Biofilms are structured communities of microorganisms embedded in a self-produced extracellular polymeric substance (EPS) matrix, whose development significantly enhances microbial resistance to antibiotics, disinfectants, and host immune defenses, posing major challenges in clinical, industrial, and environmental settings. Compared with planktonic cells, biofilm-associated microorganisms can exhibit up to 10- to 1000-fold increased tolerance to antimicrobial agents, contributing to the persistence of biofilm-associated infections (BAIs). These infections remain difficult to eradicate due to reduced penetration, altered metabolic states, and the presence of dormant or persister cells. Anti-biofilm strategies can be broadly classified into physical approaches (e.g., ultrasound, mechanical stress, and light-based approaches) that target biofilm structure; chemical and enzymatic methods (e.g., EPS-degrading enzymes) that destabilize the matrix; and biological and molecular strategies (e.g., quorum-sensing (QS) inhibitors, anti-virulence agents, bacteriophages, phage-derived antimicrobial molecules, antimicrobial peptides, and natural bioactive compounds) that modulate biofilm development and integrity by targeting regulatory pathways and matrix stability through distinct mechanisms of action. Natural compounds, including lactoferrin, lactoferrin-derived peptides, and probiotic and postbiotic fractions of lactic acid bacteria (LAB), as well as plant-derived metabolites, have shown promising anti-biofilm effects, with efficacy often enhanced through complementary or potentially synergistic interactions. However, despite these advancements, clinical translation remains limited. For example, BAIs account for approximately 80% of chronic infections, with high recurrence rates and therapeutic failure reported in device-associated infections and chronic wounds. These limitations highlight the need for clinically translatable, multimodal approaches that integrate structural biofilm disruption, antimicrobial targeting, and host response modulation to design more effective and sustainable anti-biofilm strategies.
Bexotegrast is an oral, once-daily, dual-selective inhibitor of integrins αvβ6 and αvβ1 in development for idiopathic pulmonary fibrosis (IPF). In the phase 2a study INTEGRIS-IPF study (NCT04396756), bexotegrast was well tolerated and showed antifibrotic activity. BEACON-IPF (NCT06097260) is a randomised, double-blind, placebo-controlled, dose-finding, operationally seamless, adaptive phase 2b/3 study evaluating the efficacy and safety of bexotegrast over 52 weeks in participants with IPF. The phase 2b dose selection cohort will enrol 360 participants randomised 1:1:1 to once-daily bexotegrast 160 mg, 320 mg or placebo. After enrolling the last participant in the phase 2b cohort and while conduct is ongoing, the phase 3 cohort will immediately begin enrolment with a 'seamless group' using the same 1:1:1 randomisation. Once the phase 2b cohort has completed and a dose has been selected, the remainder of the phase 3 cohort will be enrolled. Participants in the phase 2b cohort receiving the non-selected dose will be eligible for an open-label study at the selected phase 3 dose. Background therapy with pirfenidone or nintedanib is permitted in ≤70% of the study population. Participants must be adults (≥40 years), have an IPF diagnosis ≤7 years per 2018 international guidelines, per cent predicted forced vital capacity (FVCpp) ≥45% and diffusing capacity for carbon monoxide (haemoglobin adjusted) ≥30%. The primary endpoint is change from baseline in absolute FVC at week 52. Additional endpoints include safety and tolerability, time to disease progression, participant-reported symptom assessments and quantitative lung fibrosis extent. This study was approved by Advarra institutional review board (IRB; OHRP and Food and Drug Administration registration 00000971) and at each participating site by IRBs and local ethics review committees. Participants will provide written informed consent before taking part. Study results will be disseminated in peer-reviewed journals and international conferences targeted to medical, academic and patient communities. NCT06097260.
