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Femur fracture leads to loss of bone at uninjured skeletal sites, which may increase risk of subsequent fracture. Osteocytes, the most abundant bone cells, can directly resorb bone matrix and regulate osteoclast and osteoblast activity, but their role in systemic bone loss after fracture remains poorly understood. In this study we used a transgenic (TG+) mouse model that overexpresses human B-cell lymphoma 2 (BCL-2) in osteoblasts and osteocytes. This causes enhanced osteoblast proliferation, followed by disruption in lacunar-canalicular connectivity and massive osteocyte death by 10 wk of age. We hypothesized that reduced viable osteocyte density would decrease the magnitude of systemic bone loss after femur fracture, reduce perilacunar remodeling, and alter callus formation. Bone remodeling was assessed using serum biomarkers of bone formation and resorption at 5 d post-fracture. We used micro-computed tomography, high resolution x-ray microscopy, mechanical testing, and Raman spectroscopy to quantify the magnitude of systemic bone loss, as well as changes in osteocyte lacunar volume, bone strength, and bone composition 2 wk post-fracture. Fracture was associated with a reduction in circulating markers of bone resorption in non-transgenic (TG-) animals. TG+ mice exhibited high bone mass in the limbs, greater cortical elastic modulus and reduced post-yield displacement. After fracture, TG+ mice lost less trabecular bone than TG- mice, but conversely TG+ mice exhibited trends toward a lower yield point and reduced femoral cortical thickness after fracture, though these were not statistically significant. Lacunar density was greater in TG+ mice, but fracture did not alter lacunar volume in TG+ or TG- mice. These findings suggest that osteocytes potentially play a significant role in the post-traumatic systemic response to fracture, though the effects differ between trabecular and cortical bone.

The immune response to acute hypoxemia may play a critical role in high-altitude acclimatization and adaptation. However, if not properly controlled, hypoxemia-induced inflammation may exacerbate high-altitude pathologies, such as acute mountain sickness (AMS), or other hypoxia-related clinical conditions. Several studies report changes in immune cell subsets at high altitude. However, the mechanisms underlying these changes, and if these alterations are beneficial or maladaptive, remains unknown. To address this, we performed multiparameter flow cytometry on peripheral blood mononuclear cells (PBMCs) collected throughout 3 days of high-altitude acclimatization in healthy sea-level residents (n = 20). Additionally, we conducted in vitro stimulation assays to test if high-altitude hypoxia exposure influences responses of immune cells to subsequent inflammatory stimuli. We found several immune populations were altered at high altitude, including monocytes, T cells, and B cells. Some changes in immune cell populations are potentially correlated with AMS incidence and severity. In vitro high-altitude PBMC cultures stimulated with lipopolysaccharide (LPS) showed no changes in pro-inflammatory cytokine production after 1 day at high-altitude. However, by day three pro-inflammatory cytokine production in response to LPS decreased significantly. These results indicate that high-altitude exposure may initiate an inflammatory response that encompasses innate immune sensitization, with adaptive immune suppression following acclimatization.

OBJECTIVES: This study aimed to evaluate pulmonary diffusing capacity for nitric oxide (DLNO) and pulmonary diffusing capacity for carbon monoxide (DLCO) in Mexican Hispanics born and raised at 2240 m altitude (midlanders) compared with those born and raised at sea level (lowlanders). It also aimed to assess the effectiveness of race-specific reference equations for pulmonary diffusing capacity (white people vs Mexican Hispanics) in minimising root mean square errors (RMSE) compared with race-neutral equations. METHODS: DLNO, DLCO, alveolar volume (VA) and gas transfer coefficients (KNO and KCO) were measured in 392 Mexican Hispanics (5 to 78 years) and compared with 1056 white subjects (5 to 95 years). Reference equations were developed using segmented linear regression (DLNO, DLCO and VA) and multiple linear regression (KNO and KCO) and validated with Least Absolute Shrinkage and Selection Operator. RMSE comparisons between race-specific and race-neutral models were conducted using repeated k-fold cross-validation and random forests. RESULTS: Midlanders exhibited higher DLCO (mean difference: +4 mL/min/mm Hg), DLNO (mean difference: +7 mL/min/mm Hg) and VA (mean difference: +0.17 L) compared with lowlanders. The Bayesian information criterion favoured race-specific models and excluding race as a covariate increased RMSE by 61% (DLNO), 18% (DLCO) and 4% (KNO). RMSE values for VA and KCO were comparable between race-specific and race-neutral models. For DLCO and DLNO, race-neutral equations resulted in 3% to 6% false positive rates (FPRs) in Mexican Hispanics and 20% to 49% false negative rates (FNRs) in white subjects compared with race-specific equations. CONCLUSIONS: Mexican Hispanics born and raised at 2240 m exhibit higher DLCO and DLNO compared with lowlanders. Including race as a covariate in reference equations lowers the RMSE for DLNO, DLCO and KNO and reduces FPR and FNR compared with race-neutral models. This study highlights the need for altitude-specific and race-specific reference equations to improve pulmonary function assessments across diverse populations.

Hybridization is increasingly recognized as an important evolutionary process across the tree of life. In many clades, phylogenomic approaches have permitted unparalleled insight into the extent and frequency of hybridization. However, we continue to lack a deep understanding of the factors that limit and shape patterns of hybridization, especially in evolutionary radiations. In this study, we characterized patterns of introgression across Costus (Costaceae), a young evolutionary radiation of tropical understory plants that maintain widespread interfertility despite exhibiting strong prezygotic reproductive isolation. We analyzed a phylogenomic dataset of 756 genes from 54 Costus species using multiple complementary approaches - D-statistics, gene-tree-based tests, and phylogenetic network analyses - to detect and characterize introgression events throughout the evolutionary history of the radiation. Our results identified a moderate number of introgression events, including a particularly ancient, well-supported event spanning one of the deepest divergences in the clade. Most introgression events occurred between taxa or ancestral lineages that shared the same pollination syndrome (bee-pollinated or hummingbird-pollinated). These findings suggest that prezygotic barriers, including pollinator specialization, have been key to the balance between introgression and reproductive isolation in Costus.

Background: The study of notable people as advocates for raising cancer awareness began in the latter decades of the 20th century. This research aimed to identify Pan-American notable people with head and neck cancer (HNC) and to explore senior health professionals perspectives on communicating stories of notable patients with HNC to promote prevention. Method: A cross-sectional survey was conducted using an online questionnaire designed in REDCap and administered to 32 senior health professionals with long-standing academic and clinical backgrounds in HNC. In addition, a structured literature review was performed on PubMed, Scopus, EMBASE, Web of Science, LILACS, and gray literature. Results: 18 notable figures were successfully identified from the survey, and 24 from the literature review. These individuals came from the United States, Brazil, Argentina, Mexico, El Salvador, Chile, Colombia, and Peru, and were recognized primarily for their performances as actors, artists, musicians, and athletes. The professionals outlooks were positive, with 31 (96.9%) agreeing that disseminating these stories can contribute to reducing risk behaviors. Furthermore, all participants (100%) agreed that such stories can promote early detection of HNC, primarily through social media, followed by the internet, and television. Conclusions: The study identified notable individuals and gathered positive perspectives from professionals. Our results suggest that notable people could serve as potential advocates for HNC prevention. Further research is warranted to explore the potential of this prevention strategy.

We combine design-based implementation research with a pre-registered RCT to address a long-standing challenge in psychological science: How to use psychological principles to address real-world problems while designing and implementing interventions in the field. We posit this as a design methodology for optimizing the translation between psychological science and real-world applications. We tested the efficacy of an extensively co-designed version of a game-based rational number intervention, Fraction Ball, versus “business-as-usual” math instruction and physical education in a sample of 4th/5th grade Latine students (N = 360). Insights from nine co-design sessions with 20 teachers informed revisions and additions to a previous version of Fraction Ball, strengthening impacts across 10 of 12 rational number subtests. This methodology provides insights for translating psychological science research and scaling it to address real-world educational needs, such as play-based interventions that improve rational number understanding in authentic contexts.

