Mixed-charge hyperbranched polymer nanoparticles with selective antibacterial action for fighting antimicrobial resistance.

The escalating menace of antimicrobial resistance (AMR) presents a profound global threat to life and assets. However, the incapacity of metal ions/reactive oxygen species (ROS) or the indiscriminate intrinsic interaction of cationic groups to distinguish between bacteria and mammalian cells undermines the essential selectivity required in these nanomaterials for an ideal antimicrobial agent. Hence, we devised and synthesized a range of biocompatible mixed-charge hyperbranched polymer nanoparticles (MCHPNs) incorporating cationic, anionic, and neutral alkyl groups to effectively combat multidrug-resistant bacteria and mitigate AMR. This outcome stemmed from the structural, antibacterial activity, and biocompatibility analysis of seven MCHPNs, among which MCHPN7, with a ratio of cationic groups, anionic groups, and long alkyl chains at 27:59:14, emerged as the lead candidate. Importantly, owing to inherent differences in membrane potential among diverse species, alongside its nano-size (6 - 15 nm) and high hydrophilicity (Kow = 0.04), MCHPN7 exhibited exceptional selective bactericidal effects over mammalian cells (selectivity index > 564) in vitro and in vivo. By inducing physical membrane disruption, MCHPN7 effectively eradicated antibiotic-resistant bacteria and significantly delayed the emergence of bacterial resistance. Utilized as a coating, MCHPN7 endowed initially inert surfaces with the ability to impede biofilm formation and mitigate infection-related immune responses in mouse models. This research heralds the advent of biocompatible polymer nanoparticles and harbors significant implications in our ongoing combat against AMR. STATEMENT OF SIGNIFICANCE: The escalating prevalence of antimicrobial resistance (AMR) has been acknowledged as one of the most significant threats to global health. Therefore, a series of mixed-charge hyperbranched polymer nanoparticles (MCHPNs) with selective antibacterial action were designed and synthesized. Owing to inherent differences in membrane potential among diverse species and high hydrophilicity (Kow = 0.04), the optimal nanoparticles exhibited exceptional selective bactericidal effects over mammalian cells (selectivity index >564) and significantly delayed the emergence of bacterial resistance. Importantly, they endowed surfaces with the ability to impede biofilm formation and mitigate infection-related immune responses. Furthermore, the above findings focus on addressing the problem of AMR in Post-Pandemic, which will for sure attract attention from both academic and industry research.

Yam protein ameliorates cyclophosphamide-induced intestinal immunosuppression by regulating gut microbiota and its metabolites.

Yam is a dual-purpose crop used in both medicine and food that is commonly used as a dietary supplement in food processing. Since yam proteins are often lost during the production of yam starch, elucidating the functionally active value of yam proteins is an important guideline for fully utilizing yam in industrial production processes. This study aimed to explore the potential protective effect of yam protein (YP) on cyclophosphamide (CTX)-induced immunosuppression in mice. The results showed that YP can reduce immune damage caused by CTX by reversing immunoglobulins (IgA, IgG and IgM), cytokines (TNF-α, IL-6, etc.) in the intestines of mice. Moreover, YPs were found to prevent CTX-induced microbiota dysbiosis by enhancing the levels of beneficial bacteria within the microbiome, such as Lactobacillus, and lowering those of Desulfovibrio_R and Helicobacter_A. Metabolomics analyses showed that YP significantly altered differential metabolites (tryptophan, etc.) and metabolic pathways (ABC transporter protein, etc.) associated with immune responses in the gut. Furthermore, important connections were noted between particular microbiomes and metabolites, shedding light on the immunoprotective effects of YPs by regulating gut flora and metabolism. These findings deepen our understanding of the functional properties of YPs and lay a solid foundation for the utilization of yam.

Host restriction factor Rab11a limits porcine epidemic diarrhea virus invasion of cells via fusion peptide-mediated membrane fusion.

