the femoral insertion of the ACL measured by the quadrant method measuring four points was 24.2% ± 6.86% in the x-coordinate and 21.16% ± 5.14% in the y-coordinate. CONCLUSIONS: Both the quadrant method measuring four points and Bernard method were effective in femoral tunnel position evaluation on 3D reconstructed CT. Application of the quadrant method measuring four points on 3D CT showed the advantage that measurement can be taken regardless of the shape of the bone tunnel.

4-Octyl itaconate alleviates dextran sulfate sodium-induced ulcerative colitis in mice via activating the KEAP1-NRF2 pathway.

Ulcerative colitis (UC) is a chronic idiopathic inflammatory bowel disease with a relapsing-remitting course. Although its etiology remains unknown, excessive oxidative stress in colon is a major intermediate factor that can promote the progression of UC. In the present study, we investigated the effect and the underlying mechanisms of 4-Octyl itaconate (OI) on dextran sulfate sodium (DSS)-induced UC in mice. Our work identified that OI alleviated the colitis by reducing the oxidative stress and the apoptosis in colon tissue, then increasing the tight junction proteins expression and in turn enhancing the intestinal barrier function, thereby creating less severe inflammatory responses. Moreover, our results demonstrated that OI reduced the Kelch-like ECH-associated protein 1 (KEAP1) expression and subsequent upregulated nuclear factor E2-related factor (NRF2) expression and its nuclear translocation which in turn induced the expression of glutathione S-transferase (GST) and NAD(P)H: quinone oxidoreductase 1 (NQO1). In addition, ML385, a NRF2 antagonist, can inhibit the protective effects of OI on UC, indicating that the role of OI in this colitis model could be dependent on the activation of KEAP1-NRF2 pathway. Notably, OI co-administration significantly enhanced the therapeutic effects of mesalazine or 1400W on UC. Collectively, itaconate may have a great potential for use in the treatment of IBD.

Mechanisms underlying the formation of main volatile odor sulfur compounds in foods during thermal processing.

Volatile sulfur compounds (VSCs) significantly influence food flavor and garner considerable attention in flavor research due to their low sensory thresholds, diverse odor attributes, and high reactivity. Extensive research studies have explored VSC formation through thermal processes such as the Maillard reaction, thermal pyrolysis, oxidation, and enzymatic reactions. However, understanding of the specific reaction mechanisms and processes remains limited. This is due to the dispersed nature of existing studies, the undefined intermediates involved, and the complexity of the matrices and processing conditions. Given these limitations, the authors have shifted their focus from foods to sulfides. The structure, source, and chemical characteristics of common precursors (sulfur-containing amino acids and derivatives, thiamine, thioglucoside, and lentinic acid) and their corresponding reactive intermediates (hydrogen sulfide, thiol, alkyl sulfide, alkyl sulfenic acid, and thial) are provided, and the degradation mechanisms, reaction rules, and matrix conditions are summarized based on their chemical characteristics. Additionally, the VSC formation processes in several typical foods during processing are elucidated, adhering to these identified rules. This article provides a comprehensive overview of VSCs, from precursors and intermediates to end products, and is crucial for understanding the mechanisms behind VSC formation and managing the flavor qualities of processed foods.

Functional roles of conserved lncRNAs and circRNAs in eukaryotes.

Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) have emerged as critical regulators in essentially all biological processes across eukaryotes. They exert their functions through chromatin remodeling, transcriptional regulation, interacting with RNA-binding proteins (RBPs), serving as microRNA sponges, etc. Although non-coding RNAs are typically more species-specific than coding RNAs, a number of well-characterized lncRNA (such as XIST and NEAT1) and circRNA (such as CDR1as and ciRS-7) are evolutionarily conserved. The studies on conserved lncRNA and circRNAs across multiple species could facilitate a comprehensive understanding of their roles and mechanisms, thereby overcoming the limitations of single-species studies. In this review, we provide an overview of conserved lncRNAs and circRNAs, and summarize their conserved roles and mechanisms.

Optimal carbon emission reduction path of the building sector: Evidence from China.