ObjectivePatients with alcohol-associated hepatitis (AH) have a high mortality. Alcohol exacerbates liver damage by inducing gut dysbiosis, bacterial translocation and inflammation, which is characterised by increased numbers of circulating and hepatic neutrophils.DesignIn this study, we performed tandem mass tag (TMT) proteomics to analyse proteins in the faeces of controls (n=19), patients with alcohol-use disorder (AUD; n=20) and AH (n=80) from a multicentre cohort (InTeam). To identify protein groups that are disproportionately represented, we conducted over-representation analysis using Reactome pathway analysis and Gene Ontology to determine the proteins with the most significant impact. A faecal biomarker and its prognostic effect were validated by ELISA in faecal samples from patients with AH (n=70), who were recruited in a second and independent multicentre cohort (AlcHepNet).ResultFaecal proteomic profiles were overall significantly different between controls, patients with AUD and AH (principal component analysis p=0.001, dissimilarity index calculated by the method of Bray-Curtis). Proteins that showed notable differences across all three groups and displayed a progressive increase in accordance with the severity of alcohol-associated liver disease were predominantly those located in neutrophil granules. Over-representation and Reactome analyses confirmed that differentially regulated proteins are part of granules in neutrophils and the neutrophil degranulation pathway. Myeloperoxidase (MPO), the marker protein of neutrophil granules, correlates with disease severity and predicts 60-day mortality. Using an independent validation cohort, we confirmed that faecal MPO levels can predict short-term survival at 60 days.ConclusionsWe found an increased abundance of faecal proteins linked to neutrophil degranulation in patients with AH, which is predictive of short-term survival and could serve as a prognostic non-invasive marker.

Hydrostatic pressure increases with depth in the ocean, but little is known about the molecular bases of biological pressure tolerance. We describe a mode of pressure adaptation in comb jellies (ctenophores) that also constrains these animals depth range. Structural analysis of deep-sea ctenophore lipids shows that they form a nonbilayer phase at pressures under which the phase is not typically stable. Lipidomics and all-atom simulations identified phospholipids with strong negative spontaneous curvature, including plasmalogens, as a hallmark of deep-adapted membranes that causes this phase behavior. Synthesis of plasmalogens enhanced pressure tolerance in Escherichia coli, whereas low-curvature lipids had the opposite effect. Imaging of ctenophore tissues indicated that the disintegration of deep-sea animals when decompressed could be driven by a phase transition in their phospholipid membranes.

Proteus mirabilis is a leading cause of urinary tract infections and a common commensal of the gastrointestinal tract. Our recent study (JB) showed that P. mirabilis strain BL95 employs a novel contact-dependent killing system against enteric bacteria in the mouse gut and in vitro. To uncover the genetic determinants of this system, we performed whole-genome sequencing of BL95 and compared it with 98 complete genomes of P. mirabilis. BL95 carries 56 coding sequences (CDSs) not found in other P. mirabilis. Over half of these unique genes are located on a novel integrative conjugative element (ICE) named ICEPm2, inserted in tRNA-Phe and exclusive to BL95. ICEPm2 has integration, conjugation, and DNA replication modules nearly identical to ICEPm1 (common in P. mirabilis), but ICEPm2 of BL95 carries two unique operons for P. mirabilis-a phenazine biosynthesis and a contact-dependent growth inhibition (CDI) system. ICEPm2 is absent in the P. mirabilis (AR_0156) closest to BL95 and it is present in the genomes of several Escherichia coli from mouse intestines, indicating its recent horizontal mobilization. BL95 shares over 100 genes of five different secretion systems with other P. mirabilis, mostly poorly studied, making a large pool of candidate genes for the contact-dependent growth inhibition.

To unravel why computational design fails in creating viable enzymes, while directed evolution (DE) succeeds, our research delves into the laboratory evolution of protoglobin. DE has adapted this protein to efficiently catalyze carbene transfer reactions. We show that the previously proposed enhanced substrate access and binding alone cannot account for increased yields during DE. The 3D electric field in the entire active site is tracked through protein dynamics, clustered using the affinity propagation algorithm, and subjected to principal component analysis. This analysis reveals notable changes in the electric field with DE, where distinct field topologies influence transition state energetics and mechanism. A chemically meaningful field component emerges and takes the lead during DE and facilitates crossing the barrier to carbene transfer. Our findings underscore intrinsic electric field dynamic's influence on enzyme function, the ability of the field to switch mechanisms within the same protein, and the crucial role of the field in enzyme design.

Despite substantial evidence supporting the efficacy of prebiotics for promoting host health and stress resilience, few experiments present evidence documenting the dynamic changes in microbial ecology and fecal microbially modified metabolites over time. Furthermore, the literature reports a lack of reproducible effects of prebiotics on specific bacteria and bacterial-modified metabolites. The current experiments examined whether consumption of diets enriched in prebiotics (galactooligosaccharides (GOS) and polydextrose (PDX)), compared to a control diet, would consistently impact the gut microbiome and microbially modified bile acids over time and between two research sites. Male Sprague Dawley rats were fed control or prebiotic diets for several weeks, and their gut microbiomes and metabolomes were examined using 16S rRNA gene sequencing and untargeted LC-MS/MS analysis. Dietary prebiotics altered the beta diversity, relative abundance of bacterial genera, and microbially modified bile acids over time. PICRUSt2 analyses identified four inferred functional metabolic pathways modified by the prebiotic diet. Correlational network analyses between inferred metabolic pathways and microbially modified bile acids revealed deoxycholic acid as a potential network hub. All these reported effects were consistent between the two research sites, supporting the conclusion that dietary prebiotics robustly changed the gut microbial ecosystem. Consistent with our previous work demonstrating that GOS/PDX reduces the negative impacts of stressor exposure, we propose that ingesting a diet enriched in prebiotics facilitates the development of a health-promoting gut microbial ecosystem.

Neutrophils are the first line of defense of the innate immune system. In response to methicillin-resistant Staphylococcus aureus infection in the skin, hematopoietic stem, and progenitor cells (HSPCs) traffic to wounds and undergo extramedullary granulopoiesis, producing neutrophils necessary to resolve the infection. This prompted the engineering of a gelatin methacrylate (GelMA) hydrogel that encapsulates HSPCs within a matrix amenable to subcutaneous delivery. The authors study the influence of hydrogel mechanical properties to produce an artificial niche for granulocyte-monocyte progenitors (GMPs) to efficiently expand into functional neutrophils that can populate infected tissue. Lin-cKIT+ HSPCs, harvested from fluorescent neutrophil reporter mice, are encapsulated in GelMA hydrogels of varying polymer concentration and UV-crosslinked to produce HSPC-laden gels of specific stiffness and mesh sizes. Softer 5% GelMA gels yield the most viable progenitors and effective cell-matrix interactions. Compared to suspension culture, 5% GelMA results in a twofold expansion of mature neutrophils that retain antimicrobial functions including degranulation, phagocytosis, and ROS production. When implanted dermally in C57BL/6J mice, luciferase-expressing neutrophils expanded in GelMA hydrogels are visualized at the site of implantation for over 5 days. They demonstrate the potential of GelMA hydrogels for delivering HSPCs directly to the site of skin infection to promote local granulopoiesis.

