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This study presents the effect of gamma rays of up to 2000 kGy on the chemical structure and the physical properties of a poly(butylene adipate-co-terephthalate) (PBAT) with 48% mol of terephthalic units. PBAT is a polymer with properties similar to polyethylene (PE) but it is biodegradable and not toxic to the environment, and it can be prepared with a renewable content of up to 68.6% weight, with uses in biomedicine and packaging. Previous studies found in the literature have been conducted using low doses and the results were contradictory. The results for gel content and crosslinking efficiency were in agreement with the results found in the literature. Molecular weight decreased and widened with the increase in dose. Proton NMR analysis was used for the first time in PBAT to determine the changes in chemical species, the formation of new chemical species, and the bonds more susceptible to be broken by gamma rays. Both thermal and mechanical properties were explained by the scission of the chains in the amorphous phase and at the boundaries of the crystallites. The thermal parameters most affected by irradiation were the crystallization temperature and temperature of melting after cooling from the melt. Stress and strain at break suffered a continuous decrease with dose until PBAT became fragile at high dose.

Gene amplification drives oncogenesis in a broad spectrum of cancers. A number of drugs have been developed to inhibit the protein products of amplified driver genes, but their clinical efficacy is often hampered by drug resistance. Here, we introduce a therapeutic strategy for targeting cancer-associated gene amplifications by activating the DNA damage response with triplex-forming oligonucleotides (TFOs), which drive the induction of apoptosis in tumors, whereas cells without amplifications process lower levels of DNA damage. Focusing on cancers driven by HER2 amplification, we find that TFOs targeting HER2 induce copy number-dependent DNA double-strand breaks (DSBs) and activate p53-independent apoptosis in HER2-positive cancer cells and human tumor xenografts via a mechanism that is independent of HER2 cellular function. This strategy has demonstrated in vivo efficacy comparable to that of current precision medicines and provided a feasible alternative to combat drug resistance in HER2-positive breast and ovarian cancer models. These findings offer a general strategy for targeting tumors with amplified genomic loci. Amplified loci in cancer genomes are directly targeted with triplex-forming oligonucleotides.

Perinatal asphyxia is caused by lack of oxygen delivery (hypoxia) to end organs due to an hypoxemic or ischemic insult occurring in temporal proximity to labor (peripartum) or delivery (intrapartum). Hypoxic–ischemic encephalopathy is the clinical manifestation of hypoxic injury to the brain and is usually graded as mild, moderate, or severe. The search for useful biomarkers to precisely predict the severity of lesions in perinatal asphyxia and hypoxic–ischemic encephalopathy (HIE) is a field of increasing interest. As pathophysiology is not fully comprehended, the gold standard for treatment remains an active area of research. Hypothermia has proven to be an effective neuroprotective strategy and has been implemented in clinical routine. Current studies are exploring various add-on therapies, including erythropoietin, xenon, topiramate, melatonin, and stem cells. This review aims to perform an updated integration of the pathophysiological processes after perinatal asphyxia in humans and animal models to allow us to answer some questions and provide an interim update on progress in this field.

Several human-associated microbial communities exist in multiple configurations and can change their composition in response to perturbations, remaining in an altered state even after the perturbation ends. Multistability has been previously proposed to explain this behavior for gut microbiota in particular, but has not been clearly demonstrated experimentally. Here, we first investigate the life history strategies of three common human gut bacteria to identify mechanisms driving alternative states. We then use this data to build and parameterize a kinetic model, which predicts that alternative states emerge due to phenotype switching between subpopulations of the same species. Perturbation experiments support these predictions, and confirm the existence of alternative states. Finally, simulations show that phenotype switching can also explain alternative states in larger communities. Thus, a transient perturbation combined with metabolic flexibility is sufficient for alternative communities to emerge. In this study, the authors use a combination of experimental and modeling approaches to show that a human gut bacterial community can exist in different states under the same conditions. The mechanism behind these alternative states is likely based on metabolic change in response to nutrient depletion.

This study examines how rural Latinx students from California’s San Joaquin Valley make sense of and navigate access to four-year universities within a geographically and institutionally constrained college-going landscape. While prior research on Latinx college access has largely centered on urban contexts, this article highlights how race and rural place shape the availability and quality of information about four-year universities as experienced and interpreted by rural Latinx students. Guided by the nepantla stage of the college-conocimiento framework and using Chicana/Latina feminist pláticas as methodology, narratives from rural Latinx undergraduates who reflected on their high school advising and recruitment experiences were analyzed. Findings show that students perceived that counselors used labor expectations to position agricultural and low-wage work as presumed futures for students, even as they pursued four-year enrollment amid uneven institutional support. Students also reflected that four-year pathways were also less accessible through routinized counseling practices that standardized two-year enrollment and framed four-year options as less feasible. Students further described limited outreach from four-year institutions, which widened information gaps and placed the burden of navigating college on students and families. Implications emphasize the need for more equitable counseling practices and accessible outreach strategies that expand four-year information and support in rural regions.

