Search Results (887)

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet their benefits remain limited to a subset of patients, underscoring the need for more reliable biomarkers and novel therapeutic strategies. The gut microbiome has emerged as a critical modulator of systemic immunity and a promising determinant of ICI response. Evidence links specific microbial features, taxa, and bioactive metabolites to enhanced antitumor immunity, whereas disruptions, such as antibiotic exposure, are associated with poorer outcomes. Advances in sequencing and multi-omics technologies have provided more profound insights into microbiome-immune crosstalk, though methodological heterogeneity continues to challenge reproducibility. Translational studies demonstrate that microbiome-based intervention, including fecal microbiota transplantation (FMT), biotics supplementation, and engineered microbial strains, can enhance ICI efficacy or mitigate immune-related toxicities. Despite encouraging early clinical signals, broader implementation requires methodological rigor, standardized protocols, and innovative trial designs that account for host and environmental factors. For clinicians, the most immediate strategies involve prudent antibiotic stewardship and patient enrollment in microbiome-focused clinical trials. Overall, the gut microbiome is a promising biomarker and a therapeutic target, representing a new frontier for personalizing immunotherapy and improving patient outcomes in oncology. Full article

The mechanical performance of cast iron is strongly governed by the morphology of its graphite phase, yet establishing a quantitative link between microstructure and macroscopic properties remains a challenge. In this study, a three-dimensional finite element method (FEM)-based micromechanical framework is proposed to analyze and predict the mechanical behavior of cast iron with representative graphite morphologies, spheroidal and flake graphite. Realistic representative volume elements (RVEs) are reconstructed based on experimental microstructural characterization and literature-based X-ray computed tomography data, ensuring geometric fidelity and statistical representativeness. Cohesive zone modeling (CZM) is implemented at the graphite/matrix interface and within the graphite phase to simulate interfacial debonding and brittle fracture, respectively. Full-field simulations of plastic strain and stress evolution under uniaxial tensile loading reveal that spheroidal graphite promotes uniform deformation, delayed damage initiation, and enhanced ductility through effective stress distribution and progressive plastic flow. In contrast, flake graphite induces severe stress concentration at sharp tips, leading to early microcrack nucleation and rapid crack propagation along the flake planes, resulting in brittle-like failure. The simulated stress–strain responses and failure modes are consistent with experimental observations, validating the predictive capability of the model. This work establishes a microstructure–property relationship in multiphase alloys through a physics-informed computational approach, demonstrating the potential of FEM-based modeling as a powerful tool for performance prediction and microstructure-guided design of cast iron and other heterogeneous materials. Full article

The fatigue of wood is becoming increasingly important in modern engineering, as the safety of the structure must be guaranteed and the use of materials must be optimized at the same time. Predicting the fatigue behavior of wood remains a challenge for many researchers. Interest and the number of studies in this field have increased, highlighting the need for a comprehensive overview of the current state of knowledge on wood fatigue. In this paper, we focus on the study of the fatigue of wood-based materials to understand the similarities and peculiarities of fatigue behavior compared to other engineering materials and to identify opportunities for new research. We present the influence of physical and mechanical properties on fatigue life and identify similarities in the fatigue behavior of wood, polymeric materials and steel. The basic properties that differentiate the fatigue life of wood from that of other materials are heterogeneity, orthotropy, viscoelasticity, hygroscopicity, mechanosorptivity and the lack of a clear threshold value for fatigue strength. The differences in fatigue life between solid wood and laminated wood are not uniformly defined by researchers. We provide an overview of the measurement methods used to monitor the fatigue state, the models used to predict fatigue life and the simulations of the stress–strain response to cyclic loading. We identify areas where wood is subject to fatigue and determine which areas are most critical under cyclic loading. We make suggestions for further research that would contribute significantly to a better understanding and management of wood fatigue. Due to the wide variety of wood species used in the studies, it is impossible to compare the results. In order to obtain a comprehensive overview of the response of wood to fatigue under different test conditions, the test methods need to be standardized. Full article