Environmental variation commonly drives functional trait diversity within species, among species, and across communities. Climate and shared evolutionary history can both influence trait–environment relationships. We studied variation in plant functional traits among closely related Costus species occurring across environmental gradients, the extent to which this variation occurs within single species, and how that variation may be influenced by shared evolutionary history. We measured leaf, aboveground stem, rhizome, and fine root traits of 17 species of Costus in eight sites in Costa Rica and Panama, which varied in elevation, temperature, and precipitation. We then assessed the relationships among traits and environmental variables and estimated the phylogenetic signal of the traits. We observed significant relationships between functional traits and climate. Stomatal conductance decreased, but stem density and rhizome dry matter content increased with decreasing mean annual temperature and precipitation seasonality in both cross-species and single-species analyses. This suggests that herbaceous species have a similar trade-off between plant hydraulic efficiency and safety as found in woody plants. Mean annual temperature was a stronger driver of trait variation than mean annual precipitation. We also found phylogenetic signal in leaf and stem structural traits (i.e., closely related species are more similar than distantly related species), but not in physiological or belowground traits. Our results demonstrate significant trait variation within and among species of Costus, a widespread understory and herbaceous genus in the tropics, which is driven by both climate and shared evolutionary history.

Multivariate techniques better fit the anatomy of complex neuropsychiatric disorders which are characterized not by alterations in a single region, but rather by variations across distributed brain networks. Here, we used principal component analysis (PCA) to identify patterns of covariance across brain regions and relate them to clinical and demographic variables in a large generalizable dataset of individuals with bipolar disorders and controls. We then compared performance of PCA and clustering on identical sample to identify which methodology was better in capturing links between brain and clinical measures. Using data from the ENIGMA-BD working group, we investigated T1-weighted structural MRI data from 2436 participants with BD and healthy controls, and applied PCA to cortical thickness and surface area measures. We then studied the association of principal components with clinical and demographic variables using mixed regression models. We compared the PCA model with our prior clustering analyses of the same data and also tested it in a replication sample of 327 participants with BD or schizophrenia and healthy controls. The first principal component, which indexed a greater cortical thickness across all 68 cortical regions, was negatively associated with BD, BMI, antipsychotic medications, and age and was positively associated with Li treatment. PCA demonstrated superior goodness of fit to clustering when predicting diagnosis and BMI. Moreover, applying the PCA model to the replication sample yielded significant differences in cortical thickness between healthy controls and individuals with BD or schizophrenia. Cortical thickness in the same widespread regional network as determined by PCA was negatively associated with different clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. PCA outperformed clustering and provided an easy-to-use and interpret method to study multivariate associations between brain structure and system-level variables. PRACTITIONER POINTS: In this study of 2770 Individuals, we confirmed that cortical thickness in widespread regional networks as determined by principal component analysis (PCA) was negatively associated with relevant clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. Significant associations of many different system-level variables with the same brain network suggest a lack of one-to-one mapping of individual clinical and demographic factors to specific patterns of brain changes. PCA outperformed clustering analysis in the same data set when predicting group or BMI, providing a superior method for studying multivariate associations between brain structure and system-level variables.

This article describes the methods used to build a large-scale database of more than 250,000 electronic fetal monitoring (EFM) records linked to a comprehensive set of clinical information about the infant, the mother, the pregnancy, labor, and outcome. The database can be used to investigate how birth outcome is related to clinical and EFM features. The main steps involved in building the database were: (1) Acquiring the raw EFM recording and clinical records for each birth. (2) Assigning each birth to an objectively defined outcome class that included normal, acidosis, and hypoxic-ischemic encephalopathy. (3) Removing all personal health information from the EFM recordings and clinical records. (4) Preprocessing the deidentified EFM records to eliminate duplicates, reformat the signals, combine signals from different sensors, and bridge gaps to generate signals in a format that can be readily analyzed. (5) Post-processing the repaired EFM recordings to extract key features of the fetal heart rate, uterine activity, and their relations. (6) Populating a database that links the clinical information, EFM records, and EFM features to support easy querying and retrieval. •A multi-step process is required to build a comprehensive database linking electronic temporal fetal monitoring signals to a comprehensive set of clinical information about the infant, the mother, the pregnancy, labor, and outcome.•The current database documents more than 250,000 births including almost 4,000 acidosis and 400 HIE cases. This represents more than 80% of the births that occurred in 15 Northern California Kaiser Permanente Hospitals between 2011-2019. This is a valuable resource for studying the factors predictive of outcome.•The signal processing code and schemas for the database are freely available. The database will not be permitted to leave Kaiser firewalls, but a process is in place to allow interested investigators to access it.

BACKGROUND: Refeeding syndrome is the gravest possible medical complication in malnourished patients undergoing refeeding in the hospital. We previously reported that males with malnutrition secondary to eating disorders required more calories and had longer hospital stays than females; however, sex differences in electrolyte abnormalities indicating refeeding syndrome risk remain unknown. The objective of this study was to assess differences in electrolyte abnormalities indicating refeeding syndrome risk among male and female adolescents and young adults with eating disorders hospitalized for medical instability. METHODS: We retrospectively reviewed the electronic medical records of 558 patients aged 9-25 years admitted to the University of California, San Francisco Eating Disorders Program for medical instability between May 2012 and August 2020. Serum was drawn per standard of care between 5 and 7 am each morning and electrolyte abnormalities indicating refeeding syndrome risk were defined as: hypophosphatemia (

We present tomographic measurements of structure growth using cross-correlations of Atacama Cosmology Telescope (ACT) DR6 and Planck cosmic microwave background (CMB) lensing maps with the unWISE Blue and Green galaxy samples, which span the redshift ranges 0.2 ≲ z ≲ 1.1 and 0.3 ≲ z ≲ 1.8, respectively. We improve on prior unWISE cross-correlations not just by making use of the new, high-precision ACT DR6 lensing maps, but also by including additional spectroscopic data for redshift calibration and by analyzing our measurements with a more flexible theoretical model. We determine the amplitude of matter fluctuations at low redshifts (z ≃ 0.2-1.6), finding S 8 ≡ σ 8 ( Ω m / 0.3 ) 0.5 = 0.813 ± 0.021 using the ACT cross-correlation alone and S 8 = 0.810 ± 0.015 with a combination of Planck and ACT cross-correlations; these measurements are fully consistent with the predictions from primary CMB measurements assuming standard structure growth. The addition of baryon acoustic oscillation data breaks the degeneracy between σ 8 and Ωm , allowing us to measure σ 8 = 0.813 ± 0.020 from the cross-correlation of unWISE with ACT and σ 8 = 0.813 ± 0.015 from the combination of cross-correlations with ACT and Planck. These results also agree with the expectations from primary CMB extrapolations in ΛCDM cosmology; the consistency of σ 8 derived from our two redshift samples at z ∼ 0.6 and 1.1 provides a further check of our cosmological model. Our results suggest that structure formation on linear scales is well described by ΛCDM even down to low redshifts z ≲ 1.

Catalysis with engineered enzymes has provided more efficient routes for the production of active pharmaceutical agents. However, the potential of biocatalysis to assist in early-stage drug discovery campaigns remains largely untapped. In this study, we have developed a biocatalytic strategy for the construction of sp3-rich polycyclic compounds via the intramolecular cyclopropanation of benzothiophenes and related heterocycles. Two carbene transferases with complementary regioisomer selectivity were evolved to catalyse the stereoselective cyclization of benzothiophene substrates bearing diazo ester groups at the C2 or C3 position of the heterocycle. The detailed mechanisms of these reactions were elucidated by a combination of crystallographic and computational analyses. Leveraging these insights, the substrate scope of one of the biocatalysts could be expanded to include previously unreactive substrates, highlighting the value of integrating evolutionary and rational strategies to develop enzymes for new-to-nature transformations. The molecular scaffolds accessed here feature a combination of three-dimensional and stereochemical complexity with rule-of-three properties, which should make them highly valuable for fragment-based drug discovery campaigns.

