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Large-scale combination screens reveal small-molecule sensitization of antibiotic-resistant gram-negative ESKAPE pathogens

Antibiotic resistance, especially in multidrug-resistant ESKAPE pathogens, remains a worldwide problem. Combination antimicrobial therapies may be an important strategy to overcome resistance and broaden the spectrum of existing antibiotics. However, this strategy is limited by the ability to efficiently screen large combinatorial chemical spaces. Here, we deployed a high-throughput combinatorial screening platform, DropArray, to evaluate the interactions of over 30,000 compounds with up to 22 antibiotics and 6 strains of gram-negative ESKAPE pathogens, totaling to over 1.3 million unique strain-antibiotic-compound combinations. In this dataset, compounds more frequently exhibited synergy with known antibiotics than single-agent activity. We identified a compound, P2-56, and developed a more potent analog, P2-56-3, which potentiated rifampin (RIF) against antibiotic-resistant strains of Acinetobacter baumannii and Klebsiella pneumoniae . Using phenotypic assays, we showed P2-56-3 disrupts the outer membrane of A. baumannii . To identify pathways involved in the mechanism of synergy between P2-56-3 and RIF, we performed genetic screens in A. baumannii . CRISPRi-induced partial depletion of lipooligosaccharide transport genes ( lptA - D , lptFG ) resulted in hypersensitivity to P2-56-3/RIF treatment, demonstrating the genetic dependency of P2-56-3 activity and RIF sensitization on lpt genes in A. baumannii. Consistent with outer membrane homeostasis being an important determinant of P2-56-3/RIF tolerance, knockout of maintenance of lipid asymmetry complex genes and overexpression of certain resistance-nodulation-division efflux pumps—a phenotype associated with multidrug-resistance—resulted in hypersensitivity to P2-56-3. These findings demonstrate the immense scale of phenotypic antibiotic combination screens using DropArray and the potential for such approaches to discover new small molecule synergies against multidrug-resistant ESKAPE strains.

Assessing the usability of Accessercise to increase physical activity in adults with physical disabilities: A qualitative think-aloud study

Background Mobile health (mHealth) applications (apps) offer a convenient way to increase physical activity to people with disabilities. While several mHealth apps have been developed for this population, there is limited evidence assessing app usability and how this might impact physical activity. Objective To investigate the usability of a novel mHealth app, Accessercise, that aims to increase physical activity in people with physical disabilities. Methods Twelve adults with different physical disabilities participated in a face-to-face think-aloud interview. Interviews were analysed using deductive content analysis based on the User Version of the Mobile Application Rating Scale (uMARS). Findings Data mapped onto 12 uMARS domains; most participants expressed positive views concerning Accessercise, namely, entertainment, customisation, tailoring to the target group, ease of use and navigation, and visual information. Some additional elements were viewed positively but required modification to improve usability, perceived credibility, and relevance, including the app’s layout, visual appeal, interactivity, and quality/quantity of information. Conclusion This study provides an example of how the think-aloud method can be employed to evaluate mHealth apps that aims to increase physical activity in people with physical disabilities. Therefore, developers and researchers could use this study to inform future usability evaluations in this area.

Structural design and optimization of egg carrier for dynamic egg slit detection platforms

This paper presents an improved egg carrier for supporting common types of eggs during an egg slit inspection platform opeations. The carrier conveys the eggs forwards to the inspection position. The egg carrier consists of three basic modules and has the advantages of adaptability, adjustability, low maintenance and manufacturing costs, and stable and efficient operation. First, the egg carrier functions are analysed, and preliminary design concepts and solutions are proposed via TRIZ theory. Second, the egg carrier structure is designed, the material properties are analysed, and key parameters such as deformation are simulated by SolidWorks and Ansys Workbench. Finite element and fatigue analyses are carried out for the key parameters of the structure, and deformation, fatigue and other data that appear in the actual operation process are obtained. On the basis of stable egg carrying, a carrying motion mathematical model is established, and the genetic algorithm (GA) is chosen to optimize the structural parameters. Finally, motion simulation is carried out for the improved egg carrier, which verifies the optimized structure reasonableness.

