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Objective: The present study developed a measure assessing the emotional responses, "Displacement Imposition," of cigarette and e-cigarette users on a college campus with a smoking/vaping ban. It also examined the relationship between "Displacement Imposition" and readiness to quit smoking/ vaping, and how this relationship differed between cigarette and e-cigarette users. Participants: Participants (N=297) were from a large, Midwestern university. Methods: Participants completed online questionnaires assessing demographics, cigarette and e-cigarette use, "Displacement Imposition," and readiness to quit. Results: All six "Displacement Imposition" items loaded onto a single factor. A significant interaction emerged between "Displacement Imposition" and product use in predicting readiness to quit. At high levels of "Displacement Imposition," cigarette users were less ready to quit than e-cigarette users. Conclusions: Findings suggest restrictions imposed on cigarette and e-cigarette users were associated with reduced readiness to quit. Findings inform tobacco control policies as tobacco denormalization may increase the burden placed on tobacco users.

Objectives: Sexual Strategies Theory suggests people fall on a continuum between having short-term mating orientation (STMO) and long-term mating orientation. One way STMO individuals signal mating goals is via risky drinking. The current study therefore aims to investigate drinks per week (DPW) as a mediator between STMO and risky sexual behavior (RSB), with gender as a moderator between STMO and DPW. Participants: Undergraduate students (N = 300) from a Midwestern university during Fall 2019. Method: Participants completed questionnaires assessing STMO, DPW, and RSB frequency. Results: A moderated-mediation model indicated DPW significantly mediated the relationship between STMO and RSB. Positive associations were found among all three variables. Gender was not a moderator between STMO and DPW. Conclusions: Mating orientation was a correlate of alcohol use and RSB for women and men, contributing to the literature identifying STMO as an indicator of those in need of substance use and RSB intervention.

The article delves into the confusion with the interpretations and enforcement of the Migratory Bird Treaty Act (MBTA) regarding avian interactions with the built environment, particularly the intentional taking or killing of protected bird species. Topics discussed include sustainable development and voluntary initiatives for the protection of plants and animal species, provisions of the Lacey Act and MBTA on wildlife protection, and building modifications to prevent bird collisions.

BACKGROUND: Bowel dilation and bowel wall thickness are common prenatal ultrasound measurements for fetuses with gastroschisis. Data regarding antenatal sonographic bowel findings and postnatal outcomes are conflicting. Our objective was to evaluate the impact of in utero bowel measurements on perinatal outcomes in gastroschisis pregnancies. METHODS: Retrospective cohort study of 116 pregnancies complicated by gastroschisis between 2011 and 2020. We reviewed ultrasounds documenting fetal bowel measurements. To evaluate the association of these measurements with antepartum and delivery outcomes, we ran logistic and linear models using generalized estimating equations. RESULTS: Eleven perinatal outcomes reached statistical significance, although with minimal clinical impact given small magnitude of effect. Intra-abdominal bowel dilation was associated with a 0.5 week decrease in delivery gestational age (GA) (95% CI –0.07, –0.03) and a 6.93 g increase in birth weight (95% CI 1.54, 28.73). Intra-abdominal bowel wall thickness was associated with later GA of non-stress test (NST) start of 0.22 weeks (95% CI 0.07, 0.37), increased delivery GA of 0.08 weeks (95% CI 0.02, 0.15), 0.006 decrease in umbilical artery (UA) pH (95% CI –0.009, –0.003), 0.26 increase in UA base deficit (95% CI 0.09, 0.43), and decreased odds of cesarean delivery (OR = 0.83, 95% CI 0.70, 0.99). Extra-abdominal bowel wall thickness was associated with a 0.1 increase in UA base deficit (95% CI 0.02, 0.19) and a 0.05 increase in 5-min APGAR score (95% CI 0.01, 0.09). Stomach cross-section was associated with a 0.01 week decrease in delivery GA (95% CI –0.02, –0.001) and increased odds of receiving betamethasone (OR = 1.02, 95% CI 1.01, 1.04). CONCLUSIONS: In utero bowel characteristics reached statistical significance for several outcomes, but with minimal meaningful clinical differences in outcomes. [ABSTRACT FROM AUTHOR]