Porcine epidemic diarrhea virus (PEDV) causes enormous economic losses to the pork industry, and its extensive cell tropism poses a substantial challenge to public health and safety. However, the invasion mechanisms and relevant host factors of PEDV remain poorly understood. In this study, we identified 422 differentially expressed genes related to PEDV infection through transcriptome analysis. Among these, Annexin A2 (ANXA2), Prohibitin-2 (PHB2), and Caveolin-2 (CAV2) were identified through screening and verifying as having a specific interaction with the PEDV S protein, and positive regulation of PEDV internalization was validated by siRNA and overexpression tests. Subsequently, using host membrane protein interaction networks and co-immunoprecipitation analysis, we found that ANXA2 PHB2 or CAV2 directly interact with Rab11a. Next, we constructed a pseudovirus model (LV-PEDV S-GFP) to further confirm that the downregulation of Rab11a could promote PEDV invasion. In detail, ANXA2, PHB2, or CAV2 promoted PEDV invasion via downregulating Rab11a. Furthermore, we showed that the S-protein fusion peptide (FP) was sufficient for S-protein interaction with ANXA2, PHB2, CAV2, and Rab11a, and the addition of exogenous GTP could regulate the efficiency of PEDV invasion. Collectively, ANXA2, PHB2, or CAV2 influenced the membrane fusion of PEDV with host cells through the host restriction factor Rab11a. This study could be targeted for future research to develop strategies for the control of PEDV.

Azobenzene-based liposomes with nanomechanical action for cytosolic chemotherapeutic drug delivery.

The stimuli-responsive nano-carriers are at the forefront of research in nanotechnology and materials science. These advanced systems are designed to alter their physicochemical properties upon exposure to specific stimuli, enabling controllable and targeted delivery of therapeutic agents. Nevertheless, limited endosomal escape reduces the drug bioavailability in clinical use. We herein report azobenzene (Azo)-based liposomes, prepared by co-assembling the photoisomerizable cationic Azo lipids and helper lipids, which achieve controllable doxorubicin (Dox) release and enhanced cytosolic transport upon light irradiation. Azo lipids undergo reversible isomerization between cis-isomers and trans-isomer when received UV and visible (Vis) light irradiation, causing liposomal membrane permeability changes for controlled drug release. Moreover, the nanomechanical action created by the isomerization of Azo lipids promotes the endosomal escape of the liposomes. DSPC-Azo liposomes, with minimal Dox leakage, showed significant tumor cell killing upon irradiation. For in vivo study, we co-encapsulated the upconverting nanoparticles (UCNPs), which can convert the near-infrared (NIR) light into UV/Vis emissions, facilitating Azo units activation. UCNP/Dox-loaded DSPC-Azo liposomes inhibited tumor growth under NIR irradiation in a 4T1 tumor-bearing mouse model.

Tuning Lipid Nanoparticles for RNA Delivery to Extrahepatic Organs.

RNA therapeutics have been successfully transitioned into clinical applications. Lipid nanoparticles (LNPs) are widely employed as nonviral delivery vehicles for RNA therapeutics in commercial vaccine and gene therapy products. However, the bottleneck in expanding the clinical applications of LNP-based RNA therapeutics lies in the tendency of these nanoparticles to preferentially accumulate in the liver. This challenge underscores the need to design LNPs capable of delivering RNA to organs beyond the liver. In this perspective, recent progress is discussed in developing strategies for designing LNPs to deliver RNA to extrahepatic organs. Organ-selective targeting capability is achieved by either altering the composition of the LNP formulation or chemically modifying the ionizable lipid component. Both approaches result in changes in the physicochemical properties of the LNPs, which subsequently alters the composition of the biomolecular corona that adsorbs onto its surface following administration. The biomolecular corona is a known mechanism that mediates organ-selective LNP delivery. Furthermore, this perspective aims to provide an outlook on shaping the next-generation LNP delivery platforms. Potential efforts include targeting specific cell types, improving the safety profile of LNPs, and developing strategies to overcome physiological barriers against organ-specific delivery.

Breast cancer colonization by Malassezia globosa accelerates tumor growth.

