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The Space Weather Investigation Frontier (SWIFT) mission will aim at making major discoveries on the three-dimensional structure and dynamics of heliospheric structures that drive space weather. The focus will be on Interplanetary Coronal Mass Ejections (ICMEs) that originate from massive expulsions of plasma and magnetic flux from the solar corona. They cause the largest geomagnetic storms and solar energetic particle events, threatening to endanger life and disrupt technology on Earth and in space. A big current problem, both regarding fundamental solar-terrestrial physics and space weather, is that we do not yet understand spatial characteristics and temporal evolution of ICMEs and that the existing remote-sensing and in-situ observatories are not suited for resolving multi-layered and evolutionary structures in these massive storm drivers. Here, we propose a groundbreaking mission concept study using solar sail technology that, for the first time, will make continuous, in-situ multi-point observations along the Sun-Earth line beyond the Lagrange point L1 (sub-L1). This unique position, in combination with L1 assets, will allow distinguishing between local and global processes, spatial characteristics, temporal evolution, and particle energization mechanisms related to ICMEs. In addition, measurements of the magnetic field in earthbound ICMEs and their sub-structures from the SWIFT location will double the current forecasting lead-times from L1. This concept also paves the way for missions with increasingly longer forecasting lead-times, addressing NASA and NOAA’s space weather goals, as set forth by the Decadal Survey. The objective of this communication is to inform the community of the ongoing effort, including plans to further develop the mission concept, supported by the Heliophysics Flight Opportunities Studies (HFOS) program under NASA’s Research Opportunities in Space and Earth Sciences (ROSES).

Providing an accurate above-ground biomass (AGB) map is of paramount importance for carbon stock and climate change monitoring. The main objective of this study is to compare the performance of pixel-based and object-based approaches for AGB estimation of temperate forests in north-eastern of New York State. Second, the capabilities of optical, SAR, and optical + SAR data were investigated. To achieve the goals, the random forest (RF) regression algorithm was used to model and predict the AGB values. Optical (i.e. Landsat 5TM, Landsat 8 OLI, and Sentinel-2), synthetic aperture radar (SAR) (Sentinel-1 and global phased array type L-band SAR (PALSAR/PALSAR-2)), and their integration have been used to estimate the AGB. It is worth mentioning that the airborne light detection and ranging (LiDAR) AGB raster has been used as a reference data for training/testing purposes. The results demonstrate that the OBIA approach enhanced the RMSE of AGB estimation about 5.32 Mg/ha, 8.9 Mg/ha, and 5.29 Mg/ha for optical, SAR, and optical + SAR data, respectively. Moreover, optical + SAR data with the RMSE of 42.63 Mg/ha and R2 of 0.72 for pixel-based and RMSE of 37.31 Mg/ha and R2 of 0.77 for object-based approach provided the best results.

The above-ground biomass (AGB) estimation monitoring provides a powerful tool for the assessment of carbon emission and sequestration. Using remote sensing technique is an environmentally friendly way of biomass estimation. Thus, this paper investigated optical (i.e. Landsat 8 OLI and Sentinel-2), synthetic aperture radar (SAR) (global phased array type L-band SAR (PALSAR/PALSAR-2) and Sentinel-1), and their integration for AGB estimation of the Pack demonstration forest in Warrensburg, NY. Importantly, a LiDAR AGB raster of the study area was used as reference data for training/testing purposes. Then, an extreme gradient boosting (Xgboost) machine learning model was used to predict biomass values. The major goal of this study was to compare the performance of pixel-based and object-based image analysis (OBIA) for the AGB estimation. Results indicated that the object-based approach improved the RMSE of AGB prediction about 6.28 Mg/ha for optical + SAR, 6.17 Mg/ha for SAR, and 5.6 Mg/ha for optical data in comparison to the pixel-based approach. Moreover, the combination of optical and SAR data increased the prediction accuracy regardless of feature extraction approach.

Abstract Background It is unclear whether diet affects glycaemic control in type 2 diabetes (T2D), over and above its effects on bodyweight. We aimed to assess whether changes in dietary patterns altered glycaemic control independently of effects on bodyweight in newly diagnosed T2D. Methods We used data from 4-day food diaries, HbA1c and potential confounders in participants of the Early-ACTivity-In-Diabetes trial measured at 0, 6 and 12 months. At baseline, a ‘carb/fat balance’ dietary pattern and an ‘obesogenic’ dietary pattern were derived using reduced-rank regression, based on hypothesised nutrient-mediated mechanisms linking dietary intake to glycaemia directly or via obesity. Relationships between 0 and 6 month change in dietary pattern scores and baseline-adjusted HbA1c at 6 months (n = 242; primary outcome) were assessed using multivariable linear regression. Models were repeated for periods 6–12 months and 0–12 months (n = 194 and n = 214 respectively; secondary outcomes). Results Reductions over 0–6 months were observed in mean bodyweight (− 2.3 (95% CI: − 2.7, − 1.8) kg), body mass index (− 0.8 (− 0.9, − 0.6) kg/m2), energy intake (− 788 (− 953, − 624) kJ/day), and HbA1c (− 1.6 (− 2.6, -0.6) mmol/mol). Weight loss strongly associated with lower HbA1c at 0–6 months (β = − 0.70 [95% CI − 0.95, − 0.45] mmol/mol/kg lost). Average fat and carbohydrate intakes changed to be more in-line with UK healthy eating guidelines between 0 and 6 months. Dietary patterns shifting carbohydrate intakes higher and fat intakes lower were characterised by greater consumption of fresh fruit, low-fat milk and boiled/baked potatoes and eating less of higher-fat processed meats, butter/animal fats and red meat. Increases in standardised ‘carb/fat balance’ dietary pattern score associated with improvements in HbA1c at 6 months independent of weight loss (β = − 1.54 [− 2.96, − 0.13] mmol/mol/SD). No evidence of association with HbA1c was found for this dietary pattern at other time-periods. Decreases in ‘obesogenic’ dietary pattern score were associated with weight loss (β = − 0.77 [− 1.31, − 0.23] kg/SD) but not independently with HbA1c during any period. Conclusions Promoting weight loss should remain the primary nutritional strategy for improving glycaemic control in early T2D. However, improving dietary patterns to bring carbohydrate and fat intakes closer to UK guidelines may provide small, additional improvements in glycaemic control. Trial registration ISRCTN92162869 . Retrospectively registered on 25 July 2005

Abstract Background The Learning Assistant (LA) model with its subsequent support and training has evidenced significant gains for undergraduate STEM learning and persistence, especially in high-stakes courses like Calculus. Yet, when a swift and unexpected transition occurs from face-to-face to online, remote learning of the LA environment, it is unknown how LAs are able to maintain their motivation (competence, autonomy, and relatedness), adapt to these new challenges, and sustain their student-centered efforts. This study used Self-Determination Theory (SDT) to model theoretical aspects of LAs’ motivations (persistence and performance) both before and after changes were made in delivery of a Calculus II course at Texas Tech University due to COVID-19 interruptions. Results Analysis of weekly written reflections, a focus group session, and a post-course questionnaire of 13 Calculus II LAs throughout Spring semester of 2020 showed that LAs’ reports of competence proportionally decreased when they transitioned online, which was followed by a moderate proportional increase in reports of autonomy (actions they took to adapt to distance instruction) and a dramatic proportional increase in reports of relatedness (to build structures for maintaining communication and building community with undergraduate students). Conclusions Relatedness emerged as the most salient factor from SDT to maintain LA self-determination due to the COVID-19 facilitated interruption to course delivery in a high-stakes undergraduate STEM course. Given that online learning continues during the pandemic and is likely to continue after, this research provides an understanding to how LAs responded to this event and the mounting importance of relatedness when LAs are working with undergraduate STEM learners. Programmatic recommendations are given for enhancing LA preparation including selecting LAs for autonomy and relatedness factors (in addition to competence), modeling mentoring for remote learners, and coaching in best practices for online instruction.