Sexual Strategies Theory suggests people fall on a continuum between having short-term mating orientation (STMO) and long-term mating orientation. One way STMO individuals signal mating goals is via risky drinking. The current study therefore aims to investigate drinks per week (DPW) as a mediator between STMO and risky sexual behavior (RSB), with gender as a moderator between STMO and DPW. Undergraduate students (N = 300) from a Midwestern university during Fall 2019. Participants completed questionnaires assessing STMO, DPW, and RSB frequency. A moderated-mediation model indicated DPW significantly mediated the relationship between STMO and RSB. Positive associations were found among all three variables. Gender was not a moderator between STMO and DPW. Mating orientation was a correlate of alcohol use and RSB for women and men, contributing to the literature identifying STMO as an indicator of those in need of substance use and RSB intervention. [ABSTRACT FROM AUTHOR]

The present study developed a measure assessing the emotional responses, "Displacement Imposition," of cigarette and e-cigarette users on a college campus with a smoking/vaping ban. It also examined the relationship between Displacement Imposition and readiness to quit smoking/vaping, and how this relationship differed between cigarette and e-cigarette users. Participants (N = 297) were from a large, Midwestern university. Participants completed online questionnaires assessing demographics, cigarette and e-cigarette use, Displacement Imposition, and readiness to quit. All six Displacement Imposition items loaded onto a single factor. A significant interaction emerged between Displacement Imposition and product use in predicting readiness to quit. At high levels of Displacement Imposition, cigarette users were less ready to quit than e-cigarette users. Findings suggest restrictions imposed on cigarette and e-cigarette users were associated with reduced readiness to quit. Findings inform tobacco control policies as tobacco denormalization may increase the burden placed on tobacco users. [ABSTRACT FROM AUTHOR]

Child labour is the most common form of child abuse in the world today, with almost half of child workers employed in hazardous industries. The large-scale employment of children during the rapid industrialisation of the late 18th and early 19th centuries in England is well documented. During this period, the removal of pauper children from workhouses in cities to work as apprentices in rural mills in the North of England was commonplace. Whilst the experiences of some of these children have been recorded historically, this study provides the first direct evidence of their lives through bioarchaeological analysis. The excavation of a rural churchyard cemetery in the village of Fewston, North Yorkshire, yielded the skeletal remains of 154 individuals, including an unusually large proportion of children aged between 8 to 20 years. A multi-method approach was undertaken, including osteological and palaeopathological examination, stable isotope and amelogenin peptide analysis. The bioarchaeological results were integrated with historical data regarding a local textile mill in operation during the 18th-19th centuries. The results for the children were compared to those obtained from contemporaneous individuals of known identity (from coffin plates) of comparable date. Most of the children exhibited distinctive 'non-local' isotope signatures and a diet low in animal protein when compared to the named local individuals. These children also showed severe growth delays and pathological lesions indicative of early life adversity, as well as respiratory disease, which is a known occupational hazard of mill work. This study has provided unique insights into the harrowing lives of these children; born into poverty and forced to work long hours in dangerous conditions. This analysis provides a stark testimony of the impacts of industrial labour on the health, growth and mortality risk of children, with implications for the present as well as our understanding of the past. [ABSTRACT FROM AUTHOR]

Lithium’s role in the global green energy transition provides an engaging context to visualize the interconnectedness of chemistry to seismic shifts taking place in society. Lithium has seen a dramatic increase in utilization, but given lithium’s current low rates of recyclability, this development is exacerbating the e-waste problem. Equally important, we posit that lithium extraction, from either brine or ore, and the associated impacts on the environment and local communities should not be so easily decoupled from the shift in human behaviors causing its demand. Presented here is a mapping activity that was trialed in professional learning workshops organized in New Zealand for secondary/high school chemistry teachers. In their mapping activity response, the teachers were able to connect typical school chemistry content (batteries, chemical processes) with environmental (planetary systems) and social, economic, and ethical considerations (useful products, unintended consequences, inequity in access to water) of the ongoing electrification of society. The teachers indicated a positive intention to utilize the activity, or one similar with a different chemical process or product, in their own classrooms. A school-ready version of the activity is provided in the supplementary information, which was revised based on feedback from the teachers attending the workshops.

