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Abstract: Terrestrial evapotranspiration is the second‐largest component of the land water cycle, linking the water, energy, and carbon cycles and influencing the productivity and health of ecosystems. The dynamics of ET across a spectrum of spatiotemporal scales and their controls remain an active focus of research across different science disciplines. Here, we provide an overview of the current state of ET science across in situ measurements, partitioning of ET, and remote sensing, and discuss how different approaches complement one another based on their advantages and shortcomings. We aim to facilitate collaboration among a cross‐disciplinary group of ET scientists to overcome the challenges identified in this paper and ultimately advance our integrated understanding of ET.

Genetically heterogeneous UM-HET3 mice born in 2020 were used to test possible lifespan effects of alpha-ketoglutarate (AKG), 2,4-dinitrophenol (DNP), hydralazine (HYD), nebivolol (NEBI), 16α-hydroxyestriol (OH_Est), and sodium thiosulfate (THIO), and to evaluate the effects of canagliflozin (Cana) when started at 16 months of age. OH_Est produced a 15% increase (p = 0.0001) in median lifespan in males but led to a significant (7%) decline in female lifespan. Cana, started at 16 months, also led to a significant increase (14%, p = 0.004) in males and a significant decline (6%, p = 0.03) in females. Cana given to mice at 6 months led, as in our previous study, to an increase in male lifespan without any change in female lifespan, suggesting that this agent may lead to female-specific late-life harm. We found that blood levels of Cana were approximately 20-fold higher in aged females than in young males, suggesting a possible mechanism for the sex-specific disparities in its effects. NEBI was also found to produce a female-specific decline (4%, p = 0.03) in lifespan. None of the other tested drugs provided a lifespan benefit in either sex. These data bring to 7 the list of ITP-tested drugs that induce at least a 10% lifespan increase in one or both sexes, add a fourth drug with demonstrated mid-life benefits on lifespan, and provide a testable hypothesis that might explain the sexual dimorphism in lifespan effects of the SGLT2 inhibitor Cana.

This study examined the clinical utility of the Massachusetts Youth Screening Instrument--Second Version (MAYSI-2) among African American (AA) incarcerated youth and used White incarcerated youth as a comparison group. Data were analyzed for 314 incarcerated youth (193 AA offenders and 121 White offenders) of ages 13-17 years who were adjudicated delinquent from a southeastern United States medium security residential facility. Seven logistic regression and receiver operating characteristic curve (ROC) models were built to determine whether the MAYSI-2 subscales accurately identify committed AA male incarcerated youth who have a mental illness diagnosis on file. Analyses also examined how well the MAYSI-2 subscales identify specific mental illnesses among AA-committed male incarcerated youth. Results demonstrated that no MAYSI-2 subscales accurately identified and categorized AA-committed male incarcerated youth who have mental disorders, and only two subscales (Alcohol/Drug Use, Depressed/Anxious) identified and categorized White committed male incarcerated youth who have a mental disorder. Additional results and implications for research and practice are provided.

Intracellular calcium (Ca2+) is ubiquitous to cell signaling across biology. While existing fluorescent sensors and reporters can detect activated cells with elevated Ca2+ levels, these approaches require implants to deliver light to deep tissue, precluding their noninvasive use in freely behaving animals. Here we engineered an enzyme-catalyzed approach that rapidly and biochemically tags cells with elevated Ca2+ in vivo. Ca2+-activated split-TurboID (CaST) labels activated cells within 10 min with an exogenously delivered biotin molecule. The enzymatic signal increases with Ca2+ concentration and biotin labeling time, demonstrating that CaST is a time-gated integrator of total Ca2+ activity. Furthermore, the CaST readout can be performed immediately after activity labeling, in contrast to transcriptional reporters that require hours to produce signal. These capabilities allowed us to apply CaST to tag prefrontal cortex neurons activated by psilocybin, and to correlate the CaST signal with psilocybin-induced head-twitch responses in untethered mice.