Sustainable forest management is a critical topic which contributes to ecological, economical, and socio-cultural aspect of the environment. Providing accurate AGB maps is of paramount importance for sustainable forest management, carbon accounting, and climate change monitoring. The main goal of this study was to leverage the potential of two machine learning algorithms for predicting AGB using optical and synthetic aperture radar (SAR) datasets. To achieve this goal random forest (RF) and light gradient boosting machine (LightGBM) models were deployed to predict AGB values in Huntington Wild Forest (HWF) in Essex County, NY using continuous forest inventory (CFI) plots. Both models were trained and evaluated based on airborne light detection and ranging (LiDAR) data, Landsat imagery, advanced land observing satellite (ALOS) phased array type L-band Synthetic Aperture Radar (PALSAR), and their combination. The integration of airborne LiDAR, optic, and SAR datasets provided the best results in terms of root mean square error (RMSE) and mean bias error (MBE). The RF model outperformed the LightGBM in all scenarios (LiDAR, Landsat 5, ALOS PALSAR, and their combination). The RF model was able to predict AGB values with the RMSE of 51.90 Mg/ha and MBE of −0.189 Mg/ha for the combination of LiDAR, optic, and SAR data, while LightGBM estimated the AGB values with the RMSE of 52.78 Mg/ha and MBE of −0.253 Mg/ha. LightGBM is more sensitive to noise and there are lots of hyperparameters that need to be tuned which highly affect its performance.

Forest is one of the most crucial Earth’s resources. Forest above-ground biomass (AGB) mapping has been research endeavors for a long time in many applications since it provides valuable information for carbon cycle monitoring, deforestation, and forest degradation monitoring. A methodology to rapidly and accurately estimate AGB is essential for forest monitoring purposes. Thus, the main objective of this paper was to investigate the performance of decision tree-based models to predict AGB at a site in Huntington Wild Forest (HWF) in Essex County, NY using continuous forest inventory (CFI) plots. The results of decision tree, random forest, and deep forest regression models were compared using light detection and ranging (LiDAR), Landsat 5 TM, and a combination of them. The results illustrated the importance of integration of Landsat 5 TM and LiDAR data, which benefits from both vertical forest structure and spectral information reflected by canopy cover. In addition, the deep forest model with a root mean square error (RMSE) of 51.63 Mg/ha and R-squared (R2) of 0.45 outperformed other regression tree-based models, regardless of the dataset.

Purpose: There is little consensus in the literature regarding a) what it means for a school leader to lead with data, and b) how to measure data-informed leadership in a reliable and valid way. This study examines the psychometric properties of an operational measure intended to assess the extent to which a school leader is a data-informed school leader. The measurement invariance, reliabilities and construct and predictive validities of the "Data-Informed School Leadership Survey" (DISL Survey) are assessed using various psychometric statistical techniques. Methods: Using data collected from 155 teachers from 7 public schools in a southern state, the following psychometric statistics used to address our purpose: the Many-Facet Rasch (MFR) Model, Bayesian second-order Confirmatory Factor Analysis (CFA), Bayesian Structural Equation Modeling--Multiple Indicators, Multiple Causes analysis (Bayesian SEM-MIMIC), and reliability analysis. Findings: Results show an adequate fit from all MFR, Bayesian CFA, and MIMIC models and a high reliability (Cronbach [alpha] = 0.98). The DISL Survey instrument exhibits sound psychometric properties. Results likewise confirm the value of using MFR modeling and Bayesian methods to examine the psychometric properties of DISL Survey as a means of improving educational leadership measures. Implications for Research and Practice: Data from this study confirm the validity and reliability of the "Data-Informed School Leadership Survey" (DISL Survey) as an instrument to assess the strengths and weaknesses of Data-Informed School Leadership (DISL) and as a means for providing feedback for improving such leadership. Heretofore a measure for assessing this leadership was non-existent.

Background. Measuring physical activity behaviours of stroke survivors in the inpatient setting is challenging. Authors of observational studies of early poststroke report that stroke survivors are “inactive and alone”. Using activity monitoring devices may help refine clinical practice and inform therapeutic activity targets. Aim. To measure the physical activity behaviour of stroke survivors during acute inpatient hospitalisation. We hypothesized that greater levels of inactivity would be positively associated with stroke severity and age. Method. Using a cross-sectional study design, consecutive stroke patients admitted to an acute stroke unit (Geelong, Australia) and recruited within 48 hours of admission had their physical activity recorded using an ActivPAL™ accelerometer device over a minimum of 3 days. Activity was categorised as time spent inactive (lying or sitting), standing, or stepping. The number of steps per day was recorded. Demographic and ActivPal™ data are described. Results. Seventy-eight stroke survivors were recruited of whom 54 had complete data for 3 days, all starting within 2 days poststroke. Of the 54 participants, 32 had a mild stroke, 17 moderate, and five severe stroke. Nine were able to walk independently at admission. The median age was 82.5 years (interquartile range (IQR) 74-86), 26 were female. On average, during their inpatient stay, participants spent a median of 98% of their admission inactive. A median of 18 minutes per day was spent standing and less than a minute per day was spent walking amounting to a median of 169 steps taken per day. Conclusion. The ActivePal™ device was feasible to use in an acute stroke setting. We observed high levels of inactivity in the first days post-stroke, highlighting the ongoing challenge of promoting activity in the acute stroke period. To our knowledge, this is the largest study to provide objective data on time spent upright, walking, and sedentary using accelerometer data in an acute stroke setting.

Background: Laboratory measurements of trace elements such as magnesium (Mg), copper (Cu), and zinc (Zn) in red blood cells (RBCs) are essential for assessing nutritional status and diagnosing metal toxicity. The purpose of this study was to develop and validate an ICP-MS method for quantifying these elements in RBCs. Methods: Packed RBCs were aliquoted and diluted in an alkaline diluent solution containing internal standards, 0.1 % Triton X-100, 0.1 % EDTA, and 1 % ammonium hydroxide. The resulting diluted specimen was analyzed using inductively coupled plasma mass spectrometry (ICP-MS) to quantitatively determine the levels of Mg, Cu, and Zn. The method underwent validation for accuracy, precision, method comparison, linearity, analytical sensitivity, and carryover. Additionally, retrospective data were analyzed, and non-parametric reference intervals were calculated. Results: Accuracy and linearity fell within the expected range of ≤±15 % for all analytes. Within-run, between-run, and total imprecision were ≤15 % coefficient of variation. All other validation experiments met the established acceptance criteria. Retrospective data analysis was conducted on patient samples using the method. The application of Tukey’s HSD test for multiple comparisons revealed statistically significant mean differences (p

Abstract The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events. Among participants receiving the rifapentine-moxifloxacin regimen, low rifapentine exposure is the strongest driver of tuberculosis-related unfavorable outcomes (HR 0.65 for every 100 µg∙h/mL increase, 95%CI 0.54–0.77). The only other risk factors identified are markers of higher baseline disease severity, namely Xpert MTB/RIF cycle threshold and extent of disease on baseline chest radiography (Xpert: HR 1.43 for every 3-cycle-threshold decrease, 95%CI 1.07–1.91; extensive disease: HR 2.02, 95%CI 1.07–3.82). From these risk factors, we developed a simple risk stratification to classify disease phenotypes as easier-, moderately-harder, or harder-to-treat TB. Notably, high rifapentine exposures are not associated with any predefined adverse safety outcomes. Our results suggest that the easier-to-treat subgroup may be eligible for further treatment shortening while the harder-to-treat subgroup may need higher doses or longer treatment.