This analysis evaluated the effects of olokizumab (OKZ) on patient-reported outcomes (PROs) after up to 106 weeks of treatment in patients with active rheumatoid arthritis (RA) refractory to methotrexate (MTX; MTX-inadequate response [MTX-IR]) or refractory to tumor necrosis factor inhibitor (TNFi; TNFi-inadequate response [TNFi-IR]). Post-hoc analysis was performed of pooled PROs from phase III, double-blind, placebo-controlled trials (CREDO1/2 MTX-IR; CREDO3 TNFi-IR; NCT02760368/ NCT02760407/NCT03225932) and their open-label extension (OLE; up to 106 weeks) in adults with active RA despite treatment with MTX or TNFi. Patients were treated with OKZ 64 mg every 2 weeks (q2w) or every 4 weeks (q4w) + MTX versus MTX + placebo (weeks 0-24) or active comparator (CREDO2), followed by an OLE (all OKZ). The PROs analyzed were patient global assessment; pain (visual analog scale); Health Assessment Questionnaire Disability Index (HAQ-DI); 36-Item Short Form Health Survey (SF-36); Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (FACIT-F); Work Productivity Survey Rheumatoid Arthritis (WPS-RA) and the European Quality of Life-Five-Dimension Questionnaire (EQ-5D). Changes from baseline at weeks 12, 24 and 106 were analyzed using a mixed model for repeated measures; analyses included percentages of patients reporting improvements ≥ minimal clinically important difference (MCID). By week 12, treatment with OKZ compared to placebo (PBO) resulted in greater numerical and clinically meaningfully changes from baseline in all PROs for patients refractory to MTX: the HAQ-DI was - 0.60 for OKZ q2w, - 0.58 for OKZ q4w and - 0.34 for PBO; pain VAS was - 33.26, - 32.51, - 18.39, respectively; and the FACIT-F was 8.47, 8.42 and 4.69, respectively (p < 0.0001). Similar but less prominent improvements were noted in the patients with TNFi-IR. Post hoc analyses demonstrated a higher proportion of patients receiving OKZ reported improvements ≥ MCID versus those receiving PBO (p < 0.05) in all PROs in both groups at week 12. For patients treated with OKZ, the observed improvements from baseline were maintained and increased in magnitude through week 106. Treatment with OKZ over 106 weeks resulted in sustained numerically greater and clinically meaningful improvements in PROs compared to baseline in both RA patients with MTX-IR and those with TNFi-IR. These findings support the long-term benefit of OKZ on PROs. ClinicalTrials.gov identifiers NCT02760368, NCT02760407, NCT02760433, NCT03120949.
RAS inhibitors have demonstrated limited efficacy in KRAS-mutant colorectal cancer (CRC). Here, we evaluate RMC-7977, a RAS(ON) multi-selective inhibitor, which shows a heterogeneous response in a panel of preclinical CRC models. Inhibition of PI3K signaling and cyclin D1 (CCND1) expression are strongly correlated with response. We find that stratifying tumors based on the ERK dependence of cyclin D1, mediated by variability in CCND1 mRNA regulation, reveals two distinct resistance mechanisms. PI3K signaling plays a key role in driving persistent cyclin D1 expression in the less ERK-dependent tumors, and concurrent inhibition of RAS and PI3K can synergistically cause cell cycle arrest and promote apoptosis. However, in tumors with strongly ERK-dependent cyclin D1, vertical inhibition of RAS and MEK prevents feedback re-activation of the MAPK/ERK pathway and is more effective. In summary, we identify cyclin D1 as an important integrator and functional readout of upstream signaling that can inform optimal combination strategies for KRAS-mutant CRC.
In this paper, we develop a connectivity-exact bond-resolved framework for quantifying structural accessibility and persistence in drug molecules. Representing a molecule as a heavy-atom graph [Formula: see text] each bond is classified uniquely as either a connectivity-critical Entry-point bond ([Formula: see text]) or a connectivity-preserving Fortress bond ([Formula: see text]) yielding the exact identity [Formula: see text] This exhaustive partition separates fragmentation capacity from invariant scaffold structure without adjustable parameters. To refine the invariance coordinate we introduce Total Structural Entrenchment (TSE) a persistence-weighted functional defined over cycle-supported bonds and modulated by local steric wall contributions [Formula: see text]. The resulting two-parameter embedding [Formula: see text] distinguishes superficial cyclic extent from deeply embedded structural reinforcement and resolves degeneracies inherent in raw bond counts. Metabolic progression is formalized as recursive bridge depletion generating a directed migration across the architectural plane toward a bridge-depleted refractory core. Within this framework scaffold persistence is interpreted as a connectivity-driven contraction governed strictly by graph topology. The resulting invariance-variation embedding establishes a mathematically controlled bond-level representation of structural accessibility and cyclic entrenchment.
Congenital hyperinsulinism (HI) may be diazoxide-responsive or diazoxide-unresponsive. Patients with diazoxide-unresponsive HI are further classified based on having the diffuse or focal form of the disease, with different management strategies associated with each form. While patients with HI typically have only one form of the disease, here we report 3 patients who had both focal and diffuse HI. Three patients with diazoxide-unresponsive HI were transferred to our hospital for further management. All 3 patients had genetic testing which was equivocal or initially negative. Given their diazoxide status and not wanting to miss a focal lesion that was amenable to a surgical cure, all 3 patients underwent imaging with 18 F-L 3,4-dihydroxyphenylalanine positron emission tomography which identified focal pancreatic lesions in all 3 patients. They all had surgical resection of the lesions. Biopsies of the pancreas outside of the lesions noted rare or scattered islet cell nucleomegaly, indicative of diffuse disease, and subsequent fasting studies to determine if patients were cured revealed ongoing HI. Further review of genetic results suggested a mechanism for both focal and diffuse HI occurring in each of the patients. For all 3 patients, their ongoing HI could be managed with diazoxide following removal of the focal lesion. Focal and diffuse HI can occur in the same patient. Following resection of focal pancreatic lesions, the patients require careful evaluations for evidence of ongoing HI, and depending on the genetic results, diazoxide may be a management option for ongoing HI in a subset of these patients.
