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Malignant pleural mesothelioma (MPM) has relatively ineffective first/second-line therapy for advanced disease and only 18% five-year survival for early disease. Drug-induced mitochondrial priming measured by dynamic BH3 profiling identifies efficacious drugs in multiple disease settings. We use high throughput dynamic BH3 profiling (HTDBP) to identify drug combinations that prime primary MPM cells derived from patient tumors, which also prime patient derived xenograft (PDX) models. A navitoclax (BCL-xL/BCL-2/BCL-w antagonist) and AZD8055 (mTORC1/2 inhibitor) combination demonstrates efficacy in vivo in an MPM PDX model, validating HTDBP as an approach to identify efficacious drug combinations. Mechanistic investigation reveals AZD8055 treatment decreases MCL-1 protein levels, increases BIM protein levels, and increases MPM mitochondrial dependence on BCL-xL, which is exploited by navitoclax. Navitoclax treatment increases dependency on MCL-1 and increases BIM protein levels. These findings demonstrate that HTDBP can be used as a functional precision medicine tool to rationally construct combination drug regimens in MPM and other cancers. Malignant pleural mesothelioma (MPM) is an aggressive malignancy with few effective treatment options available. Here, the authors use dynamic BH3 profiling to measure drug-induced mitochondrial priming and identify AZD8055 and navitoclax as a pro-apoptotic drug combination in ex vivo and preclinical MPM models.

Conventional chemotherapy is still of great utility in oncology and rationally constructing combinations with it remains a top priority. Drug-induced mitochondrial apoptotic priming, measured by dynamic BH3 profiling (DBP), has been shown in multiple cancers to identify drugs that promote apoptosis in vivo. We therefore hypothesized that we could use DBP to identify drugs that would render cancers more sensitive to conventional chemotherapy. We found that targeted agents that increased priming of non-small cell lung cancer (NSCLC) tumor cells resulted in increased sensitivity to chemotherapy in vitro. To assess whether targeted agents that increase priming might enhance the efficacy of cytotoxic agents in vivo as well, we carried out an efficacy study in a PC9 xenograft mouse model. The BH3 mimetic navitoclax, which antagonizes BCL-xL, BCL-w, and BCL-2, consistently primed NSCLC tumors in vitro and in vivo. The BH3 mimetic venetoclax, which electively antagonizes BCL-2, did not. Combining navitoclax with etoposide significantly reduced tumor burden compared to either single agent, while adding venetoclax to etoposide had no effect on tumor burden. Next, we assessed priming of primary patient NSCLC tumor cells on drugs from a clinically relevant oncology combination screen (CROCS). Results confirmed for the first time the utility of BCL-xL inhibition by navitoclax in priming primary NSCLC tumor cells and identified combinations that primed further. This is a demonstration of the principle that DBP can be used as a functional precision medicine tool to rationally construct combination drug regimens that include BH3 mimetics in solid tumors like NSCLC.

Large-scale residential developments on expropriated lands in periurban Hanoi resemble forms of gentrification seen elsewhere. But is it gentrification? Current debate over the definition of gentrification has focused on whether the term has become too broad to be useful in different institutional and spatio-temporal contexts. While some push for a generalisable definition based in capitalist development, others argue that the term harbours Western assumptions that fail to usefully explain unique local circumstances. The paper first identifies one such conceptual assumption that must be made explicit since it provides the term’s politicising thrust: displacement generates an experience of social injustice. Then, drawing on surveys and interviews with residents as well as interviews with real estate agents, government officials and academics conducted in Hanoi between 2013 and 2017, the paper evaluates five types of displacement on the city’s outskirts. Because displacement only occurs in marginal cases and generates limited feelings of social injustice, the term ‘gentrification’ is of little use. Instead, the paper suggests that in a context of rapid urbanisation and relatively inclusive economic growth such as that of Hanoi the terms ‘livelihood dispossession’ and ‘value grabbing’ may better capture the experience of social injustice and are therefore more likely to generate political traction. 河内城郊被征用土地上的大型住宅开发类似于我们在别处看到的绅士化形式。但这是绅士化吗？当前关于绅士化定义的争论集中在这个术语是否已经变得过于宽泛，以至于在一些不同的制度和时空背景下不再有用。一些人主张基于资本主义发展模式的放之四海皆准的定义，而另一些人则认为这个术语包含了西方的假设，无法有效地解释独特的地方环境。本文首先确定了一个必须明确的概念假设，因为它提供了该术语的政治化主旨：驱逐产生了一种社会不公正的经历。然后，基于2013年至2017年期间在河内进行的对居民的调查和访谈，以及对房地产中介、政府官员和学者的访谈，本文评估了发生在城市郊区的五种类型的驱逐。由于驱逐只是个别现象，并且，其制造的社会不公正感也是有限的，所以“绅士化”一词没有什么用处。相反，本文指出，在快速城市化和相对包容性经济增长的背景下（比如河内的例子），“生计剥夺”和“价值攫取”之类的术语可能会更好地反映社会不公正经历，因此更有可能产生政治吸引力。