The primary aim of the current study is to determine the incremental efficacy of adding a novel values component to a personalized feedback intervention for young adult drinking. Undergraduate students (N = 254) were randomized to receive either traditional, traditional with values assessment, or values enhanced feedback. Results showed significant decreases in drinks per week (p <.01) and alcohol-related consequences (p <.05) across all feedback conditions. Further research is needed to determine whether using values-based feedback could enhance intervention effects and how best to incorporate feedback in a way that is feasible and acceptable to recipients. [ABSTRACT FROM AUTHOR]

Administration of oxygen microbubbles (OMBs) has been shown to increase oxygen and decrease carbon dioxide in systemic circulation, as well as reduce lung inflammation and promote survival in preclinical models of hypoxia caused by lung injury. However, their impact on microenvironmental oxygenation remains unexplored. Herein, we investigated the effects of intraperitoneal administration of OMBs in anesthetized rats exposed to hypoxic ventilation (FiO2 = 0.14). Blood oxygenation and hemodynamics were evaluated over a 2 h time frame, and then organ and tissue samples were collected for hypoxic and metabolic analyses. Data showed that OMBs improved blood SaO2 (~14%) and alleviated tissue hypoxia within the microenvironment of the kidney and intestine at 2 h of hypoxia. Metabolomic analysis revealed OMBs induced metabolic differences in the cecum, liver, kidney, heart, red blood cells and plasma. Within the spleen and lung, principal component analysis showed a metabolic phenotype more comparable to the normoxic group than the hypoxic group. In the spleen, this shift was characterized by reduced levels of fatty acids and 2-hydroxygluterate, alongside increased expression of antioxidant enzymes such as glutathione and hypoxanthine. Interestingly, there was also a shuttle effect within the metabolism of the spleen from the tricarboxylic acid cycle to the glycolysis and pentose phosphate pathways. In the lung, metabolomic analysis revealed upregulation of phosphatidylethanolamine and phosphatidylcholine synthesis, indicating a potential indirect mechanism through which OMB administration may improve lung surfactant secretion and prevent alveolar collapse. In addition, cell-protective purine salvage was increased within the lung. In summary, oxygenation with intraperitoneal OMBs improves systemic blood and local tissue oxygenation, thereby shifting metabolomic profiles of the lung and spleen toward a healthier normoxic state.

Political polarization, fueled by conflicting meta-perceptions, presents a critical obstacle to constructive discourse and collaboration. These meta-perceptions-how one group perceives another group's views of them-are often inaccurate and can lead to detrimental outcomes such as increased hostility and dehumanization. Across two studies, we introduce and experimentally test a novel approach that exposes participants to atypical, counter-stereotypical members of an opposing group who either confirm or disrupt their existing meta-perceptions. We find that disrupting meta-perceptions decreases dehumanization of the partner, increases interest in wanting to learn more about them, but fails to increase willingness to interact in the future with the partner. We conduct an exploratory text analysis to uncover differences in word choice by condition. Our research adds a new dimension to the existing body of work by examining the efficacy of alternative intervention strategies to improve intergroup relations in politically polarized settings.