Hematopoietic progenitor kinase 1 (HPK1) induces potent anti-tumor immunity in preclinical models by activating and recruiting T cells, B cells, and dendritic cells into the tumor microenvironment (TME). Here, we evaluate NDI-101150, a potent, selective HPK1 inhibitor, in a phase 1/2 trial as a monotherapy or in combination with pembrolizumab in patients with advanced solid tumors. The monotherapy maximum tolerated dose (MTD) is 150 mg once daily, and doses tested up to 100 mg once daily are combinable with pembrolizumab without reaching an MTD. In clear cell renal cell carcinoma, the investigator-assessed overall response rate with monotherapy treatment is 13.6%, including one complete response and two partial responses, with a clinical benefit rate of 27.3% and a disease control rate of 54.5%. Pharmacodynamic analyses show pharmacodynamic biomarker phospho-SLP76 inhibition and increased activated CD8+ T cells and dendritic cells in the TME, supporting continued development (clinical registration number NCT05128487).
Lifileucel is a first-in-class autologous tumor-infiltrating lymphocyte (TIL) therapy for advanced/metastatic melanoma with progression after anti-programmed cell death protein 1 (PD-1) therapy and/or BRAF inhibitor therapy, if BRAF V600 mutations are present. In the C-144-01 phase 2 trial of lymphodepleting chemotherapy, lifileucel, and interleukin 2 (IL-2), cutaneous eruption occurred in 37.2% of individuals. These eruptions remain clinically and prognostically unknown. To examine cutaneous toxic effects development in the setting of lifileucel therapy, abstract clinical and histopathologic eruption features, and test for association with objective radiographic tumor response. A retrospective cohort study was performed at Mass General Brigham (MGB)/Dana-Farber Cancer Institute (DFCI) that included all patients treated with lifileucel, outside of active clinical trials. The analysis was completed in December 2025. All individuals received cyclophosphamide/fludarabine lymphodepletion, lifileucel, and 6 or fewer IL-2 infusions. Demographics, melanoma-specific factors (M stage, pre-TIL lactate dehydrogenase levels, and number of lines of prior systemic therapy), number of IL-2 doses received, eruption features, photography, and dermatopathologic findings were abstracted. Radiographic responses 30 to 41 days, 42 to 89 days, and 90 days or longer from TIL infusion per Response Evaluation Criteria in Solid Tumors (RECIST) were abstracted. Individuals were stratified as high IL-2 (4-6 doses) or low IL-2 (1-3 doses), for objective response rate (ORR) comparison as a descriptive sensitivity analysis. An unadjusted logistic regression modeled tumor response as a binary outcome with lifileucel-associated eruption occurrence as a binary predictor. Three adjusted models included IL-2 doses (age, sex, and demographic differences) and melanoma-specific factors as covariates. Per retrospective electronic medical health record review, among 44 individuals (34.1% female individuals; mean [SD] age, 54.8 [14.5] years), treated with lifileucel (median, 4.5 IL-2 doses), 22 (50.0%) developed an associated cutaneous eruption while hospitalized, after a median of 4 post-TIL days. Photographs from 14 of 22 individuals (63.6%) with available images demonstrated central-predominant, frequently purpuric morbilliform eruptions. ORRs did not significantly differ by IL-2 stratification (high IL-2: 50.0% vs low IL-2: 37.5%; P = .53). Cutaneous eruption development was associated with a 42-day response across analyses (analysis 1: OR, 7.29; 95% CI, 1.91-27.86; P = .004; OR, 7.65; 95% CI, 1.79-32.69; P = .006; analysis 2: OR, 11.95; 95% CI, 1.90-75.39; P = .008; analysis 3: OR, 9.73; 95% CI, 2.12-44.74; P = .003); 30-day responses were statistically similarly associated. All 90-day cutaneous eruption response analyses did not detect statistical significance. In this cohort study, lifileucel treatment was frequently complicated by purpuric morbilliform eruptions, which were prognostically favorable and associated with short-term response. The lifileucel-associated eruption may be a peritreatment efficacy marker, assessable during the TIL treatment hospitalization prior to traditional 42-day restaging.