Abstract Background The primary objective of this trial is to examine the mechanisms of time-restricted eating (TRE) as an adjunct to psychiatric care for people with bipolar disorder (BD) with sleep or circadian disruptions. This study builds on prior studies of circadian disruption in BD as well as growing evidence that TRE improves circadian functioning. Methods One-hundred fifty participants diagnosed with BD 1 or II will be recruited via advertising in the local community. Main inclusion criteria include: obtaining medical treatment for BD; current sleep or circadian problems; self-reported eating period of ≥ 12 h; no eating disorder or other health conditions that would hinder or limit the safety of following TRE; and not currently experiencing a mood episode, acute suicidality, psychosis, alcohol or substance use disorder. Participants will be asked to complete a baseline period in which daily food intake is logged online for two weeks. After baseline, participants will be asked to follow TRE for 8 weeks and to continue to complete daily food logging during this time. Symptom severity interviews will be conducted by phone or videoconference at baseline, mid-intervention (6 weeks post-baseline), end of intervention (10 weeks post-baseline), and 6 months post-baseline. Self-rated symptom severity and quality of life data will be gathered online at the same time points as symptom severity interviews, and at 16 weeks post-baseline (6 weeks after the TRE period ends). To assess potential mechanisms of change, we will examine the change in diurnal amplitude of ‘clock’ gene expression as a primary mediator at 8 weeks compared to baseline. We will further test whether diurnal amplitude of clock gene expression is predictive above and beyond the role of two covariate potential mediators, glucose tolerance and inflammation at 8 weeks relative to baseline. To provide an index of whether TRE successfully decreases emotional lability, participants will be asked to complete 5 mood assessments per day for 7 days at baseline and at 10 weeks. These mood assessments will be optional. Discussion The planned research will provide novel and important information on whether TRE improves sleep/circadian rhythm problems, along with reductions in mood symptoms and improvements in quality of life, for individuals with BD. Trial registration ClinicalTrials.gov ID: NCT06555406.

Abstract PT-112 is a novel immunogenic cell death (ICD)-inducing small molecule currently under Phase 2 clinical development, including in metastatic castration-resistant prostate cancer (mCRPC), an immunologically cold and heterogeneous disease state in need of novel therapeutic approaches. PT-112 has been shown to cause ribosome biogenesis inhibition and organelle stress followed by ICD in cancer cells, culminating in anticancer immunity. In addition, clinical evidence of PT-112-driven immune effects has been observed in patient immunoprofiling. Given the unmet need for immune-based therapies in prostate cancer, along with a Phase I study (NCT#02266745) showing PT-112 activity in mCRPC patients, we investigated PT-112 effects in a panel of human prostate cancer cell lines. PT-112 demonstrated cancer cell selectivity, inhibiting cell growth and leading to cell death in prostate cancer cells without affecting the non-tumorigenic epithelial prostate cell line RWPE-1 at the concentrations tested. PT-112 also caused caspase-3 activation, as well as stress features in mitochondria including ROS generation, compromised membrane integrity, altered respiration, and morphological changes. Moreover, PT-112 induced damage-associated molecular pattern (DAMP) release, the first demonstration of ICD in human cancer cell lines, in addition to autophagy initiation across the panel. Taken together, PT-112 caused selective stress, growth inhibition and death in human prostate cancer cell lines. Our data provide additional insight into mitochondrial stress and ICD in response to PT-112. PT-112 anticancer immunogenicity could have clinical applications and is currently under investigation in a Phase 2 mCRPC study.

Abstract Background Communication is considered an inherent element of nearly every implementation strategy. Often it is seen as a means for imparting new information between stakeholders, representing a Transaction orientation to communication. From a Process orientation, communication is more than information-exchange and is acknowledged as being shaped by (and shaping) the individuals involved and their relationships with one another. As the field of Implementation Science (IS) works to strengthen theoretical integration, we encourage an interdisciplinary approach that engages communication theory to develop richer understanding of strategies and determinants of practice. Methods We interviewed 28 evaluators, 12 implementors, and 12 administrators from 21 Enterprise-Wide Initiatives funded by the Department of Veteran Affairs Office of Rural Health. Semi-structured interviews focused on experiences with implementation and evaluation strategies. We analyzed the interviews using thematic analysis identifying a range of IS constructs. Then we deductively classified those segments based on a Transaction or Process orientation to communication. Results We organized findings using the two IS constructs most commonly discussed in interviews: Collaboration and Leadership Buy-in. The majority of segments coded as Collaboration (n = 34, 74%) and Leadership Buy-in (n = 31, 70%) discussed communication from a Transaction orientation and referred to communication as synonymous with information exchange, which emphasizes the task over the relationships between the individuals performing the tasks. Conversely, when participants discussed Collaboration and Leadership Buy-in from a Process orientation, they acknowledged both constructs as the result of long-term efforts to develop positive relationships based on trust and respect, and emphasized the time costliness of such strategies. Our findings demonstrate that participants who discussed communication from a Process orientation recognized the nuance and complexity of interpersonal interactions, particularly in the context of IS. Conclusions Efficient, reliable information exchange is a critical but often overemphasized element of implementation. Practitioners and researchers must recognize and incorporate the larger role of communication in IS. Two suggestions for engaging a Process orientation to communication are to: (a) use interview probes to learn how communication is enacted, and (b) use process-oriented communication theories to develop interventions and evaluation tools.

Abstract The peptide hormone glucagon is a fundamental metabolic regulator that is also being considered as a pharmacotherapeutic option for obesity and type 2 diabetes. Despite this, we know very little regarding how glucagon exerts its pleiotropic metabolic actions. Given that the liver is a chief site of action, we performed in situ time-resolved liver phosphoproteomics to reveal glucagon signaling nodes. Through pathway analysis of the thousands of phosphopeptides identified, we reveal “membrane trafficking” as a dominant signature with the vesicle trafficking protein SEC22 Homolog B (SEC22B) S137 phosphorylation being a top hit. Hepatocyte-specific loss- and gain-of-function experiments reveal that SEC22B was a key regulator of glycogen, lipid and amino acid metabolism, with SEC22B-S137 phosphorylation playing a major role in glucagon action. Mechanistically, we identify several protein binding partners of SEC22B affected by glucagon, some of which were differentially enriched with SEC22B-S137 phosphorylation. In summary, we demonstrate that phosphorylation of SEC22B is a hepatocellular signaling node mediating the metabolic actions of glucagon and provide a rich resource for future investigations on the biology of glucagon action.