Social control drove ant evolution

The cross-sectional association between state-level public health funding per capita and physical health among adults in the United States

Objectives This study examined the association between state-level public health funding per capita and the odds of poor physical health. Study design Cross-sectional. Methods Data from the 2018 Behavioral Risk Factor Surveillance System (BRFSS) were used. Participants’ self-reported physical health was reported using the CDC Healthy Days Core Module. State-level public health funding per capita was obtained from the State Health Access Data Assistance Center website. Multilevel logistic regression was used to adjust for self-reported individual-level characteristics and state-level characteristics from the 2018 American Community Survey. We also tested whether household income or education attainment moderated any observed associations. Results A one SD increase in state-level public health funding per capita was not associated with the odds ≥  14 days of poor physical health (OR = 0.96, 95% CI: 0.90, 1.01). However, heterogeneity across household income was observed. Greater public health funding per capita was associated with lower predicted probabilities of reporting ≥  14 days of poor physical health among respondents from low household income backgrounds ( <$35,000 USD) compared to participants with high household incomes (>$75,000 USD). No associations were observed among those with moderate ($35,000 – $70,000 USD) household incomes. A similar finding was observed among participants with less than high school education when compared to participants with post-secondary education. Conclusion Greater state-level public health funding per capita appears to have a protective association against reporting ≥  14 days of poor physical health in individuals with lower household incomes and may be helpful in reducing health inequities. Future research is needed to determine whether this association is causal.

The FBXW7–KMT2 axis in cancer-associated fibroblasts controls tumor growth via an epigenetic-paracrine mechanism

F-box and WD repeat domain-containing 7 (FBXW7) is a tumor suppressor that targets various oncoproteins for degradation, but its role in modulating cancer-associated fibroblasts (CAFs) in the tumor microenvironment remains elusive. Here, we report that FBXW7 expression is gradually downregulated in CAFs during the progression of human pancreatic and lung cancers. Mechanically, FBXW7 inhibits histone lysine methyltransferase 2 (KMT2) methyltransferase activity via retinoblastoma binding protein 5 (RbBP5) binding, whereas FBXW7 depletion abrogates the binding to activate KMT2, leading to increased H3K4 methylations and global upregulation of gene expression. Activation of the interleukin-17 (IL-17) signaling pathway triggers the secretion of cytokines and chemokines to promote migration, invasion, and sphere formation of lung cancer cells. Coinjection of Fbxw7-depleted mouse embryonic fibroblasts with cancer cells enhances in vivo tumor growth, demonstrating a paracrine effect. Hypoxia downregulates CAF FBXW7 via ETS proto-oncogene 1 (ETS1) to increase H3K4 methylation, whereas conditioned media from hypoxia-exposed CAFs promotes migration and invasion of pancreatic cancer cells, highlighting FBXW7’s tumor-suppressing role through KMT2 inactivation.

Correction: Bruxism repercussions in muscular activation: Ultrasound differences in abdominal wall between women with and without bruxism: A cross-sectional study

Using net-zero carbon debt to track climate overshoot responsibility

Current emissions trends will likely deplete a 1.5 °C consistent carbon budget around the year 2030, resulting in at least a temporary exceedance, or overshoot. To clarify responsibilities for this budget exceedance, we consider “net-zero carbon debt,” a forward-looking measure of the extent to which a party is expected to breach its “fair share” of the remaining budget by the time it achieves net-zero carbon emissions. We apply this measure to all vetted mitigation scenarios assessed in the Intergovernmental Panel on Climate Change’s Sixth Assessment Report and two scenarios that model current policies and pledges, using an illustrative equal per capita allocation of a remaining 1.5 °C carbon budget starting in 1990. The resulting regional carbon debt estimates inform i) the scale and pace of regional carbon drawdown obligations necessary to address budget exceedance and ii) relative regional responsibilities for increased lifetime exposure to extreme heatwaves across age cohorts due to budget exceedance. Our work strengthens intergenerational equity considerations within an international climate equity discourse and informs the implementation of effort-sharing mechanisms that persist beyond the exhaustion of a rapidly dwindling remaining carbon budget.