ObjectivesObeticholic acid (OCA) treatment for primary biliary cholangitis (PBC) was conditionally approved in the phase 3 POISE trial. The COBALT confirmatory trial assessed whether clinical outcomes in PBC patients improve with OCA therapy.MethodsPatients randomized to OCA (5-10 mg) were compared with placebo (randomized controlled trial [RCT]) or external control (EC). The primary composite endpoint was time to death, liver transplant, model for end-stage liver disease score ≥15, uncontrolled ascites, or hospitalization for hepatic decompensation. A prespecified propensity score-weighted EC group was derived from a US healthcare claims database.ResultsIn the RCT, the primary endpoint occurred in 28.6% of OCA (n=168) and 28.9% of placebo patients (n=166; intent-to-treat [ITT] analysis hazard ratio [HR]=1.01, 95% CI=0.68-1.51), but functional unblinding and crossover to commercial therapy occurred, especially in the placebo arm. Correcting for these using inverse probability of censoring weighting (IPCW) and as-treated analyses shifted the HR to favor OCA. In the EC (n=1051), the weighted primary endpoint occurred in 10.1% of OCA and 21.5% of non-OCA patients (HR=0.39; 95% CI=0.22-0.69; P=0.001). No new safety signals were identified in the RCT.ConclusionsFunctional unblinding and treatment crossover, particularly in the placebo arm, confounded the ITT estimate of outcomes associated with OCA in the RCT. Comparison with the real-world EC showed that OCA treatment significantly reduced the risk of negative clinical outcomes. These analyses demonstrate the value of EC data in confirmatory trials and suggest that treatment with OCA improves clinical outcomes in patients with PBC.

Understanding the normal function of the Huntingtin (HTT) protein is of significance in the design and implementation of therapeutic strategies for Huntington's disease (HD). Expansion of the CAG repeat in the HTT gene, encoding an expanded polyglutamine (polyQ) repeat within the HTT protein, causes HD and may compromise HTT's normal activity contributing to HD pathology. Here, we investigated the previously defined role of HTT in autophagy specifically through studying HTT's association with ubiquitin. We find that HTT interacts directly with ubiquitin in vitro. Tandem affinity purification was used to identify ubiquitinated and ubiquitin-associated proteins that copurify with a HTT N-terminal fragment under basal conditions. Copurification is enhanced by HTT polyQ expansion and reduced by mimicking HTT serine 421 phosphorylation. The identified HTT-interacting proteins include RNA-binding proteins (RBPs) involved in mRNA translation, proteins enriched in stress granules, the nuclear proteome, the defective ribosomal products (DRiPs) proteome and the brain-derived autophagosomal proteome. To determine whether the proteins interacting with HTT are autophagic targets, HTT knockout (KO) cells and immunoprecipitation of lysosomes were used to investigate autophagy in the absence of HTT. HTT KO was associated with reduced abundance of mitochondrial proteins in the lysosome, indicating a potential compromise in basal mitophagy, and increased lysosomal abundance of RBPs which may result from compensatory up-regulation of starvation-induced macroautophagy. We suggest HTT is critical for appropriate basal clearance of mitochondrial proteins and RBPs, hence reduced HTT proteostatic function with mutation may contribute to the neuropathology of HD.

The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpreting BRCA1 and BRCA2 variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants and documentation revised for clarity and ease of use. The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 uncertain significance or conflicting, 14 pathogenic and/or likely pathogenic, and 13 benign and/or likely benign. Review resolved classification for 11/13 uncertain significance or conflicting variants and retained or improved confidence in classification for the remaining variants. Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in the research processes and the baseline ACMG/AMP criteria. Calibration of evidence strength was key to justify utility and strength of different data types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants.

Climate change is rapidly transforming Arctic landscapes where increasing soil temperatures speed up permafrost thaw. This exposes large carbon stocks to microbial decomposition, possibly worsening climate change by releasing more greenhouse gases. Understanding how microbes break down soil carbon, especially under the anaerobic conditions of thawing permafrost, is important to determine future changes. Here, we studied the microbial community dynamics and soil carbon decomposition potential in permafrost and active layer soils under anaerobic laboratory conditions that simulated an Arctic summer thaw. The microbial and viral compositions in the samples were analyzed based on metagenomes, metagenome-assembled genomes, and metagenomic viral contigs (mVCs). Following the thawing of permafrost, there was a notable shift in microbial community structure, with fermentative Firmicutes and Bacteroidota taking over from Actinobacteria and Proteobacteria over the 60-day incubation period. The increase in iron and sulfate-reducing microbes had a significant role in limiting methane production from thawed permafrost, underscoring the competition within microbial communities. We explored the growth strategies of microbial communities and found that slow growth was the major strategy in both the active layer and permafrost. Our findings challenge the assumption that fast-growing microbes mainly respond to environmental changes like permafrost thaw. Instead, they indicate a common strategy of slow growth among microbial communities, likely due to the thermodynamic constraints of soil substrates and electron acceptors, and the need for microbes to adjust to post-thaw conditions. The mVCs harbored a wide range of auxiliary metabolic genes that may support cell protection from ice formation in virus-infected cells.ImportanceAs the Arctic warms, thawing permafrost unlocks carbon, potentially accelerating climate change by releasing greenhouse gases. Our research delves into the underlying biogeochemical processes likely mediated by the soil microbial community in response to the wet and anaerobic conditions, akin to an Arctic summer thaw. We observed a significant shift in the microbial community post-thaw, with fermentative bacteria like Firmicutes and Bacteroidota taking over and switching to different fermentation pathways. The dominance of iron and sulfate-reducing bacteria likely constrained methane production in the thawing permafrost. Slow-growing microbes outweighed fast-growing ones, even after thaw, upending the expectation that rapid microbial responses to dominate after permafrost thaws. This research highlights the nuanced and complex interactions within Arctic soil microbial communities and underscores the challenges in predicting microbial response to environmental change.