One of the most important challenges researchers and managers confront in conservation ecology is predicting a population’s response to sub-lethal stressors. Such predictions have been particularly elusive when assessing responses of large marine mammals to past anthropogenic pressures. Recently developed techniques involving baleen whale earplugs combine age estimates with cortisol measurements to assess spatial and temporal stress/stressor relationships. Here we show a relationship between baseline-corrected cortisol levels and corresponding whaling counts of fin, humpback, and blue whales in the Northern Hemisphere spanning the 20th century. We also model the impact of alternative demographic and environmental factors and determine that increased anomalies of sea surface temperature over a 46-year mean (1970–2016) were positively associated with cortisol levels. While industrial whaling can deplete populations by direct harvest, our data underscore a widespread stress response in baleen whales that is peripheral to whaling activities or associated with other anthropogenic change. It has recently been found that stress hormones accumulate in the earwax of whales. Here, the authors use these signatures of stress along with time series of ocean warming and whaling pressure to demonstrate that both stressors were correlated with baleen whale stress over several decades.

Delandistrogene moxeparvovec is an rAAVrh74 vector-based gene transfer therapy that delivers a transgene encoding delandistrogene moxeparvovec micro-dystrophin, an engineered, functional form of dystrophin shown to stabilize or slow disease progression in DMD. It is approved in the US and in other select countries. Two serious adverse event cases of immune-mediated myositis (IMM) were reported in the phase Ib ENDEAVOR trial (NCT04626674). We hypothesized that immune responses to the micro-dystrophin transgene product may have mediated these IMM events. An interferon-gamma ELISpot assay was used to detect T cell responses to delandistrogene moxeparvovec micro-dystrophin peptide pools. ELISpot analysis suggested that IMM resulted from T cell-mediated responses directed against specific micro-dystrophin peptides corresponding to exons 8 and 9 (Case 1) and exon 8 (Case 2) of the DMD gene. In silico epitope mapping based on the patients’ HLA-I alleles indicated greater probability for peptides derived from exons 8 and/or 9 to bind HLA-I, providing further evidence that peptides derived from corresponding micro-dystrophin regions may have higher immunogenic potential. Collectively, these data suggest that patients with DMD gene deletions involving exons 8 and/or 9 may be at increased risk of IMM following delandistrogene moxeparvovec micro-dystrophin gene therapy infusion.

We show that the sex of human experimenters affects mouse behaviors and responses following administration of the rapid-acting antidepressant ketamine and its bioactive metabolite (2R,6R)-hydroxynorketamine. Mice showed aversion to the scent of male experimenters, preference for the scent of female experimenters and increased stress susceptibility when handled by male experimenters. This human-male-scent-induced aversion and stress susceptibility was mediated by the activation of corticotropin-releasing factor (CRF) neurons in the entorhinal cortex that project to hippocampal area CA1. Exposure to the scent of male experimenters before ketamine administration activated CA1-projecting entorhinal cortex CRF neurons, and activation of this CRF pathway modulated in vivo and in vitro antidepressant-like effects of ketamine. A better understanding of the specific and quantitative contributions of the sex of human experimenters to study outcomes in rodents may improve replicability between studies and, as we have shown, reveal biological and pharmacological mechanisms.Georgiou et al. found that the sex of the person performing experiments affects mouse behavior, including responses to stress and ketamine. This effect was mediated by corticotropin-releasing factor neurons in the entorhinal cortex that project to CA1.

Mycoplasma ovipneumoniae is a globally distributed pathogen that has been associated with pneumonia in both domestic and wild Caprinae. It is closely related to M. hyopneumoniae, a respiratory pathogen of swine that is associated with decreased growth rates of pigs as well as clinical respiratory disease. In order to assess the effects of M. ovipneumoniae on lamb performance, we generated a cohort of lambs free of M. ovipneumoniae by segregation of test negative ewes after lambing, then compared the growth and carcass quality traits of M. ovipneumoniae-free and -colonized lambs from weaning to harvest. Some signs of respiratory disease were observed during the feeding trial in both lamb groups, but the M. ovipneumoniae-exposed group included more affected lambs and higher average disease scores. At harvest, lungs of lambs in both groups showed few grossly visible lesions, although the M. ovipneumoniae-exposed group did exhibit increased microscopic lung lesions (P<0.05). In addition, M. ovipneumoniae exposed lambs produced lower average daily gains (P<0.05), and lower yield grade carcasses (P<0.05) compared to those of non-exposed lambs. The results demonstrated the feasibility of test and segregation for elimination of M. ovipneumoniae from groups of sheep and suggested that this pathogen may impair lamb growth and productivity even in the absence of overt respiratory disease.