Deep learning (DL) models for medical image classification frequently struggle to generalize to data from outside institutions. Additional clinical data are also rarely collected to comprehensively assess and understand model performance amongst subgroups. Following the development of a single-center model to identify the lung sliding artifact on lung ultrasound (LUS), we pursued a validation strategy using external LUS data. As annotated LUS data are relatively scarce—compared to other medical imaging data—we adopted a novel technique to optimize the use of limited external data to improve model generalizability. Externally acquired LUS data from three tertiary care centers, totaling 641 clips from 238 patients, were used to assess the baseline generalizability of our lung sliding model. We then employed our novel Threshold-Aware Accumulative Fine-Tuning (TAAFT) method to fine-tune the baseline model and determine the minimum amount of data required to achieve predefined performance goals. A subgroup analysis was also performed and Grad-CAM++ explanations were examined. The final model was fine-tuned on one-third of the external dataset to achieve 0.917 sensitivity, 0.817 specificity, and 0.920 area under the receiver operator characteristic curve (AUC) on the external validation dataset, exceeding our predefined performance goals. Subgroup analyses identified LUS characteristics that most greatly challenged the model’s performance. Grad-CAM++ saliency maps highlighted clinically relevant regions on M-mode images. We report a multicenter study that exploits limited available external data to improve the generalizability and performance of our lung sliding model while identifying poorly performing subgroups to inform future iterative improvements. This approach may contribute to efficiencies for DL researchers working with smaller quantities of external validation data.

This observational pilot study examined the association between diet, meal pattern and glucose over a 2-week period under free-living conditions in 26 adults with dysglycemia (D-GLYC) and 14 with normoglycemia (N-GLYC). We hypothesized that a prolonged eating window and late eating occasions (EOs), along with a higher dietary carbohydrate intake, would result in higher glucose levels and glucose variability (GV). General linear models were run with meal timing with time-stamped photographs in real time, and diet composition by dietary recalls, and their variability (SD), as predictors and glucose variables (mean glucose, mean amplitude of glucose excursions [MAGE], largest amplitude of glucose excursions [LAGE] and GV) as dependent variables. After adjusting for calories and nutrients, a later eating midpoint predicted a lower GV (β = −2.3, SE = 1.0, p = 0.03) in D-GLYC, while a later last EO predicted a higher GV (β = 1.5, SE = 0.6, p = 0.04) in N-GLYC. A higher carbohydrate intake predicted a higher MAGE (β = 0.9, SE = 0.4, p = 0.02) and GV (β = 0.4, SE = 0.2, p = 0.04) in N-GLYC, but not D-GLYC. In summary, our data suggest that meal patterns interact with dietary composition and should be evaluated as potential modifiable determinants of glucose in adults with and without dysglycemia. Future research should evaluate causality with controlled diets.

Aberrant coagulation in sickle cell disease (SCD) is linked to extracellular vesicle (EV) exposure. However, there is no consensus on the contributions of small EVs (SEVs) and large EVs (LEVs) toward underlying coagulopathy or on their molecular cargo. The present observational study compared the thrombin potential of SEVs and LEVs isolated from the plasma of stable pediatric and adult SCD patients. Further, EV lipid and protein contents were analyzed to define markers consistent with activation of thrombin and markers of underlying coagulopathy. Results suggested that LEVs—but not SEVs—from pediatrics and adults similarly enhanced phosphatidylserine (PS)-dependent thrombin generation, and cell membrane procoagulant PS (18:0;20:4 and 18:0;18:1) were the most abundant lipids found in LEVs. Further, LEVs showed activated coagulation in protein pathway analyses, while SEVs demonstrated high levels of cholesterol esters and a protein pathway analysis that identified complement factors and inflammation. We suggest that thrombin potential of EVs from both stable pediatric and adult SCD patients is similarly dependent on size and show lipid and protein contents that identify underlying markers of coagulation and inflammation.