Seed storage life in tropical areas is shortened by high humidity and temperature and the general inaccessibility to dehumidifying and refrigeration systems, resulting in rapid decreases in seed viability in storage as well as a high incidence of fungal and insect infestations. The dry chain, based on rapid and deep drying of seeds after harvest followed by packaging in moisture-proof containers, has been proposed as an effective method to maintain seed quality during medium-term storage in humid climates, even without refrigeration. In addition, seed drying with zeolite drying beads can be more effective and economical than sun or heated-air drying under these warm, humid conditions. In this paper, we review recent published literature regarding the dry chain, considering different crop species, storage environments and seed traits. In addition, we provide new original data on the application of dry chain methods and their implementation at larger scales in South Asia, Latin America and Pacific Island Countries. The clear conclusion is that the combination of reusable drying beads and waterproof storage containers enables the implementation of the dry chain in tropical climates, enhancing seed viability and quality in storage of many crop species. The dry chain approach can therefore significantly enhance seed security for farmers in many tropical countries. Finally, we propose actions and strategies that could guide further scaling-up implementation of this technology.

PURPOSE: To examine associations of prenatal biomarkers of pesticide exposure with birth size measures and length of gestation among newborns from the Infants Environmental Health (ISA) birth cohort, Costa Rica. METHODS: We included 386 singleton liveborn newborns with data on birth size measures, length of gestation, and maternal urinary biomarkers of chlorpyrifos, synthetic pyrethroids, mancozeb, pyrimethanil, and 2, 4-D during pregnancy. We associated biomarkers of exposure with birth outcomes using multivariate linear regression and generalized additive models. RESULTS: Concentrations were highest for ethylene thiourea (ETU, metabolite of mancozeb), median = 3.40; p10-90 = 1.90-6.79 µg/L, followed by 3,5,6-trichloro-2-pyridinol (TCP, metabolite of chlorpyrifos) p50 = 1.76 p10-90 = 0.97-4.36 µg/L, and lowest for 2,4-D (p50 = 0.33 p10-90 = 0.18-1.07 µg/L). Among term newborns (≥37 weeks), higher prenatal TCP was associated with lower birth weight and smaller head circumference (e.g., β per 10-fold-increase) during the second half of pregnancy = -129.6 (95% confidence interval [CI] = -255.8, -3.5) grams, and -0.61 (95% CI = -1.05, -0.17) centimeters, respectively. Also, among term newborns, prenatal 2,4-D was associated with lower birth weight (β per 10-fold-increase = -125.1; 95% CI = -228.8, -21.5), smaller head circumference (β = -0.41; 95% CI = -0.78, -0.03), and, during the second half of pregnancy, with shorter body length (β = -0.58; 95% CI = -1.09, -0.07). Furthermore, ETU was nonlinearly associated with head circumference during the second half of pregnancy. Biomarkers of pyrethroids and pyrimethanil were not associated with birth size, and none of the biomarkers explained the length of gestation. CONCLUSIONS: Prenatal exposure to chlorpyrifos and 2,4-D, and, possibly, mancozeb/ETU, may impair fetal growth.

Reptiles and amphibians (herptiles) are some of the most endangered and threatened species on the planet and numerous conservation strategies are being implemented with the goal of ensuring species recovery. Little is known, however, about the gut microbiome of wild herptiles and how it relates to the health of these populations. Here, we report results from the gut microbiome characterization of both a broad survey of herptiles, and the correlation between the fungus Basidiobolus, and the bacterial community supported by a deeper, more intensive sampling of Plethodon glutinosus, known as slimy salamanders. We demonstrate that bacterial communities sampled from frogs, lizards, and salamanders are structured by the host taxonomy and that Basidiobolus is a common and natural component of these wild gut microbiomes. Intensive sampling of multiple hosts across the ecoregions of Tennessee revealed that geography and host:geography interactions are strong predictors of distinct Basidiobolus operational taxonomic units present within a given host. Co-occurrence analyses of Basidiobolus and bacterial community diversity support a correlation and interaction between Basidiobolus and bacteria, suggesting that Basidiobolus may play a role in structuring the bacterial community. We further the hypothesis that this interaction is advanced by unique specialized metabolism originating from horizontal gene transfer from bacteria to Basidiobolus and demonstrate that Basidiobolus is capable of producing a diversity of specialized metabolites including small cyclic peptides.IMPORTANCEThis work significantly advances our understanding of biodiversity and microbial interactions in herptile microbiomes, the role that fungi play as a structural and functional members of herptile gut microbiomes, and the chemical functions that structure microbiome phenotypes. We also provide an important observational system of how the gut microbiome represents a unique environment that selects for novel metabolic functions through horizontal gene transfer between fungi and bacteria. Such studies are needed to better understand the complexity of gut microbiomes in nature and will inform conservation strategies for threatened species of herpetofauna.

Background and aim of the study: We previously published the increased frequency of new CPP cases during the Covid-19 pandemic in our pediatric endocrinology clinic at Rady Children's Hospital in San Diego, CA, US. We conducted this follow-up study to examine the incidence of new CPP cases requiring treatment with GnRH agonist (GnRHa) in our clinic during 2 years post-pandemic. Methods: We performed a retrospective comparison of the number of visits of children newly diagnosed with CPP treated with GnRHa during the 2 years following the first year of Covid-19 pandemic (5/2021–7/2023). We evaluated clinical and bone maturation data as well as differences in timing from diagnosis to onset of treatment. Results: We previously reported in the pre-Covid year, 28 children (1 boy, 27 girls) treated with GnRHa for CPP out of 2,340 new endocrinology visits (1.2% of patients seen). During Covid-19 year, 64 children (7 boys, 57 girls) were treated out of 2,261 new visits (2.8%). The incidence of new CPP cases requiring GnRHa during the pandemic more than doubled compared to pre-pandemic. In the first year post-year 1 of the pandemic (5/2021–4/2022), 46 children (3 boys, 40 girls) started treatment with GnRHa for CPP out of 2,595 new endocrinology visits (1.6% of patients seen). During the second follow-up year (5/2022–4/2023), 22 children (4 boys, 18 girls) started treatment with GnRHa for CPP out of 2,676 new endocrinology visits (0.8% of patients seen). Age at onset of treatment, degree of bone age (BA) advancement, time from diagnosis to onset of treatment, and changes in BMI during the pandemic were not different from pre-pandemic or post-pandemic. Conclusions: CPP cases requiring GnRHa treatment significantly increased during the first year of the Covid-19 pandemic and then decreased each year post-pandemic. This was not related to BMI, age at diagnosis, degree of bone age advancement, or time from diagnosis to onset of treatment as all these factors have been similar during pre-pandemic, pandemic, and post-pandemic years. It is reasonable that the postulated hypotheses published regarding the increase during the pandemic would resolve post-pandemic.

Cas13a is a recent addition to the CRISPR-Cas toolkit that exclusively targets RNA, which makes it a promising tool for RNA detection. It utilizes a CRISPR RNA (crRNA) to target RNA sequences and trigger a composite active site formed by two Higher Eukaryotes and Prokaryotes Nucleotide (HEPN) domains, cleaving any solvent-exposed RNA. In this system, an intriguing form of allosteric communication controls the RNA cleavage activity, yet its molecular details are unknown. Here, multiple-microsecond molecular dynamics simulations are combined with graph theory to decipher this intricate activation mechanism. We show that the binding of a target RNA acts as an allosteric effector, by amplifying the communication signals over the dynamical noise through interactions of the crRNA at the buried HEPN1-2 interface. By introducing a novel Signal-to-Noise Ratio (SNR) of communication efficiency, we reveal critical allosteric residues-R377, N378, and R973-that rearrange their interactions upon target RNA binding. Alanine mutation of these residues is shown to select target RNA over an extended complementary sequence beyond guide-target duplex for RNA cleavage, establishing the functional significance of these hotspots. Collectively our findings offer a fundamental understanding of the Cas13a mechanism of action and pave new avenues for the development of highly selective RNA-based cleavage and detection tools.