Introduction: Delandistrogene moxeparvovec (SRP-9001) is an investigational gene transfer therapy designed for targeted expression of SRP-9001 dystrophin protein, a shortened dystrophin retaining key functional domains of the wild-type protein. Methods: This Phase 2, double-blind, two-part (48 weeks per part) crossover study (SRP-9001-102 [Study 102]; NCT03769116) evaluated delandistrogene moxeparvovec in patients, aged ≥4 to <8 years with Duchenne muscular dystrophy. Primary endpoints (Part 1) were change from baseline (CFBL) in SRP-9001 dystrophin expression (Week 12), by Western blot, and in North Star Ambulatory Assessment (NSAA) score (Week 48). Safety assessments included treatment-related adverse events (TRAEs). Patients were randomized and stratified by age to placebo (n = 21) or delandistrogene moxeparvovec (n = 20) and crossed over for Part 2. Results: SRP-9001 dystrophin expression was achieved in all patients: mean CFBL to Week 12 was 23.82% and 39.64% normal in Parts 1 and 2, respectively. In Part 1, CFBL to Week 48 in NSAA score (least-squares mean, LSM [standard error]) was +1.7 (0.6) with treatment versus +0.9 (0.6) for placebo; p = 0.37. Disparity in baseline motor function between groups likely confounded these results. In 4- to 5-year-olds with matched baseline motor function, CFBL to Week 48 in NSAA scores was significantly different (+2.5 points; p = 0.0172), but not significantly different in 6-to-7-year-olds with imbalanced baseline motor function (−0.7 points; p = 0.5384). For patients treated with delandistrogene moxeparvovec in Part 2, CFBL to Week 48 in NSAA score was +1.3 (2.7), whereas for those treated in Part 1, NSAA scores were maintained. As all patients in Part 2 were exposed to treatment, results were compared with a propensity-score-weighted external control (EC) cohort. The LSM difference in NSAA score between the Part 2 treated group and EC cohort was statistically significant (+2.0 points; p = 0.0009). The most common TRAEs were vomiting, decreased appetite, and nausea. Most occurred within the first 90 days and all resolved. Discussion: Results indicate robust expression of SRP-9001 dystrophin and overall stabilization in NSAA up to 2 years post-treatment. Differences in NSAA between groups in Part 1 were not significant for the overall population, likely because cohorts were stratified only by age, and other critical prognostic factors were not well matched at baseline.

Background Rhinovirus (RV) is one of the most common etiologic agents of acute respiratory infection (ARI), which is a leading cause of morbidity and mortality in young children. The clinical significance of RV co-detection with other respiratory viruses, including respiratory syncytial virus (RSV), remains unclear. We aimed to compare the clinical characteristics and outcomes of children with ARI-associated RV-only detection and those with RV co-detection—with an emphasis on RV/RSV co-detection. Methods We conducted a prospective viral surveillance study (11/2015–7/2016) in Nashville, Tennessee. Children < 18 years old who presented to the emergency department (ED) or were hospitalized with fever and/or respiratory symptoms of < 14 days duration were eligible if they resided in one of nine counties in Middle Tennessee. Demographics and clinical characteristics were collected by parental interviews and medical chart abstractions. Nasal and/or throat specimens were collected and tested for RV, RSV, metapneumovirus, adenovirus, parainfluenza 1–4, and influenza A–C using reverse transcription quantitative polymerase chain reaction assays. We compared the clinical characteristics and outcomes of children with RV-only detection and those with RV co-detection using Pearson’s χ 2 test for categorical variables and the two-sample t -test with unequal variances for continuous variables. Results Of 1250 children, 904 (72.3%) were virus-positive. RV was the most common virus ( n  = 406; 44.9%), followed by RSV ( n  = 207; 19.3%). Of 406 children with RV, 289 (71.2%) had RV-only detection, and 117 (28.8%) had RV co-detection. The most common virus co-detected with RV was RSV ( n  = 43; 36.8%). Children with RV co-detection were less likely than those with RV-only detection to be diagnosed with asthma or reactive airway disease both in the ED and in-hospital. We did not identify differences in hospitalization, intensive care unit admission, supplemental oxygen use, or length of stay between children with RV-only detection and those with RV co-detection. Conclusion We found no evidence that RV co-detection was associated with poorer outcomes. However, the clinical significance of RV co-detection is heterogeneous and varies by virus pair and age group. Future studies of RV co-detection should incorporate analyses of RV/non-RV pairs and include age as a key covariate of RV contribution to clinical manifestations and infection outcomes.

The purpose of this study was to engage high school science teachers as co-design partners in refining and extending instructional frameworks to support multiple-document reading and writing in science classrooms. Using a participatory mixed-methods design, the project adapted the InSPECT framework for secondary science, developed professional development (PD) materials to introduce the framework, and explored the role of generative artificial intelligence (AI) in lesson planning. Five virtual focus group sessions guided the co-design of PD activities, followed by a pilot implementation in one biology classroom. Data included focus group and interview transcripts, surveys, and student work artifacts. Analyses examined teachers’ perceptions of PD features, framework usability, and student engagement. Teachers valued PD that was practical, relevant, and feasible within classroom constraints and described the frameworks as clear, stepwise structures that supported lesson design and literacy integration. Student work showed that paraphrasing was an accessible entry point, while bridging, elaboration, and source evaluation required additional modeling. Teachers viewed generative AI as a promising planning aid but expressed concerns about accuracy and ethics. Findings informed revisions emphasizing discipline-specific exemplars, scaffolds for higher-order strategies, and AI-literacy modules, illustrating how participatory design can yield feasible, teacher-centered PD.