To combat climate change, China's building sector, responsible for almost 50 % of national emissions, must undergo a drastic decarbonization transformation. This paper charts the optimal path to achieve this goal, leveraging a combined framework of the Low Emissions Analysis Platform (LEAP) and System Dynamics (SD) for scenario-based forecasting of energy consumption and emissions in 2021-2060. A linear programming model is further developed to identify the lowest-cost combination of 26 building green technologies that align with China's carbon peaking and carbon neutrality targets. Results show that in a business-as-usual scenario, building carbon emissions will peak at 6393 million tons of CO2 in 2041, missing the 2030 carbon peaking target. Key drivers of this shortfall include the high energy intensity for "Transport, Storage and Post" and the large carbon emission factors for "Wholesale, Retail Trades, Hotels, and Catering Services" and "Residential" sectors. Under various technology application scenarios assuming uniform penetration rates, the 2030 carbon peak target appears attainable, though at a considerably high cost. Finally, under optimal technology combinations, building carbon emissions are forecasted to peak in 2030 at 5139 million tons of CO2, a mere 4.4 % increase from 2020. The cost of this optimized combination is projected to represent only 1.5 % of the total GDP in 2060. This scenario also leads to a significantly weaker correlation between energy consumption and carbon emissions in the building sector around 2036, nearly 17 years ahead of the business-as-usual trajectory.

Protective effect of oxytocin on vincristine-induced gastrointestinal dysmotility in mice.

Aims: Vincristine (VCR), an antineoplastic drug, induces peripheral neuropathy characterized by nerve damage, limiting its use and reducing the quality of life of patients. VCR causes myenteric neuron damage, inhibits gastrointestinal motility, and results in constipation or paralytic ileus in patients. Oxytocin (OT) is an endogenous neuropeptide produced by the enteric nerve system, which regulates gastrointestinal motility and exerts neuroprotective effects. This study aimed to investigate whether OT can improve VCR-induced gastrointestinal dysmotility and evaluate the underlying mechanism. Methods: Mice were injected either with saline or VCR (0.1 mg/kg/d, i. p.) for 14 days, and OT (0.1 mg/kg/d, i.p.) was applied 1 h before each VCR injection. Gastrointestinal transit and the contractile activity of the isolated colonic segments were assessed. The concentration of OT in plasma was measured using ELISA. Immunofluorescence staining was performed to analyze myenteric neurons and reactive oxygen species (ROS) levels. Furthermore, the indicators of oxidative stress were detected. The protein expressions of Nrf2, ERK1/2, P-ERK1/2, p38, and P-p38 in the colon were tested using Western blot. Results: VCR reduced gastrointestinal transit and the responses of isolated colonic segments to electrical field stimulation and decreased the amount of neurons. Furthermore, VCR reduced neuronal nitric oxide synthase and choline acetyltransferase immunopositive neurons in the colonic myenteric nerve plexus. VCR increased the concentration of OT in plasma. Exogenous OT pretreatment ameliorated the inhibition of gastrointestinal motility and the injury of myenteric neurons caused by VCR. OT pretreatment also prevented the decrease of superoxide dismutase activity, glutathione content, total antioxidative capacity, and Nrf2 expression, the increase of ROS levels, and the phosphorylation of ERK1/2 and p38 MAPK following VCR treatment. Conclusion: Our results suggest that OT pretreatment can protect enteric neurons from VCR-induced injury by inhibiting oxidative stress and MAPK pathways (ERK1/2, p38). This may be the underlying mechanism by which it alleviates gastrointestinal dysmotility.

D-Mannose promotes recovery from experimental colitis by inducing AMPK phosphorylation to stimulate epithelial repair.

Delayed mucosal healing and impaired intestinal epithelial barrier function have been implicated in the pathogenesis of ulcerative colitis (UC). Accordingly, restoration of epithelial barrier function as a means to reshape mucosal homeostasis represents an important strategy for use in the treatment of UC. In this study, we examined the role and mechanisms of D-mannose in the recovery of colitis as assessed in both animal and cell models. We found that D-mannose ameliorated inflammation, promoted mucosal healing in the colon and therefore was able to induce the recovery of UC. Furthermore, D-mannose increased the expression of tight junction (TJ) proteins and reduced the intestinal permeability during the recovery of colitis. Moreover, D-mannose inhibited M1 macrophage polarization and promoted M2 macrophage polarization via inducing AMPK phosphorylation while reducing mTOR phosphorylation in both models. In addition, increased TJ protein expression and decreased paracellular permeability were observed in NCM460 cells when incubated with the supernatants of D-mannose-treated RAW264.7 cells, suggesting that M1/M2 polarization induced by D-mannose modulates the expression of TJ proteins. Further study showed that D-mannose significantly upregulated the expression of TJ proteins in DSS-treated NCM460 cells by inducing AMPK phosphorylation, indicating a direct protective effect on epithelial cells. Finally, the protective effects of D-mannose were significantly abrogated by the presence of compound C, an AMPK inhibitor. Taken together, our data indicate that D-mannose can alleviate inflammation and foster epithelial restitution in UC recovery by inducing the TJ protein expression, which are achieved by inducing AMPK phosphorylation in the epithelium and/or macrophages.