Abstract Semen quality and fertility has declined over the last 50 years, corresponding to ever-increasing environmental stressors. However, the cellular mechanisms involved and their impact on sperm functions remain unknown. In a repeated sampling human cohort study, we identify a significant effect of prior perceived stress to increase sperm motility 2-3 months following stress, timing that expands upon our previous studies revealing significant stress-associated changes in sperm RNA important for fertility. We mechanistically examine this post-stress timing in mice using an in vitro stress model in the epididymal epithelial cells responsible for sperm maturation and find 7282 differentially H3K27me3 bound DNA regions involving genes critical for mitochondrial and metabolic pathways. Further, prior stress exposure significantly changes the composition and size of epithelial cell-secreted extracellular vesicles that when incubated with mouse sperm, increase mitochondrial respiration and sperm motility, adding to our prior work showing impacts on embryo development. Together, these studies identify a time-dependent, translational signaling pathway that communicates stress experience to sperm, ultimately affecting reproductive functions.

Most college students do not engage in adequate physical activity. Physical education requirements (PERs) are often viewed as a potential solution to physical inactivity within this population as these courses provide opportunities for students to be physically active and/or become educated about healthy lifestyles. The potential benefits of these courses are particularly salient for Black college students who face many health disparities. The purpose of this study was to examine the health education and physical activity course offerings and requirements at Historically Black College and Universities (HBCUs). We examined the online course catalogs of all four-year accredited HBCUs in the United States (N = 86) to determine if they (1) offered and/or (2) required their students to take any health education or physical activity courses. Overall, 81 of the four-year HBCUs in this study (94%) at least offered their students a physical activity or health education course, although only 42 schools (48.8%) required either course for graduation. The remaining 44 institutions (51.1%) did not require their students to take a health education or physical activity course for graduation. PERs appear to be more prevalent at HBCUs compared to non-HBCUs; however, there has been a reduction in PERs across all institutions alike over the past few decades. Future studies should explore whether higher PERs at HBCUs are associated with Black students' actual physical activity behaviors. HBCUs are presented with a unique opportunity to support the health behaviors and knowledge of Black college students.

This qualitative multiple case study explores the collaborations between three STEM middle school teachers and three STEM undergraduate mentors of color in an urban school district. Drawing on sociocultural theories and literature on culturally relevant education, we used a comparative thematic approach to explore how mentors contributed to culturally relevant opportunities in STEM curriculum and pedagogy. We found that the partners' STEM identities, how the teacher positioned the mentor in the learners' experience, and the teachers' philosophy of the purpose of engineering influenced the contribution undergraduate mentors could make to rigorous and equitable engineering instruction.

American Indian/Alaska Native (AI/AN) communities are disproportionately affected by the opioid epidemic. AI/AN emerging adults (ages 18-25) in urban areas are at particularly high risk, with the overdose death rate among urban-dwelling AI/AN people 1.4 times higher than rural-dwelling AI/AN people. Despite these challenges, there are no evidence-based culturally tailored prevention or intervention programs to address opioid, alcohol and other drug use among urban AI/AN emerging adults. This study focused on understanding AI/AN emerging adults' experiences with two culturally tailored programs addressing opioid, cannabis, and alcohol use as part of the randomized controlled trial for Traditions and Connections for Urban Native Americans (TACUNA) in order to enhance feasibility of this intervention. Using a convergent mixed methods design at 3-month follow-up, we collected satisfaction and experience ratings and written narratives (total n = 162; intervention n = 77; control n = 85) from a sample of urban-dwelling AI/AN emerging adults who participated in both programs. We analyzed data through simultaneous examination of qualitative and quantitative data. The quantitative ratings show that both programs were rated highly. The qualitative data contextualized these ratings, illustrating pathways through which specific components were perceived to cause desired or observed behavioral change in participants. Among the elements that mattered most to these participants were the convenience of the virtual format, having a comfortable and safe space to share personal stories, and learning new information about their social networks. Negative comments focused on workshop length and inconvenient scheduling. This is one of the first studies to explore participant satisfaction and experience with culturally tailored substance use programming among a historically marginalized and understudied population. It is important to consider the voices of urban-dwelling AI/AN people in program development because hidden factors, such as limited financial resources, limited time, and misalignment with cultural values may prevent existing programs from being feasible.

Spermatogenesis is a finely regulated process of germ cell multiplication and differentiation leading to the production of spermatozoa in the seminiferous tubules. Spermatogenesis can be divided into three parts: spermatocytogenesis, meiosis and spermiogenesis. During spermatocytogenesis, germ cells engage in a cycle of several mitotic divisions that increases the yield of spermatogenesis and to renew stem cells and produce spermatogonia and primary spermatocytes. Meiosis involves duplication and exchange of genetic material and two cell divisions that reduce the chromosome number and yield four haploid round spermatids. Spermiogenesis involves the differentiation of round spermatids into fully mature spermatozoa released into the lumin of seminiferous tubules. The seminiferous epithelium is composed of several generations of germ cells due to the fact that new generations of sperm cells engage in the spermatogenic process without waiting for the preceding generations to have completed their evolution and to have disappeared as spermatozoa into the lumen of the tubules. In bulls, the duration of the seminiferous epithelium cycle is 13.5 days. The total duration of spermatogenesis is 61 days, that is 4.5 times the duration of the cycle of the seminiferous epithelium. The spermatogenetic wave is used to describe the spatial arrangement of cell associations along the tubules. Several theories have been described to explain the renewal of spermatogonia. Depending on the model, there are five or six spermatogonial mitoses explaining the renewal of stem cells and the proliferation of spermatogonia. Daily sperm production and germ cell degeneration can be quantified from numbers of germ cells in various steps of development throughout spermatogenesis. Bulls have a lower efficiency of spermatogenesis than most species examined, but higher than that of humans.

Abstract The resonant excitation of electronic transitions with coherent laser sources creates quantum coherent superpositions of the involved electronic states. Most time-resolved studies have focused on gases or isolated subsystems embedded in insulating solids, aiming for applications in quantum information. Here, we focus on the coherent control of orbital wavefunctions in the correlated quantum material Tb2Ti2O7, which forms an interacting spin liquid ground state. We show that resonant excitation with a strong THz pulse creates a coherent superposition of the lowest energy Tb 4f states. The coherence manifests itself as a macroscopic oscillating magnetic dipole, which is detected by ultrafast resonant x-ray diffraction. We envision the coherent control of orbital wavefunctions demonstrated here to become a new tool for the ultrafast manipulation and investigation of quantum materials.

Abstract Population-scale genome modification can alter the composition or fate of wild populations. Synthetic gene drives provide one set of tools, but their use is complicated by scientific, regulatory, and social issues associated with transgene persistence and flow. Here we propose an alternative approach. An Allele Sail consists of a genome editor (the Wind) that introduces DNA sequence edits, and is inherited in a Mendelian fashion. Meanwhile, the edits (the Sail) experience an arithmetic, Super-Mendelian increase in frequency. We model this system and identify contexts in which a single, low frequency release of an editor brings edits to a very high frequency. We also identify conditions in which manipulation of sex determination can bring about population suppression. In regulatory frameworks that distinguish between transgenics (GMO) and their edited non-transgenic progeny (non-GMO) Allele Sails may prove useful since the spread and persistence of the GM component can be limited.