Human immunodeficiency virus (HIV), comprising two distinct types, HIV-1 and HIV-2, remains one of the most significant global health challenges, originating from multiple cross-species transmissions of simian immunodeficiency viruses (SIVs) in the early 20th century. This review traces the evolutionary trajectory of HIV from zoonotic spillover to its establishment as a global pandemic. HIV-1, the principal strain responsible for AIDS, emerged from SIVcpz in Central African chimpanzees, with phylogenetic evidence indicating initial human transmission between the 1920s and 1940s in present day Democratic Republic of Congo. The virus disseminated through colonial trade networks, reaching the Caribbean by the 1960s before establishing endemic transmission in North America and Europe. HIV’s extraordinary genetic diversity—driven by high mutation rates (~10⁻⁵ mutations per base per replication cycle) and frequent recombination events—has generated multiple groups, subtypes, and circulating recombinant forms (CRFs) with distinct epidemiological patterns. HIV-1 Group M, comprising subtypes A through L, accounts for over 95% of global infections, with subtype C predominating in sub-Saharan Africa and Asia, while subtype B dominates in Western Europe and North America. The extensive genetic heterogeneity of HIV significantly impacts diagnostic accuracy, antiretroviral therapy efficacy, and vaccine development, as subtypes exhibit differential biological properties, transmission efficiencies, and drug resistance profiles. Contemporary advances, including next-generation sequencing (NGS) for surveillance, broadly neutralizing antibodies for cross-subtype prevention and therapy, and long-acting antiretroviral formulations to improve adherence, have transformed HIV management and prevention strategies. NGS enables near real-time surveillance of drug resistance mutations and inference of transmission networks where it is available, although access and routine application remain uneven across regions. Broadly neutralizing antibodies demonstrate cross-subtype efficacy, while long-acting formulations have the potential to improve treatment adherence. This review synthesizes recent evidence and offers actionable recommendations to optimize clinical and public health responses—including the routine use of genotypic resistance testing where feasible, targeted use of phylogenetic analysis for outbreak investigation, and the development of region-specific diagnostic and treatment algorithms informed by local subtype prevalence. While the understanding of HIV’s evolutionary dynamics has substantially improved and remains essential, translating this knowledge into universally implemented intervention strategies remains a key challenge for achieving the UNAIDS 95-95-95 targets and the goal of ending AIDS as a public health threat by 2030. Full article

Akkermansia muciniphila—a mucus-resident commensal—has emerged as a promising target at the interface of metabolism, barrier function, and immunity. Observational human studies link higher intestinal abundance of A. muciniphila with healthier adiposity and glycemic profiles, while preclinical experiments demonstrate causal benefits on adiposity, insulin resistance, gut-barrier integrity, and inflammatory tone. These effects are attributed to mucus-layer reinforcement, reduced intestinal permeability and endotoxemia, production of short-chain fatty acids, and host signaling by defined bacterial components. In a randomized proof-of-concept trial in overweight/obese insulin-resistant adults, pasteurized A. muciniphila was safe and well-tolerated and improved insulin sensitivity and total cholesterol versus placebo; live cells showed directionally favorable but non-significant trends. A separate multicenter randomized trial of a five-strain consortium that included A. muciniphila improved post-prandial glucose and HbA1c in type 2 diabetes, supporting translational potential while underscoring the need for strain-resolved studies. Evidence for liver and cardiovascular benefits is strong in animals (e.g., MASLD and atherosclerosis models) but remains preliminary in humans. Inter-individual response heterogeneity—potentially influenced by baseline Akkermansia levels and gut-barrier status—highlights the value of personalized, microbiome-guided approaches. Larger, longer clinical studies are now warranted to define optimal dosing and formulation (live vs. pasteurized), durability, safety across populations, and impacts on hard outcomes (clinically meaningful weight change, glycemic endpoints, and cardiometabolic events). Overall, A. muciniphila represents a promising microbial adjunct for metabolic health with a plausible path from postbiotic concepts to clinical application, pending confirmatory trials. Full article