Malassezia globosa is a lipophilic basidiomycetous yeast that occurs abundantly in breast tumors and that may contribute to a shortened overall survival of breast cancer (BRAC) patients, suggesting that the yeast may participate in the carcinogenesis of BRAC. However, the mechanisms involved in the M. globosa-based acceleration of BRAC are unknown. Here, we show that M. globosa can colonize mammary tissue in 7,12-dimethylbenz[a] anthracene-induced mice. The abundance of M. globosa shortened the overall survival and increased the tumor incidence. Transcriptome data illustrated that IL-17A plays a key role in tumor growth due to M. globosa colonization, and tumor-associated macrophage infiltration was elevated during M. globosa colonization which triggers M2 polarization of macrophages via toll-like receptors 4/nuclear factor kappa-B (Nf-κB) signaling. Our results show that the expression of sphingosine kinase 1 (Sphk1) is increased in breast tumors after inoculation with M. globosa. Moreover, we discovered that Sphk1-specific small interfering RNA blocked the formation of lipid droplets, which can effectively alleviate the expression of the signal transducer and activator of the transcription 3 (STAT3)/Nf-κB pathway. Taken together, our results demonstrate that M. globosa could be a possible factor for the progression of BRAC. The mechanisms by which M. globosa promotes BRAC development involve the IL-17A/macrophage axis. Meanwhile, Sphk1 overexpression was induced by M. globosa infection, which also promoted the proliferation of MCF-7 cells.IMPORTANCELiterature has suggested that Malassezia globosa is associated with breast tumors; however, this association has not been confirmed. Here, we found that M. globosa colonizes in breast fat pads leading to tumor growth. As a lipophilic yeast, the expression of sphingosine kinase 1 (Sphk1) was upregulated to promote tumor growth after M. globosa colonization. Moreover, the IL-17A/macrophages axis plays a key role in mechanisms involved in the M. globosa-induced breast cancer acceleration from the tumor immune microenvironment perspective.

Functional correlation tensors in brain white matter and the effects of normal aging.

Resting state correlations between blood oxygenation level dependent (BOLD) MRI signals from voxels in white matter (WM) are demonstrably anisotropic, so that functional correlation tensors (FCT) may be used to quantify the underlying microstructure of BOLD effects in WM tracts. However, the overall spatial distribution of FCTs and their metrics in specific populations has not yet been established, and the factors that affect their precise arrangements remain unclear. Changes in WM occur with normal aging, and these may be expected to affect FCTs. We hypothesized that FCTs exhibit a characteristic spatial pattern and may show systematic changes with aging or other factors. Here we report our analyses of the FCT characteristics of fMRI images of a large cohort of 461 cognitively normal subjects (190 females, 271 males) sourced from the Open Access Series of Imaging Studies (OASIS), with age distributions of 42 y/o - 95 y/o. Group averages and statistics of FCT indices, including axial functional correlations, radial functional correlations, mean functional correlations and fractional anisotropy, were quantified in WM bundles defined by the JHU ICBM-DTI-81 WM atlas. In addition, their variations with normal aging were examined. The results revealed a dimorphic distribution of changes in FCT metrics with age, with decreases of the functional correlations in some regions and increases in others. Supplementary analysis revealed that females exhibited significant age effects on a greater number of WM areas, but the interaction between age and sex was not significant. The findings demonstrate the reproducibility of the spatial distribution of FCT metrics and reveal subtle regional changes with age.

Evaluation of a new scoring system for assessing nerve invasion in resected pancreatic cancer: a single-center retrospective analysis.