Piscis: a novel loss estimator of the F1 score enables accurate spot detection in fluorescence microscopy images via deep learning.

Single-molecule RNA fluorescence in situ hybridization (RNA FISH)-based spatial transcriptomics methods have enabled the accurate quantification of gene expression at single-cell resolution by visualizing transcripts as diffraction-limited spots. While these methods generally scale to large samples, image analysis remains challenging, often requiring manual parameter tuning. We present Piscis, a fully automatic deep learning algorithm for spot detection trained using a novel loss function, the SmoothF1 loss, that approximates the F1 score to directly penalize false positives and false negatives but remains differentiable and hence usable for training by deep learning approaches. Piscis was trained and tested on a diverse dataset composed of 358 manually annotated experimental RNA FISH images representing multiple cell types and 240 additional synthetic images. Piscis outperforms other state-of-the-art spot detection methods, enabling accurate, high-throughput analysis of RNA FISH-derived imaging data without the need for manual parameter tuning.

Interplay between Intermediate Anionic and Cationic Species and the Reflection to Voltage Hysteresis of Oxygen-Redox Battery Electrodes: A Holistic Picture.

Ligand-to-metal charge transfer (LMCT) is conceived as a universal theory to account for voltage hysteresis in oxygen-redox battery electrodes. However, the influence of oxygen anionic species on mediating LMCT and its reflection to voltage hysteresis remain poorly understood. Herein, we demonstrate a close interplay between the chemical states of oxidized oxygen species, the cationic species, and the kinetics of LMCT and forcefully identify their influence on the magnitude of voltage hysteresis. Combining electrochemical/spectroscopic evidence and first-principles calculations, we clarify two distinct kinds of dynamic LMCT processes─that is, the formation of trapped molecular O2 accompanied by the reduction of Ni4+/Ni3+ to Ni2+ (fast LMCT) during relaxation in Li-rich cation-disordered rock-salt (DRX) Li1.3Ni0.27Ta0.43O2 with extremely large voltage hysteresis, the formation of O-O dimers, and the partial reduction of Mn4+ to Mn3+ (slow LMCT) in DRX-Li1.3Mn0.4Ta0.3O2 with medium hysteresis. We further validate the maintenance of both cationic (Mn4+) and anionic (O-•) species during relaxation in Na2Mn3O7, reconciling its nonhysteretic behavior to the absence of LMCT. This study highlights the critical role of intermediate anionic species in mediating LMCT and provides a causal explanation of various voltage hysteresis signatures of oxygen-redox materials.

Vaccination with Adenovirus Type 5 Vector-Based COVID-19 Vaccine as the Primary Series in Adults: A Randomized, Double-Blind, Placebo-Controlled Phase 1/2 Clinical Trial.