Nontuberculous mycobacteria (NTM) represent a heterogeneous group of environmental opportunistic pathogens that have emerged particularly in immunocompromised individuals and patients with underlying pulmonary disorders. NTM infections primarily affect the lungs, but can also manifest as lymphadenitis, skin and soft tissue infections, and disseminated disease. This retrospective study took into consideration 425 NTM-positive samples collected between May 2011 and December 2023, analyzed by sample type, sex, and age group (0–17, 18–49, 50–65, >65 years). Antimicrobial susceptibility analysis was performed on the 223 NTM strains with greater pathogenic power and most frequently isolated, from 2016 to 2023. Pulmonary NTM disease (NTM-PD) infections were most prevalent in patients over 65 years (52.1%), while extrapulmonary NTM disease (NTM-EPD) occurred most frequently in the 0–17 age group (56.4%). Women were slightly more affected (54.4%) than men (45.6%), with the highest incidence in female individuals over 65 years old. The most frequently isolated NTM species was the Mycobacterium avium complex (MAC) (47% of isolates). Antimicrobial susceptibility testing of 223 isolates from 2016 to 2023 revealed species-specific resistance patterns, with high susceptibility to clarithromycin in MAC (94.7%) and Mycobacterium chelonae (100%), but notable resistance in Mycobacterium abscessus complex (MABC). The increasing incidence of NTM infections underscores the need for improved diagnostic techniques and targeted treatment strategies. Full article

Individual beliefs are a critical factor in understanding human action and behavior. Certain beliefs, such as irrational beliefs and burnout, influence all forms of learning and social interaction within the school environment, primarily limiting both individual and collective development. The former are associated with the inherent human tendency to adhere to habits and behaviors not strictly dictated by rationality, often stemming from irrational thoughts held by the individual. The latter, examined within the framework of the Job Demands–Resources Theory, pertain to occupational characteristics that differentially affect employees’ well-being, job demands, and available resources. The present study aims to investigate the role of these variables in relation to teachers’ Innovative Work Behavior, a recurring, multi-stage process oriented toward the implementation of new ideas within the school context. The sample consisted of 337 preschool educators who completed self-report questionnaires. Multiple linear regression analysis indicated that both irrational beliefs (positively) and the dimension of work disengagement (negatively) significantly influenced innovative work behavior, underscoring the distinct contributions of personal belief systems and burnout dimensions. Furthermore, a hierarchical cluster analysis revealed both heterogeneity among educators and common, distinct response patterns. The identification of five different clusters suggests that the examined characteristics and the underlying beliefs represent individual traits that change dynamically, leaving open the possibility of nonlinear relationships present in the workplace. Five profiles were identified, namely Disengaged-Low Innovators, Resilient-Balanced Innovators, Adaptive Innovators, Strained but Innovative Innovators, and Belief-Driven Innovators, which highlight the complex ways in which disengagement, exhaustion, and irrational beliefs combine to shape innovative work behavior. The findings are interpretable within the framework of contemporary theories in organizational psychology and management and can be utilized by educational principals to enhance school climate and teacher performance. Full article

Background: Porcine reproductive and respiratory syndrome virus type 2 (PRRSV-2) remains a significant threat to swine production globally, including Japan. While the genetic diversity of PRRSV-2 has been reported previously, the potential association with modified live vaccines (MLVs) is not well understood. This study aimed to characterize PRRSV-2 strains currently circulating in Japan and assess possible links with MLVs. Methods: A total of 1190-nucleotide open reading frame 5 sequences of PRRSV-2 were collected across Japan between 2020 and 2023, and phylogenetic analyses were performed to classify genetic clusters. Additionally, correlations between cluster distribution and MLV usage were examined, using sequences detected in the Kanto region. Results: Phylogenetic analysis revealed that 48.5% of the sequences belonged to Cluster III, with a median nucleotide identity of 88.2% to the Japanese reference strain EDRD-1. Notably, the sequence identity between the strains detected in this study and EDRD-1 was significantly lower than that of strains identified in 1992–1993 (p < 0.05). In the Kanto region, Cluster I and II variants, which exhibited high sequence homology to MLV strains, were exclusively detected on farms with a history of MLV usage. Furthermore, Cluster IV displayed substantial genetic divergence, suggesting it comprises a heterogeneous group of distinct lineages. Conclusions: These findings demonstrated the temporal changes in the genetic diversity of Cluster III and provided suggestions of a possible influence that MLV usage influences PRRSV-2 cluster distribution, with Clusters I and II likely representing vaccine-origin viruses. The marked heterogeneity of Cluster IV also highlights the limitations of the current cluster-based classification. Full article