Nerve invasion (NI) is a characteristic feature of pancreatic cancer. Traditional dichotomous statements on the presence of NI are unreasonable because almost all cases exhibit NI when sufficient pathological sections are examined. The critical implications of NI in pancreatic cancer highlight the need for a more effective criterion. This study included 511 patients, who were categorized into a training group and a testing group at a ratio of 7:3. According to the traditional definition, NI was observed in 91.2% of patients using five pathological slides in our study. The prevalence of NI increased as more pathological slides were used. The criterion of 'two points of intraneural (endoneural) invasion in the case of four pathological slides' has the highest receiver operating characteristic (ROC) score. Based on this new criterion, NI was proved to be an independent prognostic factor for overall survival (OS) and disease-free survival (DFS) and was also correlated with tumor recurrence (P = 0.004). Interestingly, gemcitabine-based chemotherapy regimen is an independent favorable factor for patients with high NI. In the high NI group, patients who received a gemcitabine-based regimen exhibited a better prognosis than those who did not receive the gemcitabine-based regimen for OS (P = 0.000) and DFS (P = 0.001). In conclusion, this study establishes assessment criteria to evaluate the severity of NI in order to predict patient outcomes.

An estimation of future county-level cement production and associated air pollutant emissions in China through artificial neural networks.

Cement production and its air pollutant and carbon dioxides (CO2) emissions in China will be relocated greatly as a joint effect of diverse development of industrial economy and implementation of environmental policies for different regions. The future pathway and spatial pattern of emissions are important for policy making of air quality improvement and CO2 emission abatement, as well as coordinating regional development. In this study, we developed an artificial neural network (ANN) model to predict cement production at the county level and to calculate the associated emissions of air pollutants and CO2 at the county level till 2060. Results show that the cement production will decline from 2327 million metric tons (Mt) in 2015 to 704 Mt. in 2060 under the Shared Socioeconomic Pathways 1 (SSP1). Counties closer to provincial capital will experience greater retirement of cement industry. Likewise, the emissions of air pollutants and CO2 will experience a steady downward trend driven by the declining cement production and the improvement of pollution control technologies. There will be a more significant regional heterogeneity in the reduction of production and emissions at city level compared to the province level. With the clearance for nearly two-thirds of counties, future cement production and emissions will be more intensively distributed in a few cities. The shares of emissions in southwestern regions will grow from 2015 to 2060 while those of eastern regions will continue decreasing. The comparison between the changing spatial distributions of emissions and gross domestic product (GDP) indicates a positive effect of existing policies in reconciling regional economic development and air pollution controls. The outcome could support the analyses on the impact of industrial development on air quality and public health, and the method can be applied widely for other industrial sectors for a more comprehensive understanding of future emission relocation.

A histone deacetylase confers plant tolerance to heat stress by controlling protein lysine deacetylation and stress granule formation in rice.

Understanding molecular mechanisms of plant cellular response to heat stress will help to improve crop tolerance and yield in the global warming era. Here, we show that deacetylation of non-histone proteins mediated by cytoplasmic histone deacetylase HDA714 is required for plant tolerance to heat stress in rice. Heat stress reduces overall protein lysine acetylation, which depends on HDA714. Being induced by heat stress, HDA714 loss of function reduces, but its overexpression enhances rice tolerance to heat stress. Under heat stress, HDA714-mediated deacetylation of metabolic enzymes stimulates glycolysis. In addition, HDA714 protein is found within heat-induced stress granules (SGs), and many SG proteins are acetylated under normal temperature. HDA714 interacts with and deacetylates several SG proteins. HDA714 loss of function increases SG protein acetylation levels and impairs SG formation. Collectively, these results indicate that HDA714 responds to heat stress to deacetylate cellular proteins, control metabolic activities, stimulate SG formation, and confer heat tolerance in rice.

Incidence and prognostic factors of residual back pain in patients treated for osteoporotic vertebral compression fractures: a systematic review and meta-analysis.