Abstract Disparities in Latinx sexual minority men (LSMM) pre-exposure prophylaxis (PrEP) initiation and adherence demonstrate the need for innovative strategies to improve outcomes along the PrEP Care Continuum. The purpose of this study was to examine physical and virtual risk venue co-attendance among LSMM of varying stages of PrEP use living in South Florida, an Ending the HIV Epidemic (EHE) priority jurisdiction. Venue co-attendance may be leveraged to support equitable dissemination and implementation (D&I) of HIV and drug use preventive interventions to LSMM. Ninety-four LSMM completed surveys on PrEP use and identified physical and virtual sexual and drug risk venues (where men seek sex partners and/or have sex or access or use drugs). Bivariate analyses examined differences in demographics and venue endorsement by PrEP status. Exponential random graph models examined endorsement of venues by PrEP status. One-mode projection visualizations portray the structure of venue co-attendance networks by PrEP status. Participants identified 49 physical and virtual sexual and drug risk venues. A homophily effect of PrEP status on venue endorsement was identified for both sexual and drug risk venues. Network size and density differed by PrEP status and whether the venue was identified as a sexual or drug risk location. Online dating apps, bars, and saunas had the highest centrality in each network type suggesting their potential role in implementing preventive programming. This study identified specific sexual and drug risk venues that may be leveraged to both disseminate targeted PrEP and harm reduction information and to implement interventions to improve PrEP uptake and adherence among LSMM living in EHE priority jurisdictions.

Abstract People often interact with groups (i.e., ensembles) during social interactions. Given that group-level information is important in navigating social environments, we expect perceptual sensitivity to aspects of groups that are relevant for personal threat as well as social belonging. Most ensemble perception research has focused on visual ensembles, with little research looking at auditory or vocal ensembles. Across four studies, we present evidence that (i) perceivers accurately extract the sex composition of a group from voices alone, (ii) judgments of threat increase concomitantly with the number of men, and (iii) listeners’ sense of belonging depends on the number of same-sex others in the group. This work advances our understanding of social cognition, interpersonal communication, and ensemble coding to include auditory information, and reveals people’s ability to extract relevant social information from brief exposures to vocalizing groups.

By transporting warm and salty water poleward, the Gulf Stream system maintains a mild climate in northwestern Europe while also facilitating the dense water formation that feeds the deep ocean. The sensitivity of North Atlantic circulation to future greenhouse gas emissions seen in climate models has prompted an increasing effort to monitor the various ocean circulation components in recent decades. Here, we synthesize available ocean transport measurements from several observational programs in the North Atlantic and Nordic Seas, as well as an ocean state estimate (ECCOv4-r4), for an enhanced understanding of the Gulf Stream and its poleward extensions as an interconnected circulation system. We see limited coherent variability between the records on interannual timescales, highlighting the local oceanic response to atmospheric circulation patterns and variable recirculation timescales within the gyres. On decadal timescales, we find a weakening subtropical circulation between the mid-2000s and mid-2010s, while the inflow and circulation in the Nordic Seas remained stable. Differing decadal trends in the subtropics, subpolar North Atlantic, and Nordic Seas warrant caution in using observational records at a single latitude to infer large-scale circulation change.

Northern myotis Myotis septentrionalis are one of the bat species most affected by white-nose syndrome (WNS), and disease-induced declines may cause compounding effects when combined with other threats such as habitat loss and fragmentation. Recent evidence suggests that peripheral populations are persisting in post-WNS years; however, the environmental factors that influence the occurrence of this species along the Atlantic Coastal Plain are virtually unknown. We conducted a large-scale acoustic survey on 3 islands: Long Island, New York, and Martha’s Vineyard and Nantucket, Massachusetts, USA, and used a multi-scale occupancy modeling approach to determine the landscape and abiotic factors affecting the distribution of northern myotis. Our estimates of occupancy and detection probability suggest widespread presence across the islands. At the local (200 m) scale, we identified strong negative effects of development on Long Island and Nantucket and a strong positive effect of forest habitat on Martha’s Vineyard. None of the variables we measured sufficiently explained the landscape (1 km2) occupancy of this species, which was very high (ψ = 0.81-0.97), representing an outlier for this species in the post-WNS landscape. The lack of association at the landscape scale suggests that general differences in land cover are not a driving factor of higher occupancy of peripheral northern myotis populations, while local site-specific conditions may be supporting critical foraging or roosting habitat. Because islands are particularly vulnerable to human-driven habitat alteration due to the constraint of limited space, and development pressure is expected to increase, this study provides a baseline to enable managers to assess the effects of future environmental disturbances and monitor population trends to support long-term survival of northern myotis.

Abstract Our previous research revealed a key microRNA signature that is associated with spaceflight that can be used as a biomarker and to develop countermeasure treatments to mitigate the damage caused by space radiation. Here, we expand on this work to determine the biological factors rescued by the countermeasure treatment. We performed RNA-sequencing and transcriptomic analysis on 3D microvessel cell cultures exposed to simulated deep space radiation (0.5 Gy of Galactic Cosmic Radiation) with and without the antagonists to three microRNAs: miR-16-5p, miR-125b-5p, and let-7a-5p (i.e., antagomirs). Significant reduction of inflammation and DNA double strand breaks (DSBs) activity and rescue of mitochondria functions are observed after antagomir treatment. Using data from astronaut participants in the NASA Twin Study, Inspiration4, and JAXA missions, we reveal the genes and pathways implicated in the action of these antagomirs are altered in humans. Our findings indicate a countermeasure strategy that can potentially be utilized by astronauts in spaceflight missions to mitigate space radiation damage.

Abstract Background Bovine babesiosis is caused by infection with the protozoal parasite Babesia bovis, which is transmitted by Rhipicephalus (Boophilus) spp. It can cause mortality rates up to 90% in immunologically naive Bos taurus cattle. In south Texas, R. (B.) microplus is known to infest nilgai antelope (Boselaphus tragocamelus); however, their susceptibility to infection with B. bovis and their role in the transmission of the parasite remain unknown. In this study, we challenged nilgai antelope with B. bovis and evaluated their susceptibility to infection. Methods Nilgai were needle inoculated with ≈108 B. bovis-parasitized erythrocytes (merozoites) or a homogenate of B. bovis-infected larval ticks (sporozoite) delivered intravenously. Bos taurus beef calves were inoculated in parallel, as this strain of B. bovis is lethal to cattle. Temperature and hematocrit were monitored daily over the course of each study, and whole blood was collected for molecular [polymerase chain reaction (PCR)] and serological [indirect enzyme-linked immunosorbent assay (ELISA)] diagnostic evaluation. Histological sections of nilgai cerebral tissue were examined for evidence of infection. Recipient bovine calves were sub-inoculated with blood from nilgai challenged with either stage of the parasite, and they were monitored for clinical signs of infection and evaluated by a PCR diagnostic assay. Red blood cells (RBCs) from prechallenged nilgai and B. taurus beef cattle were cultured with an in vitro B. bovis merozoite culture to examine colonization of the RBCs by the parasite. Results Nilgai did not display clinical signs of infection upon inoculation with either the merozoite or sporozoite stage of B. bovis. All nilgai were PCR-negative for the parasite, and they did not develop antibodies to B. bovis. No evidence of infection was detected in histological sections of nilgai tissues, and in vitro culture analysis indicated that the nilgai RBCs were not colonized by B. bovis merozoites. Cattle subinoculated with blood from challenged nilgai did not display clinical signs of infection, and they were PCR-negative up to 45 days after transfer. Conclusions Nilgai do not appear to be susceptible to infection with a strain of B. bovis that is lethal to cattle. Tick control on these alternative hosts remains a critical priority, especially given their potential to disseminate ticks over long distances. Graphical Abstract