This paper provides a comprehensive overview of how fitting of baryon acoustic oscillations (BAO) is carried out within the upcoming Dark Energy Spectroscopic Instrument’s (DESI) 2024 results using its DR1 data set, and the associated systematic error budget from theory and modelling of the BAO. We derive new results showing how non-linearities in the clustering of galaxies can cause potential biases in measurements of the isotropic (αiso) and anisotropic (αap) BAO distance scales, and how these can be effectively removed with an appropriate choice of reconstruction algorithm. We then demonstrate how theory leads to a clear choice for how to model the BAO and develop, implement, and validate a new model for the remaining smooth-broad-band (i.e. without BAO) component of the galaxy clustering. Finally, we explore the impact of all remaining modelling choices on the BAO constraints from DESI using a suite of high-precision simulations, arriving at a set of best practices for DESI BAO fits, and an associated theory and modelling systematic error. Overall, our results demonstrate the remarkable robustness of the BAO to all our modelling choices and motivate a combined theory and modelling systematic error contribution to the post-reconstruction DESI BAO measurements of no more than 0.1 per cent (0.2 per cent) for its isotropic (anisotropic) distance measurements. We expect the theory and best practices laid out to here to be applicable to other BAO experiments in the era of DESI and beyond.

Abstract: The Lower Ordovician (Floian) Al Rose Formation from the Inyo Mountains, California, is a deeper-water, graptolitic equivalent of the well-known and richly fossiliferous successions described from Utah and Nevada. It is considered to have been originally marginal to the Laurentian paleocontinent. It has yielded a low-diversity trilobite fauna that differs strikingly from contemporary faunas to the east in its abundance of raphiophorid, nileid, olenid, and agnostoid trilobites, resembling that of the Nileid Biofacies known from scattered locations marginal to Laurentia. Two new trilobite species are described: Globampyx sexsegmentatus (Raphiophoridae) and Protopresbynileus divergens (Nileidae). Carolinites genacinaca Ross, 1951 is a link with the Great Basin. Other trilobites include the olenid Cloacaspis cf. C. ceryx anataphra Fortey, 1974, metagnostid Geragnostus cf. G. (Novoagnostus) longicollis Raymond, 1925, and pliomerid Hintzeia sp. UUID: https://zoobank.org/19a679ce-968d-4ce1-a590-f7f55bf9d62d

IntroductionSevere forms of short bowel syndrome (SBS) resulting in chronic intestinal failure (IF) have limited therapeutic options, all of which are associated with significant morbidities. Spring-mediated distraction enterogenesis (SMDE) uses an intraluminal self-expanding spring to generate mechanical force to induce intestinal stretching and sustained axial growth, providing a promising novel approach for patients with SBS. Previous studies have established this method to be safe and effective in small and large animal models. However, SMDE has previously not been implemented in a large, clinically relevant animal model.MethodsJuvenile mini-Yucatan pigs with 75% of their small intestine resected had intraluminal springs placed after an initial adaptive period. Morphological and histological assessments were performed on SMDE segments compared to the control region of the intestine undergoing normal adaptive responses to resection.ResultsWhile the initial histologic adaptive response observed following resection was attenuated after a month, the SMDE segments instead augmented these adaptive changes. Specifically, intestinal length increased 2-fold in SMDE segments, and the widths of the epithelial, muscularis, and serosal layers were enhanced in SMDE compared with control segments of the same animal. This data suggests that morphologic intestinal adaptation may be enhanced with SMDE in the setting of SBS.DiscussionHere we demonstrate the successful and reproducible implementation of SMDE in a large animal model in the setting of prior intestinal resection, making SMDE a viable and novel approach for SBS to be explored further.

Despite many interventions, science education remains highly inequitable throughout the world. Internet-enabled experimental learning has the potential to reach underserved communities and increase the diversity of the scientific workforce. Here, we demonstrate the use of lab-on-a-chip (LoC) technologies to expose Latinx life science undergraduate students to introductory concepts of computer programming by taking advantage of open-loop cloud-integrated LoCs. We developed a context-aware curriculum to train students at over 8000 km from the experimental site. Through this curriculum, the students completed an assignment testing bacteria contamination in water using LoCs. We showed that this approach was sufficient to reduce the students' fear of programming and increase their interest in continuing careers with a computer science component. Altogether, we conclude that LoC-based internet-enabled learning can become a powerful tool to train Latinx students and increase the diversity in STEM.

We investigated the human capacity to acquire multiple visuomotor mappings for de novo skills. Using a grid navigation paradigm, we tested whether contextual cues implemented as different "grid worlds", allow participants to learn two distinct key-mappings more efficiently. Our results indicate that when contextual information is provided, task performance is significantly better. The same held true for meta-reinforcement learning agents that differed in whether or not they receive contextual information when performing the task. We evaluated their accuracy in predicting human performance in the task and analyzed their internal representations. The results indicate that contextual cues allow the formation of separate representations in space and time when using different visuomotor mappings, whereas the absence of them favors sharing one representation. While both strategies can allow learning of multiple visuomotor mappings, we showed contextual cues provide a computational advantage in terms of how many mappings can be learned.

Lactam rings are found in many biologically active natural products and pharmaceuticals, including important classes of antibiotics. Methods for the asymmetric synthesis of these molecules are therefore highly desirable, particularly through the selective functionalization of unreactive aliphatic C-H bonds. Here we show the development of a strategy for the asymmetric synthesis of β-, γ-, and δ-lactams via hemoprotein-catalysed intramolecular C-H amidation reaction with readily available dioxazolone reagents. Engineered myoglobin variants serve as excellent biocatalysts for this transformation yielding the desired lactam products in high yields, high enantioselectivity, and on preparative scale. Mechanistic and computational studies elucidate the nature of the C-H amination and enantiodetermining steps and provide insights into protein-mediated control of regioselectivity and stereoselectivity. Additionally, an alkaloid natural product and a drug molecule were synthesized chemoenzymatically in much fewer steps (7-8 vs. 11-12) than previously reported, further demonstrating the power of biosynthetic strategy for the preparation of complex bioactive molecules.

We present the first result in exploring the gaseous halo and galaxy correlation using the Dark Energy Spectroscopic Instrument survey validation data in the Cosmic Evolution Survey (COSMOS) and Hyper Suprime-Cam field. We obtain multiphase gaseous halo properties in the circumgalactic medium by using 115 quasar spectra (signal-to-noise ratio > 3). We detect Mg ii absorption at redshift 0.6 < z < 2.5, C iv absorption at 1.6 < z < 3.6, and H i absorption associated with the Mg ii and C iv. By crossmatching the COSMOS2020 catalog, we identify the Mg ii and C iv host galaxies in 10 quasar fields at 0.9< z < 3.1. We find that within the impact parameter of 250 kpc, a tight correlation is seen between the strong Mg ii equivalent width and the host galaxy star formation rate. The covering fraction f c of the strong Mg ii selected galaxies, which is the ratio of the absorbing galaxy in a certain galaxy population, shows significant evolution in the main-sequence galaxies and marginal evolution in all the galaxy populations within 250 kpc at 0.9 < z < 2.2. The f c increase in the main-sequence galaxies likely suggests the coevolution of strong Mg ii absorbing gas and the main-sequence galaxies at the cosmic noon. Furthermore, Mg ii and C iv absorbing gas is detected out of the galaxy virial radius, tentatively indicating the feedback produced by the star formation and/or the environmental effects.