BACKGROUND: Osteoporotic vertebral compression fracture (OVCF) is a common consequence of osteoporosis and can significantly impact the quality of life for affected individuals. Despite treatment options such as vertebroplasty and kyphoplasty, many patients continue to experience residual back pain (RBP) even after the fracture has healed. The incidence of RBP after OVCF treatment varies among studies, and there is a need for further research to understand the risk factors associated with RBP. METHODS: A systematic review and meta-analysis were conducted following the PRISMA guidelines. Electronic databases were searched, and relevant studies were selected based on inclusion and exclusion criteria. Data extraction and quality assessment were performed independently by two authors. Statistical analysis included single-proportion meta-analyses and pooling of odds ratios (OR) using the inverse-variance method, to calculate the overall incidences of RBP and cement leakage and identify risk factors associated with RBP. RESULTS: A total of 19 studies were included in the analysis. The overall incidences of RBP and cement leakage were found to be 16% and 18%, respectively. Several risk factors were identified, including gender, bone mineral density, depression, baseline visual analog scale (VAS) score, intravertebral vacuum cleft, number of fractured segments, cement distribution, history of vertebral fracture, thoracolumbar fascial injury, and fracture non-union. CONCLUSIONS: This study provides potential value within the scope of the incidence and risk factors of RBP following treatment of OVCFs. The identified risk factors can help clinicians identify high-risk patients and tailor appropriate interventions. Future research should focus on standardizing the definition of RBP and patient selection criteria to improve the accuracy of estimates and facilitate better management strategies for OVCF patients.

De novo generation of SARS-CoV-2 antibody CDRH3 with a pre-trained generative large language model.

Artificial Intelligence (AI) techniques have made great advances in assisting antibody design. However, antibody design still heavily relies on isolating antigen-specific antibodies from serum, which is a resource-intensive and time-consuming process. To address this issue, we propose a Pre-trained Antibody generative large Language Model (PALM-H3) for the de novo generation of artificial antibodies heavy chain complementarity-determining region 3 (CDRH3) with desired antigen-binding specificity, reducing the reliance on natural antibodies. We also build a high-precision model antigen-antibody binder (A2binder) that pairs antigen epitope sequences with antibody sequences to predict binding specificity and affinity. PALM-H3-generated antibodies exhibit binding ability to SARS-CoV-2 antigens, including the emerging XBB variant, as confirmed through in-silico analysis and in-vitro assays. The in-vitro assays validate that PALM-H3-generated antibodies achieve high binding affinity and potent neutralization capability against spike proteins of SARS-CoV-2 wild-type, Alpha, Delta, and the emerging XBB variant. Meanwhile, A2binder demonstrates exceptional predictive performance on binding specificity for various epitopes and variants. Furthermore, by incorporating the attention mechanism inherent in the Roformer architecture into the PALM-H3 model, we improve its interpretability, providing crucial insights into the fundamental principles of antibody design.

Comparative Analysis of Codon Usage Bias in Six Eimeria Genomes.

The codon usage bias (CUB) of genes encoded by different species' genomes varies greatly. The analysis of codon usage patterns enriches our comprehension of genetic and evolutionary characteristics across diverse species. In this study, we performed a genome-wide analysis of CUB and its influencing factors in six sequenced Eimeria species that cause coccidiosis in poultry: Eimeria acervulina, Eimeria necatrix, Eimeria brunetti, Eimeria tenella, Eimeria praecox, and Eimeria maxima. The GC content of protein-coding genes varies between 52.67% and 58.24% among the six Eimeria species. The distribution trend of GC content at different codon positions follows GC1 > GC3 > GC2. Most high-frequency codons tend to end with C/G, except in E. maxima. Additionally, there is a positive correlation between GC3 content and GC3s/C3s, but a significantly negative correlation with A3s. Analysis of the ENC-Plot, neutrality plot, and PR2-bias plot suggests that selection pressure has a stronger influence than mutational pressure on CUB in the six Eimeria genomes. Finally, we identified from 11 to 15 optimal codons, with GCA, CAG, and AGC being the most commonly used optimal codons across these species. This study offers a thorough exploration of the relationships between CUB and selection pressures within the protein-coding genes of Eimeria species. Genetic evolution in these species appears to be influenced by mutations and selection pressures. Additionally, the findings shed light on unique characteristics and evolutionary traits specific to the six Eimeria species.

Integrative transcriptome analysis reveals the molecular events underlying impaired T-cell responses in EGFR-mutant lung cancer.