PurposeTriple-negative breast cancer (TNBC) often metastasizes to the central nervous system (CNS) and has the highest propensity among breast cancer subtypes to develop leptomeningeal disease (LMD). LMD is a spread of cancer into leptomeningeal space that speeds up the disease progression and severely aggravates the prognosis. LMD has limited treatment options. We sought to test whether the common anti-helminthic drug mebendazole (MBZ) may be effective against murine TNBC LMD.MethodsA small-molecule screen involving TNBC cell lines identified benzimidazoles as potential therapeutic agents for further study. In vitro migration assays were used to evaluate cell migration capacity and the effect of MBZ. For in vivo testing, CNS metastasis was introduced into BALB/c athymic nude mice through internal carotid artery injections of brain-tropic MDA-MB-231-BR or MCF7-BR cells. Tumor growth and spread was monitored by bioluminescence imaging and immunohistochemistry. MBZ was given orally at 50 and 100 mg/kg doses. MBZ bioavailability was assayed by mass spectrometry.ResultsBioinformatic analysis and migration assays revealed higher migratory capacity of TNBC compared to other breast cancer subtypes. MBZ effectively slowed down migration of TNBC cell line MDA-MB-231 and its brain tropic derivative MDA-MB-231-BR. In animal studies, MBZ reduced leptomeningeal spread, and extended survival in brain metastasis model produced by MDA-MB-231-BR cells. MBZ did not have an effect in the non-migratory MCF7-BR model.ConclusionsWe demonstrated that MBZ is a safe and effective oral agent in an animal model of TNBC CNS metastasis. Our findings are concordant with previous efforts involving MBZ and CNS pathology and support the drug's potential utility to slow down leptomeningeal spread.

Chronic myeloid leukemia (CML) is initiated and maintained by BCR::ABL which is clinically targeted using tyrosine kinase inhibitors (TKIs). TKIs can induce long-term remission but are also not curative. Thus, CML is an ideal system to test our hypothesis that transcriptome-based state-transition models accurately predict cancer evolution and treatment response. We collected time-sequential blood samples from tetracycline-off (Tet-Off) BCR::ABL-inducible transgenic mice and wild-type controls. From the transcriptome, we constructed a CML state-space and a three-well leukemogenic potential landscape. The potential's stable critical points defined observable disease states. Early states were characterized by anti-CML genes opposing leukemia; late states were characterized by pro-CML genes. Genes with expression patterns shaped similarly to the potential landscape were identified as drivers of disease transition. Re-introduction of tetracycline to silence the BCR::ABL gene returned diseased mice transcriptomes to a near healthy state, without reaching it, suggesting parts of the transition are irreversible. TKI only reverted the transcriptome to an intermediate disease state, without approaching a state of health; disease relapse occurred soon after treatment. Using only the earliest time-point as initial conditions, our state-transition models accurately predicted both disease progression and treatment response, supporting this as a potentially valuable approach to time clinical intervention, before phenotypic changes become detectable.