Microbiomes never stop changing. Their compositions and functions are shaped by the complex interplay of intrinsic and extrinsic drivers, such as growth and migration rates, species interactions, available nutrients and environmental conditions. Mathematical models help us make sense of these complex drivers and intuitively explain how, why and when specific microbiome states are reached while others are not. To make simulations of microbiome dynamics intuitive and accessible, we present miaSim. miaSim provides users with a wide range of possibilities to match their specific assumptions and scenarios, starting from a core implementation of four widely used models (namely the stochastic logistic model, MacArthur's consumer‐resource model, Hubbell's neutral model and the generalized Lotka‐Volterra model) and several of their derivations. The diverse model implementations share the same data structures and, whenever possible, share state variables, which significantly facilitates cross‐model combinations and comparisons. We combined and simulated some published examples of microbiome models in miaSim and performed cross‐model comparisons and tested diverse model assumptions. Our examples illustrate the reliability, robustness and user‐friendliness of the package. In addition, miaSim is accompanied by miaSimShiny, which allows users to explore the parameter space of their models in real‐time in an intuitive graphical interface. miaSim is fully compatible with the ‘miaverse’, an R/Bioconductor framework for microbiome data science, allowing users to combine and compare model simulations with microbiome datasets. The stable version of miaSim is available through Bioconductor 3.15, and the version for future development is available at https://github.com/microbiome/miaSim. miaSimShiny is available at https://github.com/gaoyu19920914/miaSimShiny. We anticipate that miaSim will significantly facilitate the task of simulating microbiome dynamics, highlighting the role of ecological simulations as important tools in microbiome data science. 摘要 微生物组持续变动，它们的组成和功能同时受到内部和外部的复杂影响，如生长、迁移速率、种间交互关系、可用营养物质及环境条件。数学模型可以帮助我们理解这些复杂的驱动因子，并直观地解释微生物群如何、为何、何时达到特定状态而非其他状态。为了让微生物生态模拟更加直观好用，我们在此介绍 miaSim。 miaSim 为用户的不同假设和场景提供了诸多模型，最初版有四个被广泛应用的模型(包括随机逻辑斯蒂模型、消费者‐资源模型、Hubbell 的中性模型、及广义 Lotka‐Volterra 种间关系模型)及它们的变体。不同模型拥有同样的数据结构，尽可能地保持状态变量的一致，极大地简化了模型之间的结合和对比。 我们利用 miaSim 进行了跨模型对比，结合并模拟了一些已发表的微生物群落模型案例，测试了不同的模型假说。这些例子验证了此程序包的可靠性、稳定性和用户友好性。另外，程序包 miaSimShiny 为 miaSim 提供了实时呈现参数和模拟结果的图形用户界面。miaSim 与 R/Bioconductor 的微生物数据科学框架 miaverse 完全兼容，允许用户将模型模拟结果与微生物组数据集组合与对比。miaSim 稳定版可通过 Bioconductor 3.15 获取，面向未来的开发版可在 https://github.com/microbiome/miaSim 获取。miaSimShiny 可在https://github.com/gaoyu19920914/miaSimShiny 获取。 我们希望 miaSim 能够简化和促进微生物动态变化的模拟，并强调生态学模型模拟作为微生物研究工具的重要意义。

Rural students face multiple issues pursuing higher education, including financial hardships, inadequate college preparation, and geographic isolation from postsecondary institutions. These issues are further complicated for rural Latinx students, especially those from immigrant farm working backgrounds, who are positioned at the intersection of multiple systems of oppression. Yet, rural Latinx students’ college choice and transition experiences are rarely centered in the higher education literature. This article examined the college choices of nine rural Latinx high school seniors from California’s San Joaquin Valley who chose to attend a public higher education institution in this agricultural region. This article drew on three indicators from the culturally engaging campus environments (CECE) model and employed a Chicana/Latina feminist pláticas methodology to analyze the campus elements that motivated rural Latinx students to enroll in public institutions in the San Joaquin Valley. Findings demonstrate that rural Latinx students purposely chose these institutions because they imagined that such institutions would (a) be racially and spatially familiar, (b) allow them to give back to their rural communities through relevant majors, and (c) offer tight-knit collegiate environments. Recommendations for higher education researchers and practitioners interested in increasing college success for rural Latinx students and expanding traditional definitions of rural-serving institutions (RSIs) are provided.