Last year marked 80 years since Edvard Beneš, President of the Czechoslovak Republic, signed a decree establishing the medical faculty in Hradec Králové as a branch of the Faculty of Medicine at Charles University in Prague. This was the beginning of medical education in the city and the wider East Bohemian region.The decision to establish the faculty here was no coincidence.For centuries, Hradec Králové was an important fortified town in the Austrian Empire, and all aspects of life in the town and its surroundings were subordinated to this fact. This situation lasted until the end of the 19th century, when the fortress was dismantled. It was only after this that the town and region underwent rapid development, a process that continued during the First Republic.The region's development led to a sharp increase in population, creating a need for better, more accessible healthcare. Thanks to the significant support and efforts of city officials, one of the largest and most modern hospitals in what was then Czechoslovakia was built. This hospital employed a number of leading experts who, in addition to their high level of professional expertise and medical experience, were also actively involved in lecturing, publishing and social activities.The region therefore possessed a high level of personnel, professional and material readiness to support a medical faculty. Its possible establishment was therefore discussed throughout the interwar period as part of the efforts to establish a university in Hradec Králové - or rather, a regional university in East Bohemia. However, this process was halted for six long years by a significant historical event: the occupation of the republic and its subjugation as the Protectorate as part of the German Reich.The desperate shortage of doctors after the liberation in 1945 increased the urgency to open a medical faculty as soon as possible. The closure of universities during the occupation, violent deaths on the battlefield, in concentration and labour camps, the post-war displacement of the German population and waves of emigration all contributed to the critical shortage of physicians. Given these circumstances, it was only logical that the city of Hradec Králové was chosen to establish a medical faculty shortly after the war ended. Thanks to the extraordinary efforts of the government, the Ministry, the district and municipal authorities, representatives of higher education and leading physicians at the Hradec Králové hospital, the city became a university town 80 years ago when a branch of the Medical Faculty of Charles University was established there.However, the beginnings were not easy. Besides having access to the state-of-the-art hospital, the school also needed adequate facilities for teaching basic theoretical subjects and high-quality teaching materials. The need for teaching facilities was resolved thanks to the opportunity to use a modern building on Šimkova Street. Built just before the war for the command corps of the Czechoslovak army, the building was seized and used by the Germans for other, more sinister purposes during the occupation. Adapting it for medical teaching was challenging, but hard work and enthusiasm resolved this issue relatively quickly. Leading physicians, scientists and respected experts became involved in managing individual departments and organising teaching. The level of interest in studying medicine was huge, and the teaching was of a very high standard, at the cutting edge. The faculty soon became a respected and recognised institution.The escalation of the international political situation in the 1950s, coupled with the world's division into irreconcilable camps, led to a rapid increase in armaments, expansion of individual armies, and a simultaneous need to bolster the ranks of military doctors. In response to political demands, the Faculty of Medicine in Hradec Králové was transformed into the Military Medical Academy in 1951. Alongside a partial change in the content of teaching and research, this resulted in significant personnel changes within various departments. Unfortunately, as a result of this transformation, a number of doctors who did not wish to become professional soldiers left the faculty. However, it should be noted that despite all the political and personnel complications, the academy's professional level remained high.Another significant milestone in the history of the Hradec Králové faculty was its return to the civilian sector in 1958, which led to the establishment of an independent Faculty of Medicine at Charles University. Basic theoretical, preclinical and clinical disciplines developed dynamically in line with the needs of modern times, and this was later supported by the opportunity to cooperate with foreign countries thanks to the partial easing of the political situation at that time. Unfortunately, the so-called 'normalisation' of the 1970s hit our entire society hard, including our faculty. Political purges led to severe staff shortages at virtually all workplaces, paralysing the development of the faculty for a long time. Recovery was slow, and the negative impact was evident for a long time.Fundamental changes occurred following the revolutionary societal changes of 1989. Academic values were reinstated, and democratic traditions in higher education were revived. Management of the faculty and university was based on new principles, and development of individual fields, departments, institutes and clinics was no longer politically restricted. Since then, there has been noticeable and sustained positive development.Teaching has also changed significantly thanks to modern teaching methods and programmes, sophisticated aids, computer technology and the internet. However, the most important thing that has remained unchanged since the beginnings of our faculty is the role of the teacher. Their experience, knowledge of the subject and personal approach, enabling the traditional transfer of acquired knowledge from generation to generation, remains as important as ever.The Faculty of Medicine currently offers degree programmes in General Medicine, Dentistry, General Nursing and Midwifery. These programmes are taught in Czech and, for hundreds of foreign students, in English. The faculty also offers doctoral programmes. A total of almost 2,000 students are currently enrolled at the faculty.However, teaching is not the only role of a modern medical faculty. Science and research are also integral to the faculty's activities as world-class research into a wide range of biomedical issues is carried out.Adequate conditions are also necessary to support all faculty activities. This is why the faculty now offers modern facilities that are ideal for teaching medicine and conducting research. These facilities are located in a carefully renovated building on Šimkova Street and in the historic Na Hradě building, as well as in study areas at individual university hospital departments. In addition, new complexes have been gradually constructed. These include a teaching centre on the grounds of the Faculty Hospital and a joint campus for the medical and pharmaceutical faculties nearby. Completing these is now one of our most important tasks. The planned opening this year will create new opportunities for our students and staff. If all goes according to plan, the 2026/27 academic year will begin in the new premises.Throughout its existence, the Faculty of Medicine has worked closely with the University Hospital in Hradec Králové. Cooperation between the two institutions is essential and is conducted on a consistently high professional level, with mutual respect. After all, the Faculty of Medicine cannot exist without its hospital, just as the University Hospital cannot exist without its faculty. Without a balanced and functional connection between the two, it would not be possible to fulfill their missions. And the University Hospital in Hradec Králové, which is now one of the largest and most modern hospitals in the country, is the main base for the practical training of our students.We also successfully cooperate with other contracted hospitals in our country when it comes to providing practical training. Our students have the opportunity to work at these facilities during their vacation and pre-exam internships.However, the Faculty of Medicine is more than just buildings. First of all, it is the people who work there and the students who study there that make it what it is, today as in previous years. It is the people who founded it and built it together over the decades. Leading experts, doctors, scientists and teachers. Outstanding students and graduates.The Faculty of Medicine in Hradec Králové has undergone a long and complex journey. During that time, it has become one of the most modern educational and scientific institutions, enjoying high prestige. An integral, solid and indispensable part of Charles University, it has its own specific character and independence, and cooperates with other medical faculties.Our history binds us together, and we are facing one of the most challenging tasks ahead. We must maintain the current high level of our faculty, whose foundations were laid 80 years ago, and continue to develop its mission, and all its responsibilities in the coming decades.