This randomized, double-blind, placebo-controlled phase 1/2 trial aimed at evaluating the safety and immunogenicity of Ad5-nCoV via aerosolized or intramuscular or intramuscular-aerosolized routes in SARS-CoV-2-negative adults aged over 18 years. In the phase 1 trial, participants were sequentially enrolled into one of five regimen cohorts: Low-Dose (two doses of aerosolized Ad5-nCoV with 0.5 × 1010 viral particles [vps] per dose), Middle-Dose (two doses of aerosolized Ad5-nCoV with 1.0 × 1010 vps per dose), High-Dose (two doses of aerosolized Ad5-nCoV with 2.0 × 1010 vps per dose), Mixed (intramuscular Ad5-nCoV with 5.0 × 1010 vps [first dose] and aerosolized Ad5-nCoV with 2.0 × 1010 vps [second dose]), and Single-Dose (one dose of aerosolized Ad5-nCoV with 1.0 × 1010 vps). Eligible participants in the phase 2 trial were stratified by 18-59 years old or ≥60 years old and then were sequentially enrolled into one of six regimen cohorts: Low-Dose, Middle-Dose, High-Dose, Mixed, Single-Dose, and Intramuscular (one dose of intramuscular Ad5-nCoV with 1.0 × 1010 vps). The intervals between the two doses were 56 days. Participants were randomly allocated in 3:1 (phase 1) and 5:1 (phase 2) ratios to receive either Ad5-nCoV or the placebo in each cohort. This study is registered on ClinicalTrials.gov, NCT04840992. Most adverse reactions that occurred during the solicited period were mild and moderate. One serious adverse event (myelodysplastic syndrome) was considered potentially related to the aerosolized Ad5-nCoV. The GMTs of neutralizing antibodies in the Mixed group were the highest with 57.03 (95% CI: 23.95, 135.80) and 97.37 (95% CI: 74.30, 127.59) in phase 1 and 2 trials, respectively, 28 days after the second dose (p < 0.0001), which showed significantly higher immune responses compared to other regimens with aerosolized or intramuscular Ad5-nCoV alone.

Destabilization of Oxidized Lattice Oxygen in Layered Oxide Cathode.

Integrating anion-redox capacity with orthodox cation-redox capacity is deemed as a promising solution for high-energy-density battery cathodes surmounting the present technical bottlenecks. However, the evolution of oxidized oxygen species during the electrochemical or chemical process easily jeopardizes the reversibility of oxygen redox and remains poorly understood. Herein, we showcase the gradual conversion of the π-interacting oxygen (localized hole states on O) to the σ-interacting oxygen upon resting at a high voltage for P3-type Na0.6Li0.2Mn0.8O2 with nominally stable ribbon-like superstructure, accompanied by the O-O dimerization and the local structural reorganization. We further pinpoint an abnormal Li+ migration process from the alkali-metal layer to the transition-metal layer for desodiated P3-Na0.6Li0.2Mn0.8O2, thereby leading to a partial reconstruction of the ribbon superstructure. The high-voltage plateau of oxygen-redox cathodes is concluded to be exclusively controlled by the oxygen stabilization mechanism rather than the superstructure ordering. In addition, there exists a kinetic competition between π and σ interaction during the uninterrupted electrochemical process.

Direct synthesis of a lithium carboxymethyl cellulose binder using wood dissolving pulp for high-performance LiFePO4 cathodes in lithium-ion batteries.

Lithium carboxymethyl cellulose (CMC-Li) is a promising novel water-based binder for lithium-ion batteries. The direct synthesis of CMC-Li was innovatively developed using abundant wood dissolving pulp materials from hardwood (HW) and softwood (SW). The resulting CMC-Li-HW and CMC-Li-SW binders possessed a suitable degree of substitutions and excellent molecular weight distributions with an appropriate quantity of long- and short-chain celluloses, which facilitated the construction of a reinforced concrete-like bonding system. When used as cathode binders in LiFePO4 batteries, they uniformly coated and dispersed the electrode materials, formed a compact and stable conductive network with high mechanical strength and showed sufficient lithium replenishment. The prepared LiFePO4 batteries exhibited good mechanical stability, low charge transfer impedance, high initial discharge capacity (∼180 mAh/g), high initial Coulombic efficiency (99 %), excellent cycling performance (<3% loss over 200 cycles) and good rate capability, thereby outperforming CMC-Na and the widely used cathode binder polyvinylidene fluoride.

Comparison of 1 Versus 2 Doses of Quadrivalent Influenza Vaccine in 3-8-Year-Old Children with Different Immunological States - Jiangsu Province, China, 2021.

What is already known about this topic?: The quadrivalent influenza vaccine (QIV) provides protection against a broader range of influenza strains by including strains of influenza A/H1N1, A/H3N2, B/Yamagata, and B/Victoria. What is added by this report?: This study aimed to assess the immunogenicity and safety of administering a single dose compared to two doses of QIV in children, taking into consideration their previous influenza vaccination history. What are the implications for public health practice?: This study provides evidence supporting the use of a single dose of the QIV in children aged 3-8 years who have previously received two or more doses of influenza vaccine. However, children who have not been previously vaccinated with influenza vaccine should still adhere to the recommended schedule of receiving two doses.