ObjectivesTo assess the reliability and validity of measuring resting cerebral blood flow (CBF) and hippocampal CBF using a single-post-labeling delay (PLD) and a multi-PLD pseudo-continuous arterial spin labeling (pCASL) protocol for cerebrovascular reactivity (CVR) testing.Methods25 healthy, midlife adults (57 ± 4 years old) were imaged in a Siemens Prisma 3T magnetic resonance imaging (MRI) scanner. Resting CBF and hippocampal CBF were assessed using two pCASL protocols, our modified single-PLD protocol (pCASL-MOD) to accommodate the needs for CVR testing and the multi-PLD Human Connectome Project (HCP) Lifespan protocol to serve as the reference control (pCASL-HCP). During pCASL-MOD, CVR was calculated as the change in CBF from rest to hypercapnia (+9 mmHg increase in end-tidal partial pressure of carbon dioxide [PETCO2]) and then normalized for PETCO2. The reliability and validity in resting gray matter (GM) CBF, white matter (WM) CBF, and hippocampal CBF between pCASL-MOD and pCASL-HCP protocols were examined using correlation analyses, paired t-tests, and Bland Altman plots.ResultsThe pCASL-MOD and pCASL-HCP protocols were significantly correlated for resting GM CBF [r = 0.72; F (1, 23) = 25.24, p < 0.0001], WM CBF [r = 0.57; F (1, 23) = 10.83, p = 0.003], and hippocampal CBF [r = 0.77; F (1, 23) = 32.65, p < 0.0001]. However, pCASL-MOD underestimated resting GM CBF (pCASL-MOD: 53.7 ± 11.1 v. pCASL-HCP: 69.1 ± 13.1 mL/100 g/min; p < 0.0001), WM CBF (pCASL-MOD: 32.4 ± 4.8 v. pCASL-HCP: 35.5 ± 6.9 mL/100 g/min; p = 0.01), and hippocampal CBF (pCASL-MOD: 50.5 ± 9.0 v. pCASL-HCP: 68.1 ± 12.5 mL/100 g/min; p < 0.0001). PETCO2 increased by 8.0 ± 0.7 mmHg to induce CVR (GM CBF: 4.8% ± 2.6%; WM CBF 2.9% ± 2.5%; and hippocampal CBF: 3.4% ± 3.8%).ConclusionOur single-PLD pCASL-MOD protocol reliably measured CBF and hippocampal CBF at rest given the significant correlation with the multi-PLD pCASL-HCP protocol. Despite the lower magnitude relative to pCASL-HCP, we recommend using our pCASL-MOD protocol for CVR testing in which an exact estimate of CBF is not required such as the assessment of relative change in CBF to hypercapnia.

IntroductionUrgency has been defined as the tendency towards rash speech and behavior in the context of emotion. Measures of Urgency have been found to have robust predictive power for psychopathologies and problematic behaviors. In the current study, we question whether emotions are unique drivers of urgency, or if emotions are potent exemplars of contexts that lead to rash speech and behavior. The Emotion Specific model and the Broader Contexts model correspond with these two conceptualizations of urgency, and they frame our pre-registered hypotheses.MethodsParticipants from two well-powered samples (n = 600,n = 588) completed 9 modified items from the Urgency and Positive Urgency scales to assess rash responses in each of four contexts – “Upset,” “Excited,” “Tired,” and “Hungry” – and a fifth “In General” set. After data cleaning, we used principal components analysis to construct a unidimensional, 4-item set that was applied to capture impulsive behavior across the five contexts.ResultsWe found that this research tool, called the Contexts of Impulsive Behaviors (CIBS), replicated in the second dataset, and it had adequate internal reliability in both samples. Although the Emotion Specific model was supported by the fact that the Upset context had a greater mean and greater variance than the Tired and Hungry contexts, most results supported the Broader Contexts model. That is, CIBS contexts were highly intercorrelated, and bivariate correlations with psychopathology were not significantly different across contexts. In partial correlations, effects of the Upset and Excited contexts were partially or fully statistically mediated by the Tired and Hungry contexts.DiscussionThese findings suggest that emotions are potent contexts for impulsive behaviors. At the same time, those with high urgency are vulnerable to impulsivity in other contexts, such as fatigue and hunger, that challenge the regulatory functions of the prefrontal cortex. Limitations, future directions, and clinical implications are discussed.

Locusts and other migratory grasshoppers are transboundary pests. Monitoring and control, therefore, involve a complex system made up of social, ecological, and technological factors. Researchers and those involved in active management are calling for more integration between these siloed but often interrelated sectors. In this paper, we bring together 38 coauthors from six continents and 34 unique organizations, representing much of the social-ecological-technological system (SETS) related to grasshopper and locust management and research around the globe, to introduce current topics of interest and review recent advancements. Together, the paper explores the relationships, strengths, and weaknesses of the organizations responsible for the management of major locust-affected regions. The authors cover topics spanning humanities, social science, and the history of locust biological research and offer insights and approaches for the future of collaborative sustainable locust management. These perspectives will help support sustainable locust management, which still faces immense challenges such as fluctuations in funding, focus, isolated agendas, trust, communication, transparency, pesticide use, and environmental and human health standards. Arizona State University launched the Global Locust Initiative (GLI) in 2018 as a response to some of these challenges. The GLI welcomes individuals with interests in locusts and grasshoppers, transboundary pests, integrated pest management, landscape-level processes, food security, and/or cross-sectoral initiatives.

Abstract Two 9‐week‐old female littermate German Shepherd puppies showed severe high‐frequency low‐amplitude trembling that worsened with movement. The white matter (WM) of the central nervous system (CNS) showed bilateral diffuse severe spongiosis in the cerebellum, brainstem, spinal cord, and the neuropil of the oculomotor and red nuclei. The cortical corona radiata was less severely affected. Rare necrotic or apoptotic glia‐like cells also were identified in the WM. Luxol fast blue staining disclosed severe diffuse myelin loss in the entire CNS; peripheral nerves were spared. Glial fibrillary acidic protein immunohistochemistry showed diffuse astrogliosis and astrocytosis in the WM. Genetic analyses of the littermates excluded the aspartoacylase (ASPA) gene as a candidate for this condition in dogs. In conclusion, this description of a rare congenital spongiform leukodystrophy in the German Shepherd breed, closely resembling to Canavan disease in humans, is likely caused by a genetic alteration unrelated to the ASPA gene.

Abstract Background The primary objective of this randomized controlled trial (RCT) is to establish the effectiveness of time-restricted eating (TRE) compared with the Mediterranean diet for people with bipolar disorder (BD) who have symptoms of sleep disorders or circadian rhythm sleep–wake disruption. This work builds on the growing evidence that TRE has benefits for improving circadian rhythms. TRE and Mediterranean diet guidance will be offered remotely using self-help materials and an app, with coaching support. Methods This study is an international RCT to compare the effectiveness of TRE and the Mediterranean diet. Three hundred participants will be recruited primarily via social media. Main inclusion criteria are: receiving treatment for a diagnosis of BD I or II (confirmed via DIAMOND structured diagnostic interview), endorsement of sleep or circadian problems, self-reported eating window of ≥ 12 h, and no current mood episode, acute suicidality, eating disorder, psychosis, alcohol or substance use disorder, or other health conditions that would interfere with or limit the safety of following the dietary guidance. Participants will be asked to complete baseline daily food logging for two weeks and then will be randomly allocated to follow TRE or the Mediterranean diet for 8 weeks, during which time, they will continue to complete daily food logging. Intervention content will be delivered via an app. Symptom severity interviews will be conducted at baseline; mid-intervention (4 weeks after the intervention begins); end of intervention; and at 6, 9, and 15 months post-baseline by phone or videoconference. Self-rated symptom severity and quality of life data will be gathered at those timepoints, as well as at 16 weeks post baseline. To provide a more refined index of whether TRE successfully decreases emotional lability and improves sleep, participants will be asked to complete a sleep diary (core CSD) each morning and complete six mood assessments per day for eight days at baseline and again at mid-intervention. Discussion The planned research will provide novel and important information on whether TRE is more beneficial than the Mediterranean diet for reducing mood symptoms and improving quality of life in individuals with BD who also experience sleep or circadian problems. Trial registration ClinicalTrials.gov ID NCT06188754.