This report serves as one of five individual documents developed over the course of Phase II of the Urban Forest Equity Collective. This document provides an overview of the Central Alameda pilot neighborhood assessment, engagement, and tree planting implementation process. It is intended to provide a transparent view into the decisions, points of analysis, and key themes derived over the course of this phase.

Triple negative breast cancer (TNBC) is highly immunogenic and high levels of tumor infiltrating lymphocytes (TILs) have been associated with a better prognosis and higher probability to achieve pathological complete response. Here, we explore the potential role of stromal TILs level and composition as a prognostic and predictive biomarker in TNBC. 195 Tumor biospecimens from patients diagnosed with TNBC were included. Stromal TILs (sTILs), positive CD4/CD8 cells were evaluated. Differences in clinic-pathological characteristics according to immune infiltration were assessed. The predictive and prognostic value of immune infiltration was analyzed by multivariate models. Higher immune infiltration was observed in patients with favorable clinical-pathological features. Survival analysis showed that longer overall survival times were observed in patients with a higher infiltration of sTILs (p = 0.00043), CD4 + (p = 0.0074) and CD8 + (p = 0.008). In the multivariate analysis, low levels of sTILs were found to be associated with a higher mortality hazard (HR: 1.59, 95% CI 1.01-2.48). CD4 and CD8 immune infiltration were associated with higher odds for pathological complete response (OR: 1.20, 95% CI 1.00-1.46, OR: 1.28, 1.02-1.65, respectively). Our results suggest that immune infiltration could be used as a prognostic marker for overall survival in TNBC patients.

Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study (GWAS) of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC (ARSE and MMP16), with evidence of significant associations in replication analyses for both novel loci. Functional assays of ARSE and MMP16 in human vascular smooth muscle cells (VSMCs) demonstrate that ARSE is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying or osteogenic phenotype. Furthermore, we show that the association of variants near ARSE with reduced CAC is likely explained by reduced ARSE expression with the G allele of enhancer variant rs5982944. Our study highlights ARSE as an important contributor to atherosclerotic vascular calcification, and a potential drug target for vascular calcific disease.

BACKGROUND AND AIMS: Data on how to teach endosonographers needle-based confocal laser endomicroscopy (nCLE)-guided histologic diagnosis of pancreatic cystic lesions (PCLs) are limited. Hence, we developed and tested a structured educational program to train early-career endosonographers in nCLE-guided diagnosis of PCLs. METHODS: Twenty-one early-career nCLE-naïve endosonographers watched a teaching module outlining nCLE criteria for diagnosing PCLs. Participants then reviewed 80 high-yield nCLE videos, recorded diagnoses, and received expert feedback (phase 1). Observers were then randomized to a refresher feedback session or self-learning at 4 weeks. Eight weeks after training, participants independently assessed the same 80 nCLE videos without feedback and provided histologic predictions (phase 2). Diagnostic performance of nCLE to differentiate mucinous versus nonmucinous PCLs and to diagnose specific subtypes were analyzed using histopathology as the criterion standard. Learning curves were determined using cumulative sum analysis. RESULTS: Accuracy and diagnostic confidence for differentiating mucinous versus nonmucinous PCLs improved as endosonographers progressed through nCLE videos in phase 1 (P < .001). Similar trends were observed with the diagnosis of PCL subtypes. Most participants achieved competency interpreting nCLE, requiring a median of 38 assessments (range, 9-67). During phase 2, participants independently differentiated PCLs with high accuracy (89%), high confidence (83%), and substantial interobserver agreement (κ = .63). Accuracy for nCLE-guided PCL subtype diagnoses ranged from 82% to 96%. The learned nCLE skills did not deteriorate at 8 weeks and were not impacted by a refresher session. CONCLUSIONS: We developed a practical, effective, and durable educational intervention to train early-career endosonographers in nCLE-guided diagnosis of PCLs.

Paneth cells (PCs), a specialized secretory cell type in the small intestine, are increasingly recognized as having an essential role in host responses to microbiome and environmental stresses. Whether and how commensal and pathogenic microbes modify PC composition to modulate inflammation remain unclear. Using newly developed PC-reporter mice under conventional and gnotobiotic conditions, we determined PC transcriptomic heterogeneity in response to commensal and invasive microbes at single cell level. Infection expands the pool of CD74+ PCs, whose number correlates with auto or allogeneic inflammatory disease progressions in mice. Similar correlation was found in human inflammatory disease tissues. Infection-stimulated cytokines increase production of reactive oxygen species (ROS) and expression of a PC-specific mucosal pentraxin (Mptx2) in activated PCs. A PC-specific ablation of MyD88 reduced CD74+ PC population, thus ameliorating pathogen-induced systemic disease. A similar phenotype was also observed in mice lacking Mptx2. Thus, infection stimulates expansion of a PC subset that influences disease progression.

Process-based land surface models are important tools for estimating global wetland methane (CH4) emissions and projecting their behavior across space and time. So far there are no performance assessments of model responses to drivers at multiple time scales. In this study, we apply wavelet analysis to identify the dominant time scales contributing to model uncertainty in the frequency domain. We evaluate seven wetland models at 23 eddy covariance tower sites. Our study first characterizes site-level patterns of freshwater wetland CH4 fluxes (FCH4) at different time scales. A Monte Carlo approach was developed to incorporate flux observation error to avoid misidentification of the time scales that dominate model error. Our results suggest that (a) significant model-observation disagreements are mainly at multi-day time scales (32 days) for the boreal and Arctic tundra wetland sites but have significant bias in variability at seasonal time scales for temperate and tropical/subtropical sites; (c) model errors exhibit increasing power spectrum as time scale increases, indicating that biases at time scales

OBJECTIVES/GOALS: Despite a disproportionate impact of COVID-19 on minority and under-resourced communities, nearly all COVID-19 resources have only been online in English. A statewide coalition of community and academic partners used community-engaged strategies to provide tailored outreach to diverse populations. METHODS/STUDY POPULATION: The STOP COVID-19 CA statewide team had a workgroup focused on communications. Members of this group represented different sectors, racial/ethnic groups, disciplines, and regions across the state. They had regular meetings to discuss and strategize how to overcome the impact of historic and structural racism on access to COVID-19 resources, including testing, vaccines, and protective equipment. The team also shared regular updates about changes in community concerns and needs as well as new, tailored resources. RESULTS/ANTICIPATED RESULTS: Together, the team has been able to reach diverse populations across the state, including providing information about COVID-19 in multiple languages and formats, from radio to virtual town halls to local health fairs. The multiple sites also increased access to vaccines and testing through trusted community leaders and locations, including church-based locations to bringing vaccines and testing directly to workplaces. These community pop-up vaccination sites have helped to vaccinate large numbers of diverse populations, some of whom were initially unsure about getting the vaccine, which has helped to reduce the gaps in community vaccination rates by race/ethnicity. DISCUSSION/SIGNIFICANCE: This network of community-engaged strategies utilized for rapid COVID-19 response could also be used to for responses to future public health emergencies, addressing chronic diseases (e.g., diabetes, hypertension), or even other complex issues that affect society and health (e.g., climate change).