EGFR mutations are critical oncogenic drivers in lung adenocarcinoma (LUAD). However, the mechanisms by which they impact the tumor microenvironment (TME) and tumor immunity are unclear. Furthermore, the reasons underlying the poor response of EGFR-mutant (EGFR-MU) LUADs to immunotherapy with PD-1/PD-L1 inhibitors are unknown. Utilizing single-cell RNA (sc-RNA) and bulk RNA sequencing datasets, we conducted high-dimensional weighted gene coexpression network analysis to identify key genes and immune-related pathways contributing to the immunosuppressive TME. EGFR-MU cancer cells downregulated MHC class I genes to evade CD8+ cytotoxic T cells, expressed substantial levels of MHC class II molecules, and engaged with CD4+ regulatory T cells (Tregs). EGFR-MU tumors may recruit Tregs primarily through the CCL17/CCL22/CCR4 axis, leading to a Treg-enriched TME. High levels of MHC class II-positive cancer-associated fibroblasts and tumor endothelial cells were found within EGFR-MU tumors. Owing to the absence of costimulatory factors, they may inhibit rather than activate the tumor antigen-specific CD4+ T-cell response, contributing further to immune suppression. Multiplex immunohistochemistry analyses in a LUAD cohort confirmed increased expression of MHC class II molecules in cancer cells and fibroblasts in EGFR-MU tumors. Our research elucidates the highly immunosuppressive TME in EGFR-MU LUAD and suggests potential targets for effective immunotherapy.

Early reapplication of prone position during venovenous ECMO for acute respiratory distress syndrome: a prospective observational study and propensity-matched analysis.

BACKGROUND: A combination of prone positioning (PP) and venovenous extracorporeal membrane oxygenation (VV-ECMO) is safe, feasible, and associated with potentially improved survival for severe acute respiratory distress syndrome (ARDS). However, whether ARDS patients, especially non-COVID-19 patients, placed in PP before VV-ECMO should continue PP after a VV-ECMO connection is unknown. This study aimed to test the hypothesis that early use of PP during VV-ECMO could increase the proportion of patients successfully weaned from ECMO support in severe ARDS patients who received PP before ECMO. METHODS: In this prospective observational study, patients with severe ARDS who were treated with VV-ECMO were divided into two groups: the prone group and the supine group, based on whether early PP was combined with VV-ECMO. The proportion of patients successfully weaned from VV-ECMO and 60-day mortality were analyzed before and after propensity score matching. RESULTS: A total of 165 patients were enrolled, 50 in the prone and 115 in the supine group. Thirty-two (64%) and 61 (53%) patients were successfully weaned from ECMO in the prone and the supine groups, respectively. The proportion of patients successfully weaned from VV-ECMO in the prone group tended to be higher, albeit not statistically significant. During PP, there was a significant increase in partial pressure of arterial oxygen (PaO2) without a change in ventilator or ECMO settings. Tidal impedance shifted significantly to the dorsal region, and lung ultrasound scores significantly decreased in the anterior and posterior regions. Forty-five propensity score-matched patients were included in each group. In this matched sample, the prone group had a higher proportion of patients successfully weaned from VV-ECMO (64.4% vs. 42.2%; P = 0.035) and lower 60-day mortality (37.8% vs. 60.0%; P = 0.035). CONCLUSIONS: Patients with severe ARDS placed in PP before VV-ECMO should continue PP after VV-ECMO support. This approach could increase the probability of successful weaning from VV-ECMO. TRIAL REGISTRATION: ClinicalTrials.Gov: NCT04139733. Registered 23 October 2019.

Structures, activities, and putative biosynthetic pathways of characteristic polyphenolic compounds from Morus plants: A review.