We explore historical variability in the volume of Labrador Sea Water (LSW) using ECCO, an ocean state estimate configuration of the Massachusetts Institute of Technology general circulation model (MITgcm). The model's adjoint, a linearization of the MITgcm, is set up to output the lagged sensitivity of the water mass volume to surface boundary conditions. This allows us to reconstruct the evolution of LSW volume over recent decades using historical surface wind stress, heat, and freshwater fluxes. Each of these boundary conditions contributes significantly to the LSW variability that we recover, but these impacts are associated with different geographical fingerprints and arise over a range of time lags. We show that the volume of LSW accumulated in the Labrador Sea exhibits a delayed response to surface wind stress and buoyancy forcing outside the convective interior of the Labrador Sea at important locations in the North Atlantic Ocean. In particular, patterns of wind and surface density anomalies can act as a “traffic controller” and regulate the North Atlantic Current's (NAC's) transport of warm and saline subtropical water masses that are precursors for the formation of LSW. This propensity for a delayed response of LSW to remote forcing allows us to predict a limited yet substantial and significant fraction of LSW variability at least 1 year into the future. Our analysis also enables us to attribute LSW variability to different boundary conditions and to gain insight into the major mechanisms that contribute to volume anomalies in this deep water mass. We point out the important role of key processes that promote the formation of LSW in both the Irminger and Labrador seas: buoyancy loss and preconditioning along the NAC pathway and in the Iceland Basin, the Irminger Sea, and the Nordic Seas.

Abstract Background Cardiovascular (CV) disease is a leading cause of death in breast cancer (BC) patients due to the increased age and treatments. While individual β-blockers have been investigated to manage CV complications, various β-blockers have not been compared for their effects on CV death in this population. We aimed to compare CV mortality in older BC patients taking one of the commonly used β-blockers. Methods This retrospective cohort study was conducted using the Surveillance, Epidemiology and End Results (SEER) - Medicare data (2010–2015). Patients of age 66 years or older at BC diagnosis receiving metoprolol, atenolol, or carvedilol monotherapy were included. The competing risk regression model was used to determine the risk of CV mortality in the three β-blocker groups. The multivariable model was adjusted for demographic and clinical covariates. The adjusted hazard ratio (HR) and 95% confidence intervals (CI) were reported for the risk of CV mortality. Results The study cohort included 6,540 patients of which 55% were metoprolol users, 30% were atenolol users, and 15% were carvedilol users. Metoprolol was associated with a 37% reduced risk of CV mortality (P = 0.03) compared to carvedilol after adjusting for the covariates (HR = 0.63; 95% CI 0.41–0.96). No significant difference in the risk of CV mortality between atenolol and carvedilol users was observed (HR = 0.74; 95% CI 0.44–1.22). Conclusions Our findings suggest that metoprolol is associated with a reduced risk of CV mortality in BC patients. Future studies are needed to confirm these findings and understand the mechanism of action.

Abstract Background Endemic domestic dog-ruminant cycles and human cystic echinococcosis caused by Echinococcus granulosus have been sporadically reported in the United States. However, there is a paucity of molecular data describing the genotypes and haplotypes of this important cestode in domestic ruminant hosts. Methods Ninety-four cysts from the lungs and/or livers of slaughtered beef cattle (76 samples), dairy cows (five samples) and sheep (13 samples) were collected from abattoirs in four states of the USA. Samples were genotyped at two mitochondrial loci, cox1 and nad5. Sequences were used to determine species, genotypes and haplotypes using median joining networks and Bayesian phylogenetic analyses. Cyst fertility was assessed in hematoxylin and eosin-stained sections. Additionally, previously reported autochthonous E. granulosus infections in the USA in various hosts were mapped. Results Based on cox1 sequences obtained from 94 cysts, 89 (94.7%) were identified as E. granulosus G1/G3, while five (5.3%) were Taenia hydatigena. Taenia hydatigena were only isolated from sheep. Based on nad5 sequences obtained from 89 hydatid cysts, 96.6% and 3.4% belonged to E. granulosus sensu stricto genotypes G1 and G3 respectively. Two haplotypes were found among E. granulosus cox1 sequences, neither of which was geographically unique. Six haplotypes were found among nad5 sequences in genotype G1, of which five were novel, while one haplotype was found in genotype G3. In the concatenated cox1-nad5 dataset, seven haplotypes were identified, of which six were geographically unique. All cysts from cattle were non-fertile. Four cysts from sheep were fertile. Conclusions All genotyped samples belonged to E. granulosus s.s. This is the first study to our knowledge to confirm the presence of genotypes G1 and G3 in domestic cattle and sheep intermediate hosts in the USA and provide data for future diagnostic and epidemiological studies. Sequences have been deposited in GenBank (cox1 sequences: OR398494-OR398496, nad5 sequences: OR400695-OR400702). Graphical Abstract

Objective To compare a remotely supervised weight loss and exercise intervention to lifestyle counseling for effects on cardiovascular disease risk, disease activity, and patient‐reported outcomes in older patients with rheumatoid arthritis (RA) and overweight/obesity. Methods Twenty older (60–80 years), previously sedentary participants with seropositive RA and overweight/obesity were randomized to 16 weeks of either Supervised Weight loss and Exercise Training (SWET) or Counseling Health As Treatment (CHAT). The SWET group completed aerobic training (150 minutes/week moderate‐to‐vigorous intensity), resistance training (two days/week), and a hypocaloric diet (7% weight loss goal). The CHAT control group completed two lifestyle counseling sessions followed by monthly check‐ins. The primary outcome was a composite metabolic syndrome z‐score (MSSc) derived from fasting glucose, triglycerides, high density lipoprotein–cholesterol, minimal waist circumference, and mean arterial pressure. Secondary outcomes included RA disease activity and patient‐reported outcomes. Results Both groups improved MSSc (absolute change −1.67 ± 0.64 in SWET; −1.34 ± 1.30 in CHAT; P

ABSTRACTBackground: PTSD is a significant mental health problem worldwide. Current evidence-based interventions suffer various limitations. Ketamine is a novel agent that is hoped to be incrementally better than extant interventions.Objective: Several randomized control trials (RCTs) of ketamine interventions for PTSD have now been published. We sought to systematically review and meta-analyse results from these trials to evaluate preliminary evidence for ketamine’s incremental benefit above-and-beyond control interventions in PTSD treatment.Results: Omnibus findings from 52 effect sizes extracted across six studies (n = 221) yielded a small advantage for ketamine over control conditions at reducing PTSD symptoms (g = 0.27, 95% CI = 0.03, 0.51). However, bias-correction estimates attenuated this effect (adjusted g = 0.20, 95%, CI = −0.08, 0.48). Bias estimates indicated smaller studies reported larger effect sizes favouring ketamine. The only consistent timepoint assessed across RCTs was 24-hours post-initial infusion. Effects at 24-hours post-initial infusion suggest ketamine has a small relative advantage over controls (g = 0.35, 95% CI = 0.06, 0.64). Post-hoc analyses at 24-hours post-initial infusion indicated that ketamine was significantly better than passive controls (g = 0.44, 95% CI = 0.03, 0.85), but not active controls (g = 0.24, 95% CI = −0.30, 0.78). Comparisons one-week into intervention suggested no meaningful group differences (g = 0.24, 95% CI = 0.00, 0.48). No significant differences were evident for RCTs that examined effects two-weeks post initial infusion (g = 0.17, 95% CI = −0.10, 0.44).Conclusions: Altogether, ketamine-for-PTSD RCTs reveal a nominal initial therapeutic advantage relative to controls. However, bias and heterogeneity appear problematic. While rapid acting effects were observed, all control agents (including saline) also evidenced rapid acting effects. We argue blind penetration to be a serious concern, and that placebo is the likely mechanism behind reported therapeutic effects.