Psychometric properties of the Bangla version of the sense of coherence scale among university students in Bangladesh

Introduction Sense of coherence is a key concept in psychological science that contributes to mental health by helping people cope with various stressors in their daily lives. A literature review demonstrated the unavailability of a tool for measuring sense of coherence in Bangladesh. This study aimed to translate the 13-item Sense of Coherence scale (SOC-13) into the Bangla language and to examine its validity, dimensionality, and reliability. Method After translating the SOC-13, a cross-sectional online survey was conducted with 510 undergraduate students at a university in Bangladesh from July to October 2021. Construct validity was assessed through confirmatory factor analysis to analyze the structural validity of the Bangla SOC-13 scale, and by examining correlations with related constructs (self-esteem, well-being, and psychological distress). The alpha coefficient was calculated to examine internal consistency. Data were analyzed using SPSS version 22 and R statistical software. Results A total of 320 respondents provided valid responses (response rate: 62.7%). The structural validity of the SOC-13, as examined through confirmatory factor analysis, was consistent across studies (a three-factor structure with an acceptable fit), and convergent validity was evidenced through a statistically significant positive relationships between sense of coherence and both self-esteem and well-being, as well as criterion validity was supported by a significant negative relationship with psychological distress. The internal consistency of the total scores by the coefficient alpha was good (α =  0.74), whereas the alphas of each subscale showed mediocre to fair reliability. Conclusion The Bangla version of the SOC-13 showed good construct validity, acceptable criterion validity, and good reliability based on overall internal consistency. Thus, it can be used to assess sense of coherence in young adults, although there is scope for further examination.

Genomic analysis of 11,555 probands identifies 60 dominant congenital heart disease genes

Congenital heart disease (CHD) is a leading cause of infant mortality. We analyzed de novo mutations (DNMs) and very rare transmitted/unphased damaging variants in 248 prespecified genes in 11,555 CHD probands. The results identified 60 genes with a significant burden of heterozygous damaging variants. Variants in these genes accounted for CHD in 10.1% of probands with similar contributions from de novo and transmitted variants in parent–offspring trios that showed incomplete penetrance. DNMs in these genes accounted for 58% of the signal from DNMs. Thirty-three genes were linked to a single CHD subtype while 12 genes were associated with 2 to 4 subtypes. Seven genes were only associated with isolated CHD, while 37 were associated with 1 or more extracardiac abnormalities. Genes selectively expressed in the cardiomyocyte lineage were associated with isolated CHD, while those widely expressed in the brain were also associated with neurodevelopmental delay (NDD). Missense variants introducing or removing cysteines in epidermal growth factor (EGF)-like domains of NOTCH1 were enriched in tetralogy of Fallot and conotruncal defects, unlike the broader CHD spectrum seen with loss of function variants. Transmitted damaging missense variants in MYH6 were enriched in multiple CHD phenotypes and account for ~1% of all probands. Probands with characteristic mutations causing syndromic CHD were frequently not diagnosed clinically, often due to missing cardinal phenotypes. CHD genes that were positively or negatively associated with development of NDD suggest clinical value of genetic testing. These findings expand the understanding of CHD genetics and support the use of molecular diagnostics in CHD.

Risk factors for postoperative delirium in patients undergoing orthopedic procedures: a systematic review and meta-analysis

Delirium is a common complication in surgical patients following operative procedures; it often occurs in patients undergoing lower-extremity surgery. It is essential to identify and prevent the risk factors for postoperative delirium (POD) in these cases. We aimed to determine the risk factors for POD in patients who underwent lower-extremity surgery through a systematic review and meta-analysis. We included observational studies identifying risk factors for POD in patients undergoing orthopedic surgery. Data sources included the Cumulative Index to Nursing and Allied Health Literature and MEDLINE. We extracted the variables related to delirium that were analyzed by two or more studies meeting the eligibility criteria. A random-effects model was used to calculate the pooled odds ratio, standardized mean difference, and 95% confidence interval. Data were considered significant when p <  0.05. Twenty-seven studies with a total sample size of 9,044 were evaluated. Our meta-analysis revealed 20 risk factors for patients with POD undergoing orthopedic surgery, including age, cognitive scores, various preoperative laboratory values (such as serum albumin, C-reactive protein, and thyroid hormones), length of hospital stay, surgery and anesthesia duration, blood transfusion, and previous health conditions such as dementia and cardiovascular disease. Gathering preoperative and postoperative data was crucial for identifying high-risk patients for POD. In addition, preventive measures targeting POD risk factors could reduce its occurrence after orthopedic surgery.