Healthy lifestyle behaviors can improve health-related quality of life (HRQOL) in cancer survivors; but the combination of behaviors most important for HRQOL is not known. This study investigated the patterns of lifestyle behaviors among cancer survivors and differences in HRQOL between behavioral classes. Cancer survivors (n = 2,463) were invited to participate in a cross-sectional survey. Participants (N= 591) were predominately female (63%) and non-Hispanic White (90%). Survey items included self-reported physical activity, diet, smoking, sleep, HRQOL, and demographics. Behavioral classes were estimated by latent class analysis. Differences between classes were assessed by latent class regression. Compared with the "healthy lifestyles" class (higher probabilities of meeting aerobic/strength-based activity guidelines, high fruit/vegetable intake, and no sleep problems; 11% of sample), the "sleep and diet problems with inconsistent physical activity" class (higher probabilities of not meeting strength-based guidelines, low fruit/vegetable intake, some sleep problems; marginally higher probability of meeting aerobic guidelines; 41%) had poorer general and physical HRQOL. The "poor physical activity and diet" class (higher probabilities of not meeting aerobic/strength-based guidelines, low fruit/vegetable intake, and some sleep problems; 48%) had poorer general, physical, and mental HRQOL. Few participants exhibited healthy lifestyle patterns associated with HRQOL. The findings provide opportunities to develop differentiated multiple behavior-change interventions, targeted to two common patterns of behavior. A large subgroup of cancer survivors was susceptible to suboptimal physical activity and diet, warranting interventions exclusively targeting these behaviors. Another subgroup was susceptible to suboptimal physical activity, diet, and sleep, indicating interventions for this group should include strategies targeting these three behaviors.

Schools of choice need to provide equitable access and opportunities to all students, including students with disabilities and emergent bilinguals. In the context of Early College High Schools, principals and school districts should be partners in ensuring admissions processes are non-discriminatory. In this fictional case, a new principal in a high-performing early college high school becomes concerned that the school has been denying or not actively recruiting students with disabilities and emergent bilingual students. However, when she raises her concern with her supervisors and predecessor, she gets no support. The teaching notes of this case review the literature on ethical leadership, school administration dilemmas, and bounded ethicality.

Education in Doctor of Medicine programs has moved towards an emphasis on clinical competency, with entrustable professional activities providing a framework of learning objectives and outcomes to be assessed within the clinical environment. While the identification and structured definition of objectives and outcomes have evolved, many methods employed to assess clerkship students' clinical skills remain relatively unchanged. There is a paucity of medical education research applying advanced statistical design and analytic techniques to investigate the validity of clinical skills assessment. One robust statistical method, multitrait-multimethod matrix analysis, can be applied to investigate construct validity across multiple assessment instruments and settings. Four traits were operationalized to represent the construct of critical clinical skills (professionalism, data gathering, data synthesis, and data delivery). The traits were assessed using three methods (direct observations by faculty coaches, clinical workplace-based evaluations, and objective structured clinical examination type clinical practice examinations). The four traits and three methods were intercorrelated for the multitrait-multimethod matrix analysis. The results indicated reliability values in the adequate to good range across the three methods with the majority of the validity coefficients demonstrating statistical significance. The clearest evidence for convergent and divergent validity was with the professionalism trait. The correlations on the same method/different traits analyses indicated substantial method effect; particularly on clinical workplace-based assessments. The multitrait-multimethod matrix approach, currently underutilized in medical education, could be employed to explore validity evidence of complex constructs such as clinical skills. These results can inform faculty development programs to improve the reliability and validity of assessments within the clinical environment.

A major challenge for juvenile correctional facilities (JCF) is providing literacy instruction to a transitory student population with a wide range of literacy abilities. The purpose of this study was to identify unique literacy profiles of students in long-term JCF taking into consideration their reading abilities, language abilities, intelligence quotient (IQ), disability classification, age, and grade level. Using latent profile analyses with a sample of 370 in the southeastern United States, we identified three distinct classes. Three ability groups of students (average literacy abilities, below-average literacy abilities, substantially below-average literacy abilities) were identified. Thirty-six percent performed at the average level, 55% performed below grade level; and 8% had substantial literacy deficits with an overrepresentation of students with emotional disturbance (ED) and specific learning disability (SLD). Findings provide the foundation for an evidence-based multi-tiered system of supports literacy framework within JCF. Instructional implications concerning the provision of English Language Arts in JCF are provided.