Morus plants played a pivotal role in ancient Chinese sericulture and silk production, which served as critical components of economy and culture. Besides, many parts of mulberry trees, including roots, leaves, stems, and fruits, hold various medicinal value, and have been utilized in traditional medicine for thousands of years. The chemical composition of mulberry has been reported in many literatures, while the characteristic compounds have not been systematically summarized. In this review, we focused on the polyphenolic compounds in mulberry, including flavonoids, 2-arylbenzofurans, and Diels-Alder (D-A) adducts, and summarized their structural features, structure-activity relationships, and potential biosynthetic pathways. The results revealed a characteristic class of 2'-hydroxylated flavonoids and stilbenes which played an important role in the biosynthesis of downstream 2-arylbenzofurans and D-A adducts in mulberry but had been overlooked by most studies. The prenylated modifications of different compounds were also discussed and their function as precursors of D-A adducts was emphasized. We also describe the effects of different modifications on biological activities. Besides, the chemical composition of Morus was most similar to that of Artocarpus in the Moraceae family in that they had almost identical characteristic compounds. Finally, a putative total biosynthetic pathway of D-A adducts in mulberry was proposed based on structure derivation and combination of verified reactions. This review contributes to the understanding of the biological activity and biosynthesis of the characteristic components of Morus plants.

Chiral whispering gallery modes and chirality-dependent symmetric optical force induced by a spin-polarized surface wave of photonic Dirac semimetal.

Dirac degeneracy is a fourfold band crossing point in a three-dimensional momentum space, which possesses Fermi-arc-like surface states, and has extensive application prospects. In this work, we systematically study the exceptional effects of the robust chiral surface wave supported by photonic Dirac semimetal acts on the dielectric particles. Theoretical results show that orthogonal electromagnetic modes and helical or chiral whispering gallery modes (WGMs) of dielectric particles can be efficiently excited by the unidirectional spin-polarized surface wave. More importantly, optical forces exerted by the spin-polarized surface wave exhibit chirality-dependent symmetric behavior and high chiral Q factor with precise size selectivity. Our findings may provide potential applications in the area of chiral microcavity, spin optical devices, and optical manipulations.

Centrifuge tests on the deformation law of pipelines crossing slopes with different water contents.

The deformation law of pipelines crossing landslide areas is an important prerequisite for the scientific design of pipelines. Most current studies find it difficult to simulate the real stress and strain state of pipelines on site. This study conducted two centrifuge model tests to observe pipeline failure indicators (deformation, stress, strain) and slope failure indicators (crack width, soil pressure, landslide displacement) in response to changes in acceleration. The experimental findings align with the results obtained from numerical simulations. The findings indicate that slope failure with high moisture content is more serious. At a moisture content of 15%, the slope has a maximum displacement of 70 mm in close reach to the buried pipeline. The pipeline has a "bimodal distribution" of strain along its axial length. The largest amount of deformation occurs at a distance of L/4 from the center of the pipeline, and the deformation value is 9000 µÎµ. Moreover, the maximum deformation in the mid-span is 21 mm, which corresponds to the result accumulated from the numerical simulation. Thus, the pipeline needs to improve the disaster prevention capabilities at the mid-span and L/4 of the pipeline.

Therapeutic inhibition of the JAK-STAT pathway in the treatment of inflammatory bowel disease.

Inflammatory bowel disease (IBD) encompasses a group of non-specific chronic intestinal inflammatory conditions of unclear etiology. The current treatment and long-term management primarily involve biologics. Nevertheless, some patients experience treatment failure or intolerance to biologics [1], making these patients a primary focus of IBD research. The Janus kinase (JAK)-Signal Transducers and Activator of Transcription (STAT) signal transduction pathway is crucial to the regulation of immune and inflammatory responses [2], and plays an important role in the pathogenesis of IBD. JAK inhibitors alleviate IBD by suppressing the transmission of JAK-STAT signaling pathway. As the first small-molecule oral inhibitor for IBD, JAK inhibitors greatly improved the treatment of IBD and have demonstrated significant efficacy, with tofacitinib and upadacitinib being approved for the treatment of ulcerative colitis (UC) [3]. JAK inhibitors can effectively alleviate intestinal inflammation in IBD patients who have failed to receive biologics, which may bring new treatment opportunities for refractory IBD patients. This review aims to elucidate the crucial roles of JAK-STAT signal transduction pathway in IBD pathogenesis, examine its role in various cell types within IBD, and explore the research progress of JAK inhibitors as therapeutic agents, paving the road for new IBD treatment strategies.