The present experimental study investigated the dynamics of single- and multi-port gaseous jet diffusion flames exposed to acoustic excitation via a standing wave situated in a closed waveguide at atmospheric pressure. High-speed imaging of the oscillatory flame was analysed via proper orthogonal decomposition (POD), revealing distinct signatures in both mode shapes and phase portraits for transitions in the acoustically coupled combustion process. For Reynolds numbers between 20 and 100, and for low to moderate forcing amplitudes, the flame exhibited sustained oscillatory combustion (SOC) that was highly coupled to the acoustic forcing. Frequency analysis of the temporal POD modes accurately recovered the forcing frequency and its higher harmonics. At higher forcing amplitudes, a multi-frequency response was observed, resulting from a combination of the forcing frequency and much lower frequency oscillations due to periodic lift-off and reattachment (PLOR) of the flame, preceding a transition to flame blow-off (BO). For both single- and triple-jet flames, transitions from SOC to PLOR to BO were characterized by significant alterations in primary modal energetic content, deflection and eventual smearing in phase portraits, and the development of additional frequencies in modal spectra, although transitional behaviour for the triple jet flames involved additional complexity in the dynamics due to its structure. These features provide the potential for the development of reduced-order models that can characterize and predict acoustically coupled combustion behaviour.

OBJECTIVE: To examine differences in the use of high- and low-value health care between immigrant and US-born adults. DATA SOURCE: The 2007-2019 Medical Expenditure Panel Survey. STUDY DESIGN: We split the sample into younger (ages 18-64 years) and older adults (ages 65 years and over). Our outcome measures included the use of high-value care (eight services) and low-value care (seven services). Our key independent variable was immigration status. For each outcome, we ran regressions with and without individual-level characteristics. DATA COLLECTION/EXTRACTION METHODS: N/A. PRINCIPAL FINDINGS: Before accounting for individual-level characteristics, the use of high- and low-value care was lower among immigrant adults than US-born adults. After accounting for individual-level characteristics, this difference decreased in both groups of younger and older adults. For high-value care, significant differences were observed in five services and the direction of the differences was mixed. The use of breast cancer screening was lower among immigrant than US-born younger and older adults (-5.7 [95% CI: -7.4 to -3.9] and -2.9 percentage points [95% CI: -5.6 to -0.2]) while the use of colorectal cancer screening was higher among immigrant than US-born younger and older adults (2.6 [95% CI: 0.5 to 4.8] and 3.6 [95% CI: 0.2 to 7.0] percentage points). For low-value care, we did not identify significant differences except for antibiotics for acute upper respiratory infection among younger adults and opioids for back pain among older adults (-3.5 [95% CI: -5.5 to -1.5] and -3.8[95% CI: -7.3 to -0.2] percentage points). Particularly, differences in socioeconomic status, health insurance, and care access between immigrant and US-born adults played a key role in accounting for differences in the use of high- and low-value health care. The use of high-value care among immigrant and US-born adults increased over time, but the use of low-value care did not decrease. CONCLUSION: Differential use of high- and low-value care between immigrant and US-born adults may be partly attributable to differences in individual-level characteristics, especially socioeconomic status, health insurance, and access to care.

Environmental mercury (Hg) contamination of the global tropics outpaces our understanding of its consequences for biodiversity. Knowledge gaps of pollution exposure could obscure conservation threats in the Neotropics: a region that supports over half of the worlds species, but faces ongoing land-use change and Hg emission via artisanal and small-scale gold mining (ASGM). Due to their global distribution and sensitivity to pollution, birds provide a valuable opportunity as bioindicators to assess how accelerating Hg emissions impact an ecosystems ability to support biodiversity, and ultimately, global health. We present the largest database on Neotropical bird Hg concentrations (n = 2316) and establish exposure baselines for 322 bird species spanning nine countries across Central America, South America, and the West Indies. Patterns of avian Hg exposure in the Neotropics broadly align with those in temperate regions: consistent bioaccumulation across functional groups and high spatiotemporal variation. Bird species occupying higher trophic positions and aquatic habitats exhibited elevated Hg concentrations that have been previously associated with reductions in reproductive success. Notably, bird Hg concentrations were over four times higher at sites impacted by ASGM activities and differed by season for certain trophic niches. We developed this synthesis via a collaborative research network, the Tropical Research for Avian Conservation and Ecotoxicology (TRACE) Initiative, which exemplifies inclusive, equitable, and international data-sharing. While our findings signal an urgent need to assess sampling biases, mechanisms, and consequences of Hg exposure to tropical avian communities, the TRACE Initiative provides a meaningful framework to achieve such goals. Ultimately, our collective efforts support and inform local, scientific, and government entities, including Parties of the United Nations Minamata Convention on Mercury, as we continue working together to understand how Hg pollution impacts biodiversity conservation, ecosystem function, and public health in the tropics.

Wetlands are responsible for 20%–31% of global methane (CH4) emissions and account for a large source of uncertainty in the global CH4 budget. Data-driven upscaling of CH4 fluxes from eddy covariance measurements can provide new and independent bottom-up estimates of wetland CH4 emissions. Here, we develop a six-predictor random forest upscaling model (UpCH4), trained on 119 site-years of eddy covariance CH4 flux data from 43 freshwater wetland sites in the FLUXNET-CH4 Community Product. Network patterns in site-level annual means and mean seasonal cycles of CH4 fluxes were reproduced accurately in tundra, boreal, and temperate regions (Nash-Sutcliffe Efficiency ∼0.52–0.63 and 0.53). UpCH4 estimated annual global wetland CH4 emissions of 146 ± 43 TgCH4 y−1 for 2001–2018 which agrees closely with current bottom-up land surface models (102–181 TgCH4 y−1) and overlaps with top-down atmospheric inversion models (155–200 TgCH4 y−1). However, UpCH4 diverged from both types of models in the spatial pattern and seasonal dynamics of tropical wetland emissions. We conclude that upscaling of eddy covariance CH4 fluxes has the potential to produce realistic extra-tropical wetland CH4 emissions estimates which will improve with more flux data. To reduce uncertainty in upscaled estimates, researchers could prioritize new wetland flux sites along humid-to-arid tropical climate gradients, from major rainforest basins (Congo, Amazon, and SE Asia), into monsoon (Bangladesh and India) and savannah regions (African Sahel) and be paired with improved knowledge of wetland extent seasonal dynamics in these regions. The monthly wetland methane products gridded at 0.25° from UpCH4 are available via ORNL DAAC (https://doi.org/10.3334/ORNLDAAC/2253).

Advances in electrocatalysis research rely heavily on building a thorough mechanistic understanding of catalyst active sites under realistic operating conditions. Only recently have techniques emerged that enable sensitive spectroscopic data collection to distinguish catalytically relevant surface sites from the underlying bulk material under applied potential in the presence of an electrolyte layer. Here, we demonstrate that operando high-energy-resolution fluorescence detected X-ray absorption spectroscopy (HERFD-XAS) is a powerful spectroscopic method which offers critical surface chemistry insights in CO2 electroreduction with sub-electronvolt energy resolution using hard X-rays. Combined with the high surface area-to-volume ratio of 5 nm copper nanoparticles, operando HERFD-XAS allows us to observe with clear evidence the breaking of chemical bonds between the ligands and the Cu surface as part of the ligand desorption process occurring under electrochemical potentials relevant for the CO2 reduction reaction (CO2RR). In addition, the dynamic evolution of oxidation state and coordination number throughout the operation of the nanocatalyst was continuously tracked. With these results in hand, undercoordinated metallic copper nanograins are proposed to be the real active sites in the CO2RR. This work emphasizes the importance of HERFD-XAS compared to routine XAS in catalyst characterization and mechanism exploration, especially in the complicated electrochemical CO2RR.