BACKGROUND: Organophosphate esters (OPEs), used ubiquitously as flame retardants and plasticizers in consumer products, are suspected of having developmental toxicity. OBJECTIVES: Our study aimed to estimate associations between prenatal exposure to OPEs and fetal growth, including both ultrasound (head circumference, abdominal circumference, femur length, and estimated fetal weight) and delivery [birth weight z-score, small-for-gestational age (SGA), and large-for-gestational age (LGA)] measures of growth. METHODS: In the LIFECODES Fetal Growth Study (2008-2018), an enriched case--cohort of 900 babies born at the small and large ends of the growth spectrum, we quantified OPE biomarkers in three urine samples per pregnant participant and abstracted ultrasound and delivery measures of fetal growth from medical records. We estimated associations between pregnancy-averaged log-transformed OPE biomarkers and repeated ultrasound measures of fetal growth using linear mixed-effects models, and delivery measures of fetal growth using linear (birth weight) and logistic (SGA and LGA) regression models. RESULTS: Most OPE biomarkers were positively associated with at least one ultrasound measure of fetal growth, but associations with delivery measures were largely null. For example, an interquartile range (IQR; 1.31 ng=mL) increase in bis(2-chloroethyl) phosphate concentration was associated with larger z-scores in head circumference [mean difference (difference): 0.09; 95% confidence interval (CI): 0.01, 0.17], abdominal circumference (difference: 0.10; 95% CI: 0.02, 0.18), femur length (difference: 0.11; 95% CI: 0.03, 0.19), and estimated fetal weight (difference: 0.13; 95% CI: 0.04, 0.22) but not birth weight (difference: 0.04; 95% CI: -0.08, 0.17). At delivery, an IQR (1.00 ng=mL) increase in diphenyl phosphate (DPHP) concentration was associated with an SGA birth (odds ratio: 1.46; 95% CI: 1.10, 1.94). CONCLUSIONS: In a large prospective cohort, gestational OPE exposures were associated with larger fetal size during pregnancy, but associations at delivery were null. DPHP concentrations were associated with heightened risk of an SGA birth. These findings suggest that OPE exposure may affect fetal development. https://doi.org/10.1289/EHP14647, Introduction Organophosphate esters (OPEs) are high-production chemicals in widespread global use. (1) They are organic esters of phosphoric acid--containing alkyl chains or aryl groups, which may be halo-genated or nonhalogenated. [...]

Secondary-postsecondary partnership reforms have grown in scale and importance throughout the past few decades as part of the national agenda to increase college access, equity, and completion. However, little research has examined the role of the principal in cross-sector partnerships. This qualitative case study explores how one nationally acclaimed principal at an award-winning early college high school made sense of the cross-sector context and negotiated with K-12 and higher education stakeholders to maximize college opportunity for low-income, Latinx, and first-generation students. Our analysis integrates sensemaking and micropolitical theory to identify leadership practices that facilitate effective cross-sector collaboration, with implications for K-12 leadership and cross-sector partnership reform.

This longitudinal study examined the relationship between two content formats of the basic communication course (BCC) and first-year college student retention over a 4-year period (N = 5,653). Chi-square and logistic regression models indicated students who completed the BCC were more likely to be retained than those who did not complete the BCC. While completing the BCC was associated with retention for both formats, the hybrid BCC was more consistently related to retention than the public speaking BCC. Students from certain demographic groups who completed the hybrid BCC were retained more frequently than students from the same demographic who did not complete the hybrid BCC. Demographics for the public speaking BCC revealed a different retention profile. Implications and future directions concerning the BCC are discussed.

How can we engage new engineering and computer science graduate students in meaningful conversations about research and publication ethics without establishing a common understanding of the issues and expectations? Most universities offer extensive responsible conduct of research (RCR) training programs, which are usually a semester-long. Absent a requirement, it is unlikely that engineering and computer graduate students and their advisors would prioritize a lengthy training during the student's first semester. Recognizing this, the University of Nevada, Las Vegas' Howard R. Hughes College of Engineering designed and implemented an introductory research ethics workshop for all graduate students entering engineering and computer science. We engaged an interdisciplinary team of faculty and staff in the workshop's design and implementation, and approached our design within the sensemaking framework for ethical decision-making. Each workshop included lecture content in four priority topic areas identified by the college faculty: research design and data ethics, publication ethics, computer coding ethics, and intellectual property. The workshops also included a face-to-face panel discussion with experts including engineering, computer science, and law professors; librarians; and technical writers. Our assessment showed that after completing the workshop, students demonstrated increased content knowledge, and their self-assessed expertise ratings were better aligned with their content knowledge.