Nanosilica supplementation in tomato increases oviposition on stems and caterpillar mortality in the tomato pinworm

Silicon-induced responses play a key role in plant defense against herbivory, though the underlying mechanisms remain underexplored. In this study, we examined how mesoporous silica nanoparticles (MSNs) affect tomato ( Solanum lycopersicum ) defense against an invasive and highly destructive lepidopteran herbivore, the tomato pinworm (TPW), Phthorimaea absoluta . In tomato plants supplemented with MSN, prior exposure to TPW oviposition shifted subsequent egg-laying from a preference for leaves to an even distribution between stems and leaves. This shift was not observed in nonsilicon-supplemented plants. Prolonged oviposition triggered pigmentation in the basal cells of type I glandular trichomes on the stems of silicon-supplemented plants. Chemical analysis by coupled gas chromatography-mass spectrometry revealed that the pigmented trichome was rich in soluble sugars (sucrose and l -arabinose) and waxes, dominated by the saturated hydrocarbon tetracosane. Bioassays with the crude extract of the pigmented trichome and a three-component sugar–wax blend replicated the oviposition and caterpillar response observed with the pigmented trichome, while individual components produced variable effects. While l -arabinose alone replicated the oviposition effects of the three-component sugar–wax blend, sucrose increased oviposition and caterpillar feeding and survival, while l -arabinose and tetracosane caused the highest caterpillar mortality. Additionally, these treatments altered caterpillar gut microbiota composition and influenced frass volatiles, which attracted the TPW natural enemies, Nesidiocoris tenuis (predator) and Neochrysocharis formosa (parasitoid). Our findings suggest that silicon supplementation increases tomato defense against TPW through oviposition-induced responses, which promotes recruitment of natural enemies.

Inflammatory and neutrophil extracellular trap markers to predict cardiac events after ST-segment elevation myocardial infarction

Background and aims Inflammation plays a pivotal role in the pathophysiology of ST-elevation myocardial infarction (STEMI). This involves neutrophil activation and the local release of pro-inflammatory mediators. The formation of neutrophil extracellular traps (NETs) in coronary thrombosis has been linked to poor short-term prognosis following STEMI, but the usefulness of specific circulating NET components as prognostic markers is unclear. We aimed to evaluate the NET-specific marker nucleosomal citrullinated histone H3 (H3Cit-DNA) and other classical inflammatory markers to predict adverse events after STEMI. Methods This is a single-center retrospective cohort study of patients with STEMI undergoing primary percutaneous coronary intervention (PCI) from 2015 to 2019. We analyzed the association between serum H3Cit-DNA levels, double-stranded DNA, and classical inflammatory markers –such us interleukin (IL) 6 and 1β, TNF-α, and C-reactive protein (CRP)– on admission and the occurrence of major cardiovascular events (MACE), including death, reinfarction, urgent revascularization, or heart failure, after STEMI. Results A total of 487 patients were studied, of which 380 were men [78%]; mean [SD] age of patients was 63 [13] years, and median [95%CI] follow-up was 5.4 [5.2-5.5] years. Median [IQR] H3Cit level was 179.30 [105.30-281.47] ng/ml. No relevant association was found between H3Cit-DNA levels and 30-day mortality (OR, 1.03 [95%CI, 0.71-1.50], p = 0.861) or MACE (0.98 [0.72-1.32], p = 0.879), Killip class (0.95 [0.74-1.21], p = 0.664), or left ventricular ejection fraction (ref.cat. > 50%; < 35%, RRR 1.01 [95%CI, 0.74-1.38], p = 0.952; 35-50%, 1.26 [1.07-1.48], p = 0.005]. Adding CRP and IL-6 levels as covariates to a model based on classical risk factors significantly improved the prediction of MACE at 30 days after STEMI (IDI 0.13; NRI 0.32, p < 0.05). Conclusions Circulating levels of the NET marker H3Cit-DNA at the time of primary PCI were not predictive of cardiovascular events following STEMI. In contrast, the classical inflammatory markers CRP and interleukin-6 significantly enhanced the discriminative capacity of a clinical 30-day risk prediction model. These findings suggest that measuring circulating NET-specific markers may have limited utility in assessing the inflammatory state during the early stages of STEMI.