Biodiversity loss and socioeconomic inequities are closely linked, yet conservation efforts often prioritize ecological goals, resulting in unsustainable outcomes. We propose a justice-centered socioecological framework that integrates biodiversity conservation with human well-being based on the principles of sustainable development theory and the concepts of distributive, procedural, and recognition justice. We reviewed the recent literature on fortress and market-based conservation approaches (2020-2025) to examine their impact on local communities. This review showed that fortress conservation and market-based approaches often exclude local communities, thereby undermining their livelihoods and the sustainability of their communities. In the proposed model, participatory governance, livelihood-aligned strategies (e.g., agroecology), and policy reforms (e.g., rights-based legislation) are integrated to promote equitable and resilient outcomes. Examples of successful use of an integrated approach include Namibia's conservancies, in which wildlife is jointly managed with the community and the community receives wildlife-related income, and Bhutan's Gross National Happiness (GNH) framework, which requires every development (road, mine, and protected area) to be screened for its effects on forest cover and cultural well-being. In these cases, there is adaptive governance (i.e., iterative, community-led rulemaking that changes based on ecological data) and redirection of subsidies from large commercial ranches to communal conservancy trusts, which positively affect biodiversity and human well-being. The GNH is a transformative and scalable approach because justice-based participatory mapping, livelihood-aligned incentives, and right-based policies are embedded in every conservation intervention, thereby aligning with global sustainability goals (e.g., UN Sustainable Development Goals 1 and 15). Centering justice in conservation planning is ethically and pragmatically essential for long-term success. Un marco para soluciones integradoras de conservación socioecológica Resumen La pérdida de biodiversidad y las desigualdades socioeconómicas están estrechamente relacionadas, pero los esfuerzos de conservación suelen dar prioridad a los objetivos ecológicos, lo que da lugar a resultados insostenibles. Proponemos un marco socioecológico centrado en la justicia que integra la conservación de la biodiversidad con el bienestar humano, basado en los principios de la teoría del desarrollo sostenible y los conceptos de justicia distributiva, procesal y de reconocimiento. Revisamos la bibliografía reciente sobre los enfoques de conservación basados en fortalezas y en el mercado (2020‐2025) para examinar su impacto en las comunidades locales. Esta revisión demostró que la conservación de fortalezas y los enfoques basados en el mercado a menudo excluyen a las comunidades locales, lo que socava sus medios de vida y la sostenibilidad de sus comunidades. En el modelo propuesto, la gobernanza participativa, las estrategias alineadas con los medios de vida (por ejemplo, la agroecología) y las reformas políticas (por ejemplo, la legislación basada en los derechos) se integran para promover resultados equitativos y resilientes. Entre los ejemplos de uso exitoso de un enfoque integrado se incluyen las reservas naturales de Namibia, en las que la fauna silvestre se gestiona conjuntamente con la comunidad y esta recibe ingresos relacionados con la fauna silvestre, y el marco de la Felicidad Nacional Bruta (FNB) de Bután, que exige que todos los proyectos de desarrollo (carreteras, minas y áreas protegidas) se sometan a un examen para evaluar sus efectos sobre la cobertura forestal y el bienestar cultural. En estos casos, existe una gobernanza adaptativa (es decir, una elaboración de normas iterativa y dirigida por la comunidad que cambia en función de los datos ecológicos) y una reorientación de las subvenciones de las grandes explotaciones ganaderas comerciales hacia los fideicomisos comunitarios de conservación, lo que repercute positivamente en la biodiversidad y el bienestar humano. El FNB es un enfoque transformador y escalable porque el mapeo participativo basado en la justicia, los incentivos alineados con los medios de vida y las políticas basadas en derechos están integrados en todas las intervenciones de conservación, alineándose así con los objetivos globales de sostenibilidad (por ejemplo, los objetivos de desarrollo sostenible 1 y 15 de las Naciones Unidas). Centrar la justicia en la planificación de la conservación es ética y pragmáticamente esencial para el éxito a largo plazo. 生物多样性丧失与社会经济不平等存在密切关联, 但传统保护策略往往偏重生态目标, 导致保护成果难以持续。我们基于可持续发展理论原则, 融合分配正义、程序正义与承认正义理念, 提出一个以正义为导向的社会生态框架, 旨在协同推进生物多样性保护与人类福祉。通过系统评析2020年至2025年间关于“堡垒式保护”与“市场化保护”路径的文献, 我们发现这两种主流模式常将当地社区置于决策与利益格局之外, 不仅削弱其民生基础, 也危及社区可持续发展的根基。我们提出的框架整合了参与式治理、民生协同策略(如生态农业)与权利导向的政策改革(如基于权利的法律制度), 以促进公平且具韧性的保护成果。其中成功案例包括:纳米比亚社区保护地实行野生动物与社区收益协同管理;不丹以国民幸福总值(GNH)框架为指导, 其涵盖九大领域的政策审查机制要求所有发展项目(包括道路建设、采矿与保护区规划等)必须符合综合福祉标准。这些实践通过适应性治理(即依据生态反馈、由社区主导的动态规则调整)以及将补贴从大型商业牧场转向社区保护信托基金等措施, 同步提升了生物多样性保护成效与社区福祉。本框架将基于正义的参与式空间规划、与民生协调的激励机制以及权利保障政策系统性融入保护干预措施, 形成兼具变革性与可扩展性的实施路径, 从而与全球可持续发展目标(如联合国可持续发展目标1和15)相契合。在保护规划中确立正义的核心地位, 不仅是伦理上的必然要求, 更是实现长期保护成效的现实关键。 综合性社会‐生态保护解决方案框架.