Stenotrophomonas maltophilia is considered one of the emerging bacterial agents causing healthcare-associated infections (HAIs) in hospital environments. This microorganism has been identified as multidrug-resistant, capable of forming mature biofilms—an ability that promotes adherence to surfaces and invasive medical devices, favoring persistence in hospital environments and the potential to generate outbreaks. The aim of this study was to characterize S. maltophilia strains isolated from HAI cases at the Hospital Juárez de México and to determine the presence of hidden outbreaks. Antibiotic resistance profiles were determined, along with the typing of 20 genes associated with virulence factors and the assessment of the ability to form mature biofilms on inert surfaces. Finally, sequence type (ST) was obtained through multilocus sequence typing (MLST) analysis, and a phylogenetic tree was constructed to determine the clonal diversity of the isolates. All strains showed uniform resistance to β-lactam antibiotics tested while remaining sensitive to fluoroquinolones, phenicols, tetracyclines, and trimethoprim/sulfamethoxazole. Some isolates exhibited adherent activity, with the “strong biofilm-former” phenotype predominating. Sixteen virulence-related genes were heterogeneously detected, revealing broad genetic diversity. MLST analysis grouped the isolates into nine ST related to infection cases reported in others countries. Phylogenetic analyses demonstrated the presence of three potential clones distributed across Internal Medicine and the Pediatric Intensive Care Unit. These results highlight the importance of investigating S. maltophilia as an HAI-associated pathogen that remains understudied. Full article

Bulk metallic glasses (BMGs), classified as metastable materials, necessitate melt quenching at critical cooling rates higher than 10² K/s to kinetically bypass crystalline phase formation during solidification. Owing to this rapid quenching, the microstructure of BMGs can be regarded as melt quenched. This study examines how their melt state governs the thermal stability, structural characteristics, and plasticity behavior of Zr₅₀Cu₄₀Al₁₀ BMG. Rod samples were prepared via injection casting at controlled melt temperatures and suction casting. Experimental observations demonstrated a positive correlation between elevated melt temperatures and enhanced glass forming ability (GFA) along with improved thermal stability (T-A) in BMGs during processing. Structural analyses confirmed the glassy nature of the prepared BMGs with different melt states and revealed their temperature-dependent atomic-scale heterogeneity: the samples quenched at low melt temperatures exhibited significant Cu-rich clustering as determined via energy-dispersive X-ray spectroscopy (EDS) mapping, and those at high melt temperatures formed homogeneous structures. This structure heterogeneity was directly correlated with good plastic deformation behavior, i.e., the rod sample prepared at the lowest melt temperature achieved 9.7% plastic strain. The transition is attributed to liquid-liquid phase transition (LLPT): below the LLPT threshold, metastable Cu-rich clusters persist in the melt and are retained upon quenching, creating structural defects that facilitate shear band multiplication. These findings highlight melt temperature as a crucial factor in tailoring the structure characteristic and mechanical behavior of Zr₅₀Cu₄₀Al₁₀ BMGs. Full article

Influenza virus is one of the most frequent causes of respiratory infection in humans. Recent studies suggest that extracellular vesicles (EVs)—small particles released by cells during influenza virus infection—can influence the immune response and viral pathogenesis. However, during viral replication, infected cells can also release EVs, which may include different subtypes. This study aimed to purify and characterize viral preparations and EVs using sequential ultracentrifugation methods. Influenza A/H1N1, A/H3N2, and B virus strains were produced in human Calu-3 and A549 cell lines. Viral supernatants then underwent a series of differential ultracentrifugation steps at 3000× g, 17,000× g, and 100,000× g. Dynamic light scattering analysis (DLS) validated size heterogeneity for all three types of EVs. Measurement of infectious virus particles for all three pellets showed virus enrichment at 17,000× g and 100,000× g. Dot blot analysis confirmed the enrichment of virus particles in these fractions and the presence of EV protein. This study demonstrates the presence of EVs in virus preparations and highlights the need for improved separation methods to characterize them better and explore their role in viral infection pathogenesis. Full article