We present the first detection of the baryon acoustic oscillations (BAOs) signal obtained using unblinded data collected during the initial 2 months of operations of the Stage-IV ground-based Dark Energy Spectroscopic Instrument (DESI). From a selected sample of 261 291 luminous red galaxies spanning the redshift interval 0.4 < z < 1.1 and covering 1651 square degrees with a 57.9 per cent completeness level, we report a ∼5σ level BAO detection and the measurement of the BAO location at a precision of 1.7 per cent. Using a bright galaxy sample of 109 523 galaxies in the redshift range 0.1 < z < 0.5, over 3677 square degrees with a 50.0 per cent completeness, we also detect the BAO feature at ∼3σ significance with a 2.6 per cent precision. These first BAO measurements represent an important milestone, acting as a quality control on the optimal performance of the complex robotically actuated, fibre-fed DESI spectrograph, as well as an early validation of the DESI spectroscopic pipeline and data management system. Based on these first promising results, we forecast that DESI is on target to achieve a high-significance BAO detection at sub-per cent precision with the completed 5-yr survey data, meeting the top-level science requirements on BAO measurements. This exquisite level of precision will set new standards in cosmology and confirm DESI as the most competitive BAO experiment for the remainder of this decade.

Interferon lambda 4 (IFN-λ4) is a novel type-III interferon that can be expressed only by carriers of the genetic variant rs368234815-dG within the first exon of the IFNL4 gene. Genetic inability to produce IFN-λ4 (in carriers of the rs368234815-TT/TT genotype) has been associated with improved clearance of hepatitis C virus (HCV) infection. The IFN-λ4-expressing rs368234815-dG allele (IFNL4-dG) is most common (up to 78%) in West sub-Saharan Africa (SSA), compared to 35% of Europeans and 5% of individuals from East Asia. The negative selection of IFNL4-dG outside Africa suggests that its retention in African populations could provide survival benefits, most likely in children. To explore this hypothesis, we conducted a comprehensive association analysis between IFNL4 genotypes and the risk of childhood Burkitt lymphoma (BL), a lethal infection-associated cancer most common in SSA. We used genetic, epidemiologic, and clinical data for 4,038 children from the Epidemiology of Burkitt Lymphoma in East African Children and Minors (EMBLEM) and the Malawi Infections and Childhood Cancer case-control studies. Generalized linear mixed models fit with the logit link controlling for age, sex, country, P. falciparum infection status, population stratification, and relatedness found no significant association between BL risk and 3 coding genetic variants within IFNL4 (rs368234815, rs117648444, and rs142981501) and their combinations. Because BL occurs in children 6-9 years of age who survived early childhood infections, our results suggest that additional studies should explore the associations of IFNL4-dG allele in younger children. This comprehensive study represents an important baseline in defining the health effects of IFN-λ4 in African populations.

Abstract: The tropical forest carbon sink is known to be drought sensitive, but it is unclear which forests are the most vulnerable to extreme events. Forests with hotter and drier baseline conditions may be protected by prior adaptation, or more vulnerable because they operate closer to physiological limits. Here we report that forests in drier South American climates experienced the greatest impacts of the 2015–2016 El Niño, indicating greater vulnerability to extreme temperatures and drought. The long-term, ground-measured tree-by-tree responses of 123 forest plots across tropical South America show that the biomass carbon sink ceased during the event with carbon balance becoming indistinguishable from zero (−0.02 ± 0.37 Mg C ha−1 per year). However, intact tropical South American forests overall were no more sensitive to the extreme 2015–2016 El Niño than to previous less intense events, remaining a key defence against climate change as long as they are protected.

The cervicovaginal microbiota is influenced by host physiology, immunology, lifestyle, and ethnicity. We hypothesized that there would be differences in the cervicovaginal microbiota among pregnant, nonpregnant, and menopausal women living in Puerto Rico (PR) with and without human papillomavirus (HPV) infection and cervical cancer. We specifically wanted to determine if the microbiota is associated with variations in cervical cytology. A total of 294 women, including reproductive-age nonpregnant (N = 196), pregnant (N = 37), and menopausal (N = 61) women, were enrolled. The cervicovaginal bacteria were characterized by 16S rRNA amplicon sequencing, the HPV was genotyped with SPF10-LiPA, and cervical cytology was quantified. High-risk HPV (HR-HPV, 67.3%) was prevalent, including genotypes not covered by the 9vt HPV vaccine. Cervical lesions (34%) were also common. The cervical microbiota was dominated by Lactobacillus iners. Pregnant women in the second and third trimesters exhibited a decrease in diversity and abundance of microbes associated with bacterial vaginosis. Women in menopause had greater alpha diversity, a greater proportion of facultative and strictly anaerobic bacteria, and higher cervicovaginal pH than premenopausal women. Cervical lesions were associated with greater alpha diversity. However, no significant associations between the microbiota and HPV infection (HR or LR-HPV types) were found. The cervicovaginal microbiota of women living in Puerto Rican were either dominated by L. iners or diverse microbial communities regardless of a womans physiological stage. We postulate that the microbiota and the high prevalence of HR-HPV increase the risk of cervical lesions among women living in PR. IMPORTANCE In the enclosed manuscript, we provide the first in-depth characterization of the cervicovaginal microbiota of Hispanic women living in Puerto Rico (PR), using a 16S rRNA approach, and include women of different physiological stages. Surprisingly we found that high-risk HPV was ubiquitous with a prevalence of 67.3%, including types not covered by the 9vt HPV vaccine. We also found highly diverse microbial communities across women groups-with a reduction in pregnant women, but dominated by nonoptimal Lactobacillus iners. Additionally, we found vaginosis-associated bacteria as Dialister spp., Gardnerella spp., Clostridium, or Prevotella among most women. We believe this is a relevant and timely article expanding knowledge on the cervicovaginal microbiome of PR women, where we postulate that these highly diverse communities are conducive to cervical disease.

Taxes on sugar-sweetened beverages (SSBs), or drinks with added sugars, show promise in decreasing purchases and consumption of SSBs. Some have called for coupling such taxes with improvements in access to safe drinking water as a strategy for reducing inequities in SSB intake, yet no studies have examined such an approach. Drink Tap is a San Francisco-based program in which public tap water stations were installed in parks and public spaces (winter 2017) and promotional efforts (fall and winter 2018) encouraged water intake. At the same time, San Francisco and surrounding communities were also implementing SSB taxes. We conducted a quasi-experimental study to examine whether water access and promotion combined with SSB taxes affected beverage intake habits more than SSB taxes alone. We conducted 1-hour observations (N = 960) at 10 intervention parks (Drink Tap plus SSB taxes) and 20 comparison parks (SSB taxes only) in San Francisco Bay Area cities before (July-September 2016) and after (June-August 2019) implementation of Drink Tap. We found significant adjusted percentage increases in drinking water among visitors to intervention parks, compared with comparison parks: water from park water sources (+80%, P < .001) and water from reusable bottles (+40%, P = .02). We found no significant reductions in visitors observed drinking bottled water, juices, or SSBs. The Drink Tap intervention led to increases in water intake from park sources and reusable bottles across parks that surpassed increases achieved through SSB taxes alone. Jurisdictions should consider coupling tap water access and promotion with policies for reducing intake of SSBs.

An aerosol jet printing-enabled dual-function biosensor for the sensitive detection of pathogens using SARS-CoV-2 RNA as an example has been developed. A CRISPR-Cas13:guide-RNA complex is activated in the presence of a target RNA, leading to the collateral trans-cleavage of ssRNA probes that contain a horseradish peroxidase (HRP) tag. This, in turn, catalyzes the oxidation of 3,3,5,5-tetramethylbenzidine (TMB) by HRP, resulting in a color change and electrochemical signal change. The colorimetric and electrochemical sensing protocol does not require complicated target amplification and probe immobilization and exhibits a detection sensitivity in the femtomolar range. Additionally, our biosensor demonstrates a wide dynamic range of 5 orders of magnitude. This low-cost aerosol inkjet printing technique allows for an amplification-free and integrated dual-function biosensor platform, which operates at physiological temperature and is designed for simple, rapid, and accurate point-of-care (POC) diagnostics in either low-resource settings or hospitals.