Central TYK2 inhibition identifies TYK2 as a key neuroimmune modulator

GWAS have identified tyrosine kinase 2 (TYK2) variants in multiple inflammatory disorders, specifically a protective hypomorphic TYK2 allele (P1104A) in multiple sclerosis (MS). Impaired TYK2 signaling within the central nervous system (CNS) may impart the protective effects of TYK2 P1104A allele in MS. We deployed brain-penetrant TYK2 inhibitors (cTYK2i) alongside the peripherally restricted TYK2 inhibitor (pTYK2i; BMS-986165) to untangle the contributions of central TYK2 inhibition in diverse models of neuroinflammation. While pTYK2i had little impact, cTYK2i reduced clinical score, lymphoid cell infiltration, and cytokines/chemokines in experimental autoimmune encephalomyelitis (EAE). Microglial activation was attenuated in cTYK2i-treated EAE spinal cords and circulating neurofilament light (NfL) was reduced in plasma and cerebral spinal fluid (CSF). Additionally, cTYK2i was protective in an antibody-mediated mouse model of primary progressive MS (PPMS). Finally, we demonstrate TYK2 inhibition has a robust impact on a unique subset of activated astrocytes termed Interferon-Responsive-Reactive-Astrocytes (IRRA). The data presented herein identify a key role for CNS TYK2 signaling in regulating neuroinflammation and solidify TYK2 as a potential therapeutic target for MS.

Striking the balance: Complexity, simplicity, and credibility in mathematical biology

Climate change amplifies neurotoxic methylmercury threat to Asian fish consumers

Climate change is intricately influencing the accumulation of neurotoxic methylmercury (MeHg) in human food webs, potentially leading to uneven exposure risks across regions. Here, we reveal that climate change will elevate MeHg risks in China, with implications for regional inequalities in Asia through a climate-mercury-food-health nexus. Using a compiled fish mercury dataset from 13,000 samples and machine learning, we find that freshwater wild fish—an essential component of the Asian diet—is an underappreciated MeHg source. Specifically, MeHg concentrations in freshwater wild fish are 2.9 to 6.2 times higher than in freshwater farmed fish and 1.7 times higher than in marine wild fish. Individual climate factors influence MeHg accumulation differently, while their combined effects significantly increase MeHg concentrations in freshwater wild fish. Under SSP2–4.5 and SSP5–8.5 by 2031 to 2060, national average MeHg concentrations in freshwater wild fish are projected to increase by about 60%, adding a maximum annual economic loss of US$18 million (2022 USD) from intelligence quotient decrements in Chinese newborns. This loss may vary regionally within China and among Asian countries, disproportionately affecting less developed areas. Coordinating climate action with mercury emission reduction strategies could mitigate these overlooked regional risks, reduce regional inequalities in food safety, and ultimately contribute to sustainable development.

A national megastudy shows that email nudges to elementary school teachers boost student math achievement, particularly when personalized

In response to the alarming recent decline in US math achievement, we conducted a national megastudy in which 140,461 elementary school teachers who collectively taught 2,992,027 students were randomly assigned to receive a variety of behaviorally informed email nudges aimed at improving students’ progress in math. Specifically, we partnered with the nonprofit educational platform Zearn Math to compare the impact of 15 different interventions with a reminder-only megastudy control condition. All 16 conditions entailed weekly emails delivered to teachers over 4-wk in the fall of 2021. The best-performing intervention, which encouraged teachers to log into Zearn Math for an updated report on how their students were doing that week, produced a 5.06% increase in students’ math progress (3.30% after accounting for the winner’s curse). In exploratory analyses, teachers who received any behaviorally informed email nudge (vs. a reminder-only megastudy control) saw their students’ math progress boosted by an average of 1.89% during the 4-wk intervention period; emails referencing personalized data (i.e., classroom-specific statistics) outperformed emails that did not by 2.26%. While small in size, these intervention effects were consistent across school socioeconomic status and school type (public, private, etc.) and, further, persisted in the 8-wk post-intervention period. Collectively, these findings underscore both how difficult it is to change behavior and the need for large-scale, rigorous, empirical research of the sort undertaken in this megastudy.