Nasal Staphylococcus aureus Carriage and Antimicrobial Resistance Profiles Among Community-Dwelling Adults in Jiangsu, China.

INTRODUCTION: Persistent nasal carriage has been associated with Staphylococcus aureus infection. Previous S. aureus studies in Asia have primarily focused on clinical patients, providing limited information on persistent nasal carriage among the general adult population. METHODS: This study examined 143 healthy adults in a community in Jiangsu, China. Nasal swab samples were collected 10 times. The colonization status was identified using SPA typing. We also determined antimicrobial susceptibility, genotype, and genomic characteristics of S. aureus. RESULTS: The prevalence of S. aureus nasal carriage among the community individuals was on average 16.78%. The carriage rates of methicillin-resistant S. aureus and multidrug-resistant S. aureus were 6.29% and 7.69%, respectively. We identified 8.39% persistent carriers, 39.16% intermittent carriers, and 52.45% noncarriers. Furthermore, family members displayed concordance in terms of genotype and genomic characteristics. CONCLUSION: Persistent nasal sampling captured intermittent carriers that were missed during short-term sampling, thus highlighting the necessity for regular community testing. SPA typing can serve as a rapid method for determining S. aureus colonization. The potential for intrafamilial transmission of S. aureus is evident, with persistent carriers being the most probable source of infection.

ISGylation by HERCs facilitates STING activation.

Optimal activation of stimulator of interferon genes (STING) protein is crucial for host defenses against pathogens and avoiding detrimental effects. Various post-translational modifications control STING activity. However, the function of interferon (IFN)-stimulated gene (ISG) 15 modification (ISGylation) in controlling STING stability and activation is unclear. Here, we show that the E3 ISGylation ligases HECT domain- and RCC1-like domain-containing proteins (HERCs; HERC5 in humans and HERC6 in mice) facilitate STING activation by mediating ISGylation of STING at K150, preventing its K48-linked ubiquitination and degradation. Concordantly, Herc6 deficiency suppresses herpes simplex virus 1 infection-induced type I IFN responses and facilitates viral replication both in vitro and in vivo. Notably, severe acute respiratory syndrome coronavirus 2 protein papain-like protease cleaves HERC5-mediated ISGylation of STING, suppressing host antiviral responses. These data identify a mechanism by which HERCs-mediated ISGylation controls STING stability and activation and uncover the correlations and interactions of ISGylation and ubiquitination during STING activation.

Unraveling the global burden of inflammatory bowel disease (1990-2019): A Joinpoint regression analysis of divergent trends in 10-24 and 50-69 age cohorts.

BACKGROUND AND AIMS: The escalating prevalence of IBD within specific age cohorts, 10-24 and 50-69 years, necessitates a refined understanding of its epidemiological patterns. Prior investigations have often been constrained by their limited scope, particularly in employing age-specific analyses and utilizing advanced statistical methods such as joinpoint regression. Our research examines these demographic segments to elucidate the epidemiological trajectory of IBD. METHODS: This study analyzed GBD 2019 data on IBD, focusing on age groups 10-24 and 50-69. We integrated the socio-demographic index for socio-economic context and employed joinpoint regression to analyze time-segmented disease trends, prioritizing average annual percent change for a comprehensive view. RESULTS: A notable global decline in IBD incidence, particularly in the 50-69 age group, was observed. The 10-24 cohort, however, presented a marginal rise across three decades, with a discernible decline between 2010 and 2019. The study also revealed pivotal gender disparities, with increasing incidence rates in males, especially in the High-income Asia Pacific region. Conversely, females demonstrated decreasing trends across the board. Regional variations accentuated East Asia's escalated IBD incidence and prevalence, whereas high-income North American and Asia-Pacific regions, along with Europe, reflected the highest age-standardized incidence rates. CONCLUSION: The burden of IBD between 1990 and 2019 presents notable disparities across different regions and age demographics. While older populations are seeing a decrease in IBD incidence, young adults and adolescents in regions like East Asia and high-income Asia Pacific are experiencing a concerning uptick. This uneven distribution, influenced by both age and gender, underscores the multifaceted nature of IBD's global impact.