The reuse of rubber inclusions obtained from End-of-Life Tires (ELTs) offers both environmental and technical benefits in civil engineering applications, reducing landfill disposal and enhancing the dynamic properties of geomaterials. The use of well-graded Gravel–Rubber Mixtures (wgGRMs), produced by blending well-graded gravel with granulated rubber, has been investigated for use in different geotechnical applications. The percentage of rubber inclusions included in wgGRMs significantly modifies the mechanical response of these mixtures, influencing stiffness, strength, dilatancy and dynamic properties. Due to the material heterogeneity (i.e., stiff gravel and soft rubber), the effective implementation of wgGRMs requires the development of constitutive models that can capture the non-linear stress–strain response of wgGRMs subjected to representative in situ loading conditions. In this study, a critical state-based generalized plasticity model is presented and tailored for wgGRMs. Calibration is performed using experimental data from isotropically consolidated drained triaxial tests on wgGRMs with different rubber contents. It is shown that the model accurately reproduces key features observed experimentally, including post-peak strain softening, peak strength variation, and volumetric changes across different confining pressure levels and rubber content fractions. This model represents a useful tool for predicting the behavior of wgGRMs in engineering practice, supporting the reuse of ELT-derived rubber. Full article

The rapid growth of electric vehicle (EV) charging demand poses significant challenges to distribution networks (DNs), particularly during public holidays when concentrated peaks occur near scenic areas and urban transport hubs. These sudden surges can strain transformer capacity and compromise supply reliability. Fixed soft open points (SOPs) are costly and underutilized, limiting their effectiveness in DNs with multiple transformers and asynchronous peak loads. To address this, from the perspective of power supply companies, this study proposes a mobile soft open point (MSOP)-based approach to enhance the hosting capacity of EV charging stations. The method pre-installs a limited number of fast-access interfaces (FAIs) at candidate transformers and integrates a semi-rolling horizon optimization framework to gradually expand interface availability while scheduling MSOPs daily. An automatic peak period identification algorithm ensures optimization focuses on critical load periods. Case studies on a multi-feeder distribution system coupled with a realistic traffic network demonstrate that the proposed method effectively balances heterogeneous peak loads, matches limited interfaces with MSOPs, and enhances system-level hosting capacity. Compared with fixed SOP deployment, the strategy improves hosting capacity during peak periods while reducing construction costs. The results indicate that MSOPs provide a practical, flexible, and economically efficient solution for power supply companies to manage concentrated holiday charging surges in DNs. Full article

Coxiella burnetii, the causative agent of human Q fever, subverts macrophage antimicrobial functions to establish an intracellular replicative niche. To better understand host–pathogen interactions, we investigated the transcriptional responses of human alveolar macrophages (hAMs) infected with virulent [NMI, G (Q212)], attenuated (NMII), and avirulent (Dugway) strains of C. burnetii. RNA sequencing indicated that all strains activated proinflammatory pathways, particularly IL-17 signaling, though the magnitude and nature of the response varied by strain. Infections with NMI, NMII or G (Q212) resulted in differential expression of roughly the same number of genes, while Dugway infection induced a stronger transcriptional response. Dugway and G (Q212) tended to polarize macrophages toward M1-like states, whereas responses to NMI and NMII were variable. Cytokine assays of NMII-infected THP-1 macrophages suggested the activation of IL-17 signaling, but only at later stages of infection, and single-cell RNA sequencing of NMII-infected THP-1 macrophages indicated heterogeneity in host response to infection, with distinct subpopulations exhibiting M1-like and M2-like inflammatory profiles. These findings highlight the complexity of macrophage response to C. burnetii and underscore the importance of strain-specific and cell-specific factors in shaping host immunity. Understanding these dynamics may inform the development of targeted therapies for Q fever. Full article

Understanding the microscopic interaction between agricultural tillage tools and soil is essential for improving wear resistance. In this study, molecular dynamics (MD) simulations are employed to investigate the tribological behavior of the Fe–SiO₂ interface under varying loads and sliding velocities. The results demonstrate that the coefficient of friction increases with both normal load and sliding velocity, accompanied by a clear running-in stage. Under high loads, significant plastic deformation occurs, characterized by asymmetric atomic pile-up, expansion of the strain field, and heterogeneous von Mises strain distribution. Energy analysis reveals intensified kinetic and potential energy variations, indicating enhanced defect accumulation and interfacial non-equilibrium states. Temperature distributions are highly localized at the interface, with thermal saturation observed under high-velocity conditions. Mean square displacement (MSD) results confirm that higher loads and velocities promote atomic migration and plastic flow. This study provides atomic-scale insights into wear mechanisms under extreme mechanical conditions, offering theoretical support for the design of durable soil-engaging components in agricultural machinery. Full article