Reinforced concrete buildings with masonry-induced soft-storey irregularities exhibit extreme seismic vulnerability, a critical risk often underestimated by conventional code-based design. Standard equivalent static methods typically fail to capture the intense concentration of seismic demand at the flexible ground level, leading to unconservative designs that do not meet performance objectives. This research proposes a corrective linear–static methodology to address this deficiency. A new Equivalent Lateral Force profile (ELFi1) was developed, derived from modal analyses of 235 representative soft-storey archetypes to accurately account for stiffness heterogeneity. This profile was integrated with a realistic response modification coefficient (Ri1 = 5.04), determined to be 37% lower than the normative R-factor (R = 8) prescribed by code. Nonlinear static analyses confirmed that conventional design resulted in “irreparable” damage (mean Global Damage Index = 0.82). In contrast, redesigning the structure using the proposed ELFi1 and Ri1 methodology successfully mitigated damage concentration, upgrading structural performance to a “repairable” state (mean Global Damage Index = 0.52). Finally, Incremental Dynamic Analysis validated the approach; the redesigned structure satisfied FEMA P695 collapse prevention criteria, achieving an Adjusted Collapse Margin Ratio (ACMR) of 2.10. This study confirms the proposed method is a robust and practical design alternative for soft-storey mechanisms within a simplified linear framework.

The probiotic yeast Saccharomyces boulardii has been shown to ameliorate disease severity in the context of many infectious and inflammatory conditions. However, use of S. boulardii as a prophylactic agent or therapeutic delivery vector would require delivery of S. boulardii to a healthy, uninflamed intestine. In contrast to inflamed mucosal tissue, the diverse microbiota, intact epithelial barrier, and fewer inflammatory immune cells within the healthy intestine may all limit the degree to which S. boulardii contacts and influences the host mucosal immune system. Understanding the nature of these interactions is crucial for application of S. boulardii as a prophylactic agent or therapeutic delivery vehicle. In this study, we explore both intrinsic and immunomodulatory properties of S. boulardii in the healthy mucosal immune system. Genomic sequencing and morphological analysis of S. boulardii reveals changes in cell wall components compared to non-probiotic S. cerevisiae that may partially account for probiotic functions of S. boulardii. Flow cytometry and immunohistochemistry demonstrate limited S. boulardii association with murine Peyer's patches. We also show that although S. boulardii induces a systemic humoral immune response, this response is small in magnitude and not directed against S. boulardii itself. RNA-seq of the draining mesenteric lymph nodes indicates that even repeated administration of S. boulardii induces few transcriptional changes in the healthy intestine. Together these data strongly suggest that interaction between S. boulardii and the mucosal immune system in the healthy intestine is limited, with important implications for future work examining S. boulardii as a prophylactic agent and therapeutic delivery vehicle.

Many natural prion diseases of humans and animals are considered to be acquired through oral consumption of contaminated food or pasture. Determining the route by which prions establish host infection will identify the important factors that influence oral prion disease susceptibility and to which intervention strategies can be developed. After exposure, the early accumulation and replication of prions within small intestinal Peyer's patches is essential for the efficient spread of disease to the brain. To replicate within Peyer's patches, the prions must first cross the gut epithelium. M cells are specialised epithelial cells within the epithelia covering Peyer's patches that transcytose particulate antigens and microorganisms. M cell-development is dependent upon RANKL-RANK-signalling, and mice in which RANK is deleted only in the gut epithelium completely lack M cells. In the specific absence of M cells in these mice, the accumulation of prions within Peyer's patches and the spread of disease to the brain was blocked, demonstrating a critical role for M cells in the initial transfer of prions across the gut epithelium in order to establish host infection. Since pathogens, inflammatory stimuli and aging can modify M cell-density in the gut, these factors may also influence oral prion disease susceptibility. Mice were therefore treated with RANKL to enhance M cell density in the gut. We show that prion uptake from the gut lumen was enhanced in RANKL-treated mice, resulting in shortened survival times and increased disease susceptibility, equivalent to a 10-fold higher infectious titre of prions. Together these data demonstrate that M cells are the critical gatekeepers of oral prion infection, whose density in the gut epithelium directly limits or enhances disease susceptibility. Our data suggest that factors which alter M cell-density in the gut epithelium may be important risk factors which influence host susceptibility to orally acquired prion diseases.