Competition response of cloud supersaturation explains diminished Twomey effect for smoky aerosol in the tropical Atlantic

The Twomey effect brightens clouds by increasing aerosol concentrations, which activates more droplets and decreases cloud supersaturation in response to more competition for water vapor. To quantify this competition response, we used marine low cloud observations in clean and smoky conditions at Ascension Island in the tropical South Atlantic during the Layered Aerosol Smoke Interactions with Cloud (LASIC) campaign. These observations show similar increases in droplet number for increased accumulation-mode particles from surface-based and satellite cloud retrievals, demonstrating the importance of below-cloud aerosol measurements for retrieving aerosol–cloud interactions (ACI) in clean and smoky aerosol conditions. Four methods for estimating cloud supersaturation from aerosol–cloud measurements were compared, with cloud scene-based and parcel-based methods showing sufficient variability for a strong dependence on both aerosol accumulation number concentration and cloud-base updraft velocities. Decomposing aerosol-related changes in cloud albedo and optical depth shows the calculated competition response accounts for dampening the activation response by 12 to 35%, explaining the diminished Twomey effect at high aerosol concentrations observed for smoky conditions at LASIC and previously around the world. This result was consistent for independent supersaturation retrievals by cloud scene-based droplet number and cloud condensation nuclei and parcel-based multimode size-resolving Lagrangian methods. Translating aerosol effects to local radiative forcing with clean conditions as a proxy for preindustrial and smoky conditions for present-day showed that the competition response reduces cooling from the Twomey radiative forcing by 12 to 35%, providing an essential process-specific constraint for improving the representation of aerosol competition in climate model simulation of indirect aerosol forcing.

Targeted degradation of α-Synuclein using an evolved botulinum toxin protease

There is considerable interest in the targeted degradation of proteins implicated in human disease. The use of sequence-specific proteases for this purpose is severely limited by the difficulty in engineering the numerous enzyme–substrate interactions required to yield highly selective proteases while maintaining catalytic activity. Herein, we report a strategy to evolve a protease for the programmed degradation of α-Synuclein, a presynaptic protein closely linked to Parkinson’s disease. Our structure-guided evolution campaign uses the protease from botulinum neurotoxin and showcases the stepwise change of specificity from its native substrate SNAP25 to the selective degradation of α-Synuclein. The protease’s selectivity is further demonstrated in human cells where near complete degradation of overexpressed human α-Synuclein is observed with no significant effects on cell proliferation. This stepwise strategy may serve as a general approach to evolve highly selective proteases targeting dysregulated proteins.

Control of circadian muscle glucose metabolism through the BMAL1–HIF axis in obesity

Disruptions of circadian rhythms are widespread in modern society and lead to accelerated and worsened symptoms of metabolic syndrome. In healthy mice, the circadian clock factor BMAL1 is required for skeletal muscle function and metabolism. However, the importance of muscle BMAL1 in the development of metabolic diseases, such as diet-induced obesity (DIO), remains unclear. Here, we demonstrate that skeletal muscle–specific BMAL1-deficient mice exhibit worsened glucose tolerance upon high-fat diet feeding, despite no evidence of increased weight gain. Metabolite profiling from Bmal1 -deficient muscles revealed impaired glucose utilization specifically at early steps in glycolysis that dictate the switch between anabolic and catabolic glucose fate. We provide evidence that this is due to abnormal control of the nutrient stress–responsive hypoxia-inducible factor (HIF) pathway. Genetic HIF1α stabilization in muscle Bmal1 -deficient mice restores glucose tolerance and expression of 217/736 dysregulated genes during DIO, including glycolytic enzymes. Together, these data indicate that during DIO, skeletal muscle BMAL1 is an important regulator of HIF-driven glycolysis and metabolic flexibility, which influences the development of high-fat-diet-induced glucose intolerance.