Alternaria alternata apple pathotype causes Alternaria blotch of susceptible apple cultivars through the production of a cyclic peptide host-specific toxin, AM-toxin. PCR (polymerase chain reaction), with primers designed to conserved domains of peptide synthetase genes, amplified several products from A. alternata apple pathotype that showed high similarity to other fungal peptide synthetases and were specific to the apple pathotype. Screening of a Lambda Zap genomic library with these PCR-generated probes identified overlapping clones containing a complete cyclic peptide synthetase gene of 13.1 kb in length with no introns. Disruption of this gene, designated AM-toxin synthetase (AMT), by transformation of wild-type A. alternata apple pathotype with disruption vectors resulted in toxin-minus mutants, which were also unable to cause disease symptoms on susceptible apple cultivars. AM-toxin synthetase is therefore a primary determinant of virulence and specificity in the A. alternata apple pathotype/apple interaction.

Numerous aspects of cellular signaling are regulated by the kinome—the network of over 500 protein kinases that guides and modulates information transfer throughout the cell. The key role played by both individual kinases and assemblies of kinases organized into functional subnetworks leads to kinome dysregulation driving many diseases, particularly cancer. In the case of pancreatic ductal adenocarcinoma (PDAC), a variety of kinases and associated signaling pathways have been identified for their key role in the establishment of disease as well as its progression. However, the identification of additional relevant therapeutic targets has been slow and is further confounded by interactions between the tumor and the surrounding tumor microenvironment. In this work, we attempt to link the state of the human kinome, or kinotype, with cell viability in treated, patient-derived PDAC tumor and cancer-associated fibroblast cell lines. We applied classification models to independent kinome perturbation and kinase inhibitor cell screen data, and found that the inferred kinotype of a cell has a significant and predictive relationship with cell viability. We further find that models are able to identify a set of kinases whose behavior in response to perturbation drive the majority of viability responses in these cell lines, including the understudied kinases CSNK2A1/3, CAMKK2, and PIP4K2C. We next utilized these models to predict the response of new, clinical kinase inhibitors that were not present in the initial dataset for model devlopment and conducted a validation screen that confirmed the accuracy of the models. These results suggest that characterizing the perturbed state of the human protein kinome provides significant opportunity for better understanding of signaling behavior and downstream cell phenotypes, as well as providing insight into the broader design of potential therapeutic strategies for PDAC.

Summary: Endosomal Toll-like receptors (eTLRs) are essential for the sensing of non-self through RNA and DNA detection. Here, using spatiotemporal analysis of vesicular dynamics, super-resolution microscopy studies, and functional assays, we show that endomembrane defects associated with the deficiency of the small GTPase Rab27a cause delayed eTLR ligand recognition, defective early signaling, and impaired cytokine secretion. Rab27a-deficient neutrophils show retention of eTLRs in amphisomes and impaired ligand internalization. Extracellular signal-regulated kinase (ERK) signaling and β2-integrin upregulation, early responses to TLR7 and TLR9 ligands, are defective in Rab27a deficiency. CpG-stimulated Rab27a-deficient neutrophils present increased tumor necrosis factor alpha (TNF-α) secretion and decreased secretion of a selected group of mediators, including interleukin (IL)-10. In vivo, CpG-challenged Rab27a-null mice show decreased production of type I interferons (IFNs) and IFN-γ, and the IFN-α secretion defect is confirmed in Rab27a-null plasmacytoid dendritic cells. Our findings have significant implications for immunodeficiency, inflammation, and CpG adjuvant vaccination.

Summary: Peripheral viral infection disrupts oligodendrocyte (OL) homeostasis such that endogenous remyelination may be affected. Here, we demonstrate that influenza A virus infection perpetuated a demyelination- and disease-associated OL phenotype following cuprizone-induced demyelination that resulted in delayed OL maturation and remyelination in the prefrontal cortex. Furthermore, we assessed cellular metabolism ex vivo, and found that infection altered brain OL and microglia metabolism in a manner that opposed the metabolic profile induced by remyelination. Specifically, infection increased glycolytic capacity of OLs and microglia, an effect that was recapitulated by lipopolysaccharide (LPS) stimulation of mixed glia cultures. In contrast, mitochondrial dependence was increased in OLs during remyelination, which was similarly observed in OLs of myelinating P14 mice compared to adult and aged mice. Collectively, our data indicate that respiratory viral infection is capable of suppressing remyelination, and suggest that metabolic dysfunction of OLs is implicated in remyelination impairment.

Road mortality adversely affects wildlife populations. As urbanization and infrastructure densities expand, transportation and wildlife management aim to mitigate wildlife–vehicle conflicts while conserving biodiversity. Roadways in aridland ecosystems can invariably and adversely impact wildlife differently from temperate and other biomes, yet these rapidly urbanizing regions are understudied as are urban–rural gradients. We conducted road-cruise surveys (n = 204; 2018–2023) to assess anthropogenic, environmental, and temporal factors associated with vertebrate roadkill across the wildland–urban interface of Arizona’s biodiverse Sonoran Desert ecoregion—already subjected to increased human development and climate change. Of n = 2019 vertebrates observed, 28.5% were roadkill. Increasing urbanization levels were associated with reduced vertebrate abundance on roads and increased road-killed endothermic vertebrates. Traffic volume was strongly associated with reduced vertebrate abundance and increased roadkill; additive effects on roadkill began at approximately 20 vehicles. Daily low temperature and/or relative humidity were also associated with roadkill across vertebrate groups. We provide empirical evidence to understand wildlife–roadkill associations across expanding wildland–urban interfaces to inform effective roadkill mitigation and wildlife conservation management strategies in biodiverse aridland regions. We recommend that managers mitigate or avoid development in rural areas that possess high biodiversity, valuable waterways or migration corridors, and populations of vulnerable species.

Abstract The Atlantic Meridional Overturning Circulation (AMOC) plays a critical role in the global climate system through the redistribution of heat, freshwater and carbon. At 26.5°N, the meridional heat transport has traditionally been partitioned geometrically into vertical and horizontal circulation cells; however, attributing these components to the AMOC and Subtropical Gyre (STG) flow structures remains widely debated. Using water parcel trajectories evaluated within an eddy‐rich ocean hindcast, we present the first Lagrangian decomposition of the meridional heat transport at 26.5°N. We find that water parcels recirculating within the STG account for 37% (0.36 PW) of the total heat transport across 26.5°N, more than twice that of the classical horizontal gyre component (15%). Our findings indicate that STG heat transport cannot be meaningfully distinguished from that of the basin‐scale overturning since water parcels cooled within the gyre subsequently feed the northward, subsurface limb of the AMOC.