A growing challenge in mobile robotics is the reliance on complex graphical interfaces and rigid control pipelines, which limit accessibility for non-expert users. This work introduces a latency-aware benchmarking framework that enables natural-language robot navigation by integrating multiple Large Language Models (LLMs) with the Robot Operating System 2 (ROS 2) Navigation 2 (Nav2) stack. The system allows robots to interpret and act upon free-form text instructions, replacing traditional Human-Machine Interfaces (HMIs) with conversational interaction. Using a simulated TurtleBot4 platform in Gazebo Fortress, we benchmarked a diverse set of contemporary LLMs, including GPT-3.5, GPT-4, GPT-5, Claude 3.7, Gemini 2.5, Mistral-7B Instruct, DeepSeek-R1, and LLaMA-3.3-70B, across three local planners, namely Dynamic Window Approach (DWB), Timed Elastic Band (TEB), and Regulated Pure Pursuit (RPP). The framework measures end-to-end response latency, instruction-parsing accuracy, path quality, and task success rate in standardised indoor scenarios. The results show that there are clear trade-offs between latency and accuracy, where smaller models respond quickly but have less spatial reasoning, while larger models have more consistent navigation intent but take longer to respond. The proposed framework is the first reproducible multi-LLM system with multi-planner evaluations within ROS 2, supporting the development of intuitive and latency-efficient natural-language interfaces for robot navigation.
For decades, we have viewed pancreatic fibrosis as a passive scar-the end-stage wreckage of chronic inflammation or a late accomplice of growing tumors. A recent study by He Ren and colleagues sheds critical light on the origins of the phenomenon tracing it to an unexpected cellular culprit: a rare subset of pancreatic epithelial cells that express FOXP3-a transcription factor predominantly associated with regulatory T cells. These epithelial FOXP3 (E-FOXP3) positive cells do not need oncogenic Kras or overt inflammation to ignite fibrosis. On their own, they orchestrate a glycosylation-dependent IL-6 switch that turns quiescent pancreatic stellate cells into a self-amplifying fibrotic machine. In discovering a proto-fibrogenic "trigger cell" that acts silently, long before any symptom or radiological sign, the work redefines the cellular hierarchy of pancreatic fibrocarcinogenesis. Further, the paper identifies a post-translational "sugar code" as a therapeutic foothold, and opens a long-sought preemptive window for intercepting pancreatic cancer at its most curable stage-before the desmoplastic fortress is ever built.
It is generally accepted that non-coding DNA constitutes the vast majority of most eukaryotic genomes and is concentrated at the nuclear periphery and nucleolar surface. Building upon this spatial organization, we have previously proposed that this layer of abundant, peripherally localized non-coding DNA functions as a 3D buffer that transiently absorbs or permanently excludes DNA damage to protect the genome and the relatively central exome from external and internal mutagens in somatic cells. This review explores the potential role of non-coding DNA as a physical barrier in genome safeguarding during early developmental stages and major evolutionary transitions. During gametogenesis and early embryogenesis the barrier is first provided by abundant non-coding DNA; as heterochromatin matures from non-coding DNA, many species programmatically eliminate the now-redundant non-coding DNA. Across evolution, whole-genome duplications and repeat amplification expand the shield, facilitating major evolutionary transitions such as vertebrate origins, water-to-land colonization and survival through mass-extinction crises. Conversely, in stable ecosystems selection favors genome streamlining: redundant non-coding DNA is lost to reduce fitness costs. Thus, the dosage of non-coding DNA is negatively correlated with the strength of apomorphic safeguards (adaptive immunity, viviparity) and positively correlated with ecological or developmental stress. By integrating comparative genomics, 3D nuclear architecture and evolution, we unify a single conceptual framework: non-coding DNA acts as a malleable fortress whose thickness is tuned to the variable need for genome protection during both ontogeny and phylogeny. This perspective offers new explanatory power for the accumulation or loss of non-coding DNA and can predict genome-size trajectories.
Silverleaf whitefly (Bemisia tabaci), silverleaf disorder (SLD), and whitefly-transmitted viruses (WTVs) are major constraints to cucurbit production in the southeastern United States. Two field trials were conducted in Tifton, Georgia, USA, during the fall of 2023 and 2024 to evaluate yellow squash and zucchini (Cucurbita pepo L.) cultivars for tolerance to SLD and WTVs. In one experiment, 10 yellow squash cultivars (8 straight neck: 'Cougar,' 'Lioness,' 'Multipik,' 'Lazor,' 'Grand Prize,' 'Gold Prize,' 'Enterprise,' and 'Fortune'; and 2 semi-crook neck: 'Gentry' and 'Gold Star') were evaluated. In another experiment, 10 zucchini cultivars: three spineless ('Spineless Perfection,' 'Spineless King,' and 'Spineless Supreme'), 2 gray types ('Hurakan,' and 'Rocio'), and 5 green types ('MGO477, 'Everglade,' 'Cardea,' 'Fortress,' and 'Renegade') were evaluated. 'Gold Star' and 'Spineless Perfection' served as susceptible controls. In yellow squash, 'Lioness' and 'Cougar' displayed the lowest SLD progression. Area under symptom progress curve (AUSPC) values for SLD were 203 in 2023 and 202 in 2024 for 'Lioness,' and 446 in 2023 and 490 in 2024 for 'Cougar.' Virus incidence was also lowest in 'Lioness' (area under disease progress curve (AUDPC) values 315 in 2023 and 403 in 2024) and 'Cougar' (AUDPC values of 548 in 2023 and 516 in 2024). Aligned rank transformed (ART) values for virus severity were smallest in 'Lioness' (7), followed by 'Enterprise' and 'Grand Prize' (27), and 'Cougar' (31). 'Cougar' and 'Lioness' cultivars produced the highest marketable yields (25,986 and 24,565 kg ha⁻¹ respectively in 2023). In zucchini, 'Rocio' and 'Hurakan' had the lowest AUSPC values (204 in 2023 and 197 in 2024 for 'Rocio' and 497 in 2023 and 427 in 2024 for 'Hurakan). 'Rocio,' 'Hurakan', and 'Renegade' recorded the lowest AUDPC values and virus severity (ART = 13). Marketable yields were highest in 'Renegade' (40,421 kg ha⁻¹), followed by 'Hurakan' and 'Rocio.' Across crops and years, cucurbit chlorotic yellows virus (CCYV) predominated over cucurbit yellow stunting disorder virus (CYSDV) and cucurbit leaf crumple virus (CuLCrV). Overall, 'Lioness', 'Cougar', 'Renegade', 'Hurakan', and 'Rocio' demonstrated superior performance with tolerance to SLD and WTVs while maintaining high yield.
Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic study (n = 544,513), we expand the number of genetic loci from 16 to 29, and additionally identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to an increased oocyte number and/or availability across the lifespan. Hormonal regulation in the etiology of this condition, through metabolic and reproductive features, was emphasized. The proteomic analysis highlighted metabolic biology known to be related to PCOS. A polygenic risk score (PRS) was associated with adverse cardiometabolic outcomes, with differing relevance of testosterone and body mass index in women and men. Finally, while oligo-anovulation and anovulatory infertility are features of PCOS, we observed no impact of PCOS susceptibility on childlessness. We suggest that PCOS susceptibility confers balanced pleiotropic influences on fertility in women, and life-long adverse metabolic consequences in both sexes.
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The HGF/SF (hepatocyte growth factor/scatter factor) receptor tyrosine kinase MET is overexpressed and/or activated in many tumors, providing therapeutic targets for antibody-drug conjugates and tyrosine kinase inhibitors. Reliable measurement of activated MET is fundamental for pharmacodynamic assessment of MET-targeted therapies and for expanded and proper use of such therapies in patients with tumors driven by activated MET with or without associated MET amplification or known activating mutations. To address the paucity of tools for directly measuring MET activation in tumor cells within patient biopsy specimens, we developed a robust, quantitative immunofluorescence microscopy assay to measure levels of pY1235MET and total MET in in vitro, in vivo, and patient tumor specimens. We validated this assay through assessment of MET inhibitor-treated preclinical models, peptide blocking experiments to demonstrate specificity, and concordance with corresponding measurements from the same specimens using a previously validated sandwich immunoassay of tumor lysates. Given the importance of plasma membrane-associated MET in initiating its canonical signaling cascades, as well as the demonstrated non-canonical signaling from nuclear localized MET in different tumor cell types and in response to various environmental stimuli, we developed assay capability to measure levels of pY1235MET and total MET within the plasma membrane or nucleus; these assays enable future explorations of the biological and clinical relevance of MET subcellular localization patterns. Finally, using tissue microarrays of over 50 resected tumor specimens from patients with colorectal carcinoma or non-small cell lung cancer, we demonstrated that tumor levels of pY1235MET do not always track total MET expression, suggesting that measurement of activated MET in tumor could hold potential as an independent biomarker to identify additional patients who might benefit from MET-directed targeted therapy-beyond those with tumor MET amplification, MET overexpression, or established MET-activating mutations.
Periodontitis is driven by a self-reinforcing cycle of persistent inflammation and cellular senescence, further exacerbated by pathogenic microbial colonization. To address this challenge, inspired by the "fortress effect", we report an allicin-based nanoplatform of biolubrication (PPCG) that establishes a physical and biological protective barrier for precise modulation of the periodontal microenvironment. PPCG integrates hydration-lubricating diblock copolymer P(DMA-bMPC) (PDMPC) with bioactive allicin. The lubricating PDMPC barrier may suppress pathogenic microbial adhesion and biofilm formation, constituting an "outer fortress wall" against bacterial invasion. Concurrently, sustained release of allicin could regulate bone marrow mesenchymal stem cells (BMMSCs) and mitigate inflammatory responses. It could preserve stemness and multipotent differentiation potential, thereby forming an "inner defensive citadel" that promotes soft and hard tissue regeneration. This dual protective barrier can markedly attenuate periodontal tissue senescence and inflammatory and prevent alveolar bone loss in mice periodontitis model. Furthermore, PPCG could rebalance the oral microbiota and maintain ecological homeostasis. Therapeutic efficacy is also corroborated using an artificial intelligence-assisted detection system based on the YOLO v8 deep learning model. Collectively, this study presents a therapeutic intervention strategy for periodontitis, offering a scalable and translational approach for treating inflammation and senescence.
Chimeric antigen receptor-T (CAR-T) cell therapies are highly effective in treating hematologic malignancies. Cases of second primary malignancies (SPMs) have been reported post-treatment, although risk factors remain unclear. This real-world study evaluated predictors of SPMs among patients treated with CAR-T. Patients with multiple myeloma (MM) or lymphoma/leukemia treated with CAR-T were identified from the Komodo Research Database (January 1, 2016-June 30, 2024). Incidences of SPMs and hematologic SPMs were evaluated following CAR-T infusion (index date) and predictors were evaluated 12 months pre-index. LASSO regression was used to identify predictors of SPMs and hematologic SPMs, separately. Multivariate Cox regression was used to assess the magnitude and direction of each predictor. Among 2,609 patients receiving CAR-T (MM: 683, lymphoma/leukemia: 1,926) and over a median follow-up of 14.5 months, the incidences of SPMs and hematologic SPMs were 11.8% and 5.0%, respectively (0.3% for peripheral T-cell lymphoma). Median time-to-event was approximately 8 months for SPMs and hematologic SPMs. Adjusting for other predictors in the models, there was no association between CAR-T indicated for MM versus lymphoma/leukemia and the risk of SPMs (hazard ratio: 0.85, P = .32). Relative to lymphoma/leukemia, MM was associated with a significantly lower risk of hematologic SPMs (hazard ratio: 0.24, P < .05). This study found no association between CAR-Ts used in MM versus lymphoma/leukemia and the risk of subsequent SPMs, while a lower risk of hematologic SPMs was observed in patients with MM. T-cell malignancies were infrequent. Ongoing research into potential risk factors of SPMs following CAR-T could help inform individualized management strategies.
Phototherapy not only targets tumor cells for destruction but also triggers immunogenic cell death (ICD), thereby activating systemic immunity. Traditional photothermal therapy (PTT), however, damages adjacent normal tissues, and photodynamic therapy (PDT) creates severe hypoxia within tumor tissues, which promotes immune evasion and reduces the effectiveness of immunotherapy. In this study, we developed a biomimetic nanomodulators-cell membrane-coated gambogic acid/indocyanine green micelles loaded with HIF-1α siRNA (CM-IGM/siRNA) to achieve mild photothermal therapy (mPTT), enhance photodynamic therapy (PDT), and modulate the tumor microenvironment (TME). This platform utilizes gambogic acid (GA) to inhibit HSP90 expression and synergizes with HIF-1α siRNA to suppress HIF-1α expression, thereby ameliorating hypoxic and immunosuppressive TME. HSP90 inhibition further reduces tumor cell thermotolerance, enabling effective tumor cell ablation at mild hyperthermia temperatures (42-45 °C) characteristic of mPTT. Furthermore, we found that π-π stacking of GA with indocyanine green (ICG) enhances ICG photostability and boosts reactive oxygen species (ROS) generation. The elevated ROS production significantly improves PDT efficacy and, in combination with mPTT, potentiates the ICD of tumor cells. Overall, this strategy offers a significant advancement in cancer immunotherapy by improving the tumor microenvironment and enhancing immune activation.