IntroductionHuman and murine sickle cell disease (SCD) associated pulmonary hypertension (PH) is defined by hemolysis, nitric oxide depletion, inflammation, and thrombosis. Further, hemoglobin (Hb), heme, and iron accumulation are consistently observed in pulmonary adventitial macrophages at autopsy and in hypoxia driven rodent models of SCD, which show distribution of ferric and ferrous Hb as well as HO-1 and ferritin heavy chain. The anatomic localization of these macrophages is consistent with areas of significant vascular remodeling. However, their contributions toward progressive disease may include unique, but also common mechanisms, that overlap with idiopathic and other forms of pulmonary hypertension. These processes likely extend to the vasculature of other organs that are consistently impaired in advanced SCD.MethodsTo date, limited information is available on the metabolism of macrophages or monocytes isolated from lung, spleen, and peripheral blood in humans or murine models of SCD.ResultsHere we hypothesize that metabolism of macrophages and monocytes isolated from this triad of tissue differs between Berkley SCD mice exposed for ten weeks to moderate hypobaric hypoxia (simulated 8,000 ft, 15.4% O2) or normoxia (Denver altitude, 5000 ft) with normoxia exposed wild type mice evaluated as controls.DiscussionThis study represents an initial set of data that describes the metabolism in monocytes and macrophages isolated from moderately hypoxic SCD mice peripheral lung, spleen, and blood mononuclear cells.

An experimental design was used to examine the effects of interviewer gender and (mis)understanding on physiological stress (i.e., cortisol). A total of 103 undergraduate students wrote about a recent social conflict and then discussed that conflict with either a male or a female interviewer. During these discussions, the interviewer displayed verbal and nonverbal cues of (mis)understanding toward the participants. Participants' cortisol was assessed four times throughout the study. Results from a 2 × 2 × 4 mixed‐model analysis of variance demonstrated an interaction between the gender of the interviewer, understanding condition, and time such that cortisol decreased the most over time when the interviewer used cues of understanding that matched stereotypical expectations for the interviewers' gender (i.e., when women were understanding and men were misunderstanding). [ABSTRACT FROM AUTHOR]

Sickle cell anemia and β‐thalassemia intermedia are very different genetically determined hemoglobinopathies predisposing to pulmonary hypertension. The etiologies responsible for the associated development of pulmonary hypertension in both diseases are multi‐factorial with extensive mechanistic contributors described. Both sickle cell anemia and β‐thalassemia intermedia present with intra and extravascular hemolysis. And because sickle cell anemia and β‐thalassemia intermedia share features of extravascular hemolysis, macrophage iron excess and anemia we sought to characterize the common features of the pulmonary hypertension phenotype, cardiac mechanics, and function as well as lung and right ventricular metabolism. Within the concept of iron, we have defined a unique pulmonary vascular iron accumulation in lungs of sickle cell anemia pulmonary hypertension patients at autopsy. This observation is unlike findings in idiopathic or other forms of pulmonary arterial hypertension. In this study, we hypothesized that a common pathophysiology would characterize the pulmonary hypertension phenotype in sickle cell anemia and β‐thalassemia intermedia murine models. However, unlike sickle cell anemia, β‐thalassemia is also a disease of dyserythropoiesis, with increased iron absorption and cellular iron extrusion. This process is mediated by high erythroferrone and low hepcidin levels as well as dysregulated iron transport due transferrin saturation, so there may be differences as well. Herein we describe common and divergent features of pulmonary hypertension in aged Berk‐ss (sickle cell anemia) and Hbbth/3+ (intermediate β‐thalassemia) mice and suggest translational utility as proof‐of‐concept models to study pulmonary hypertension therapeutics specific to genetic anemias.

Macrophages are a heterogeneous population with both pro‐ and anti‐inflammatory functions play an essential role in maintaining tissue homeostasis, promoting inflammation under pathological conditions, and tissue repair after injury. In pulmonary hypertension, the M1 phenotype is more pro‐inflammatory compared to the M2 phenotype, which is involved in tissue repair. The role of macrophages in the initiation and progression of pulmonary hypertension is well studied. However, their role in the regression of established pulmonary hypertension is not well known. Rats chronically exposed to hemoglobin (Hb) plus hypoxia (HX) share similarities to humans with pulmonary hypertension associated with hemolytic disease, including the presence of a unique macrophage phenotype surrounding distal vessels that are associated with vascular remodeling. These lung macrophages are characterized by high iron content, HO‐1, ET‐1, and IL‐6, and are recruited from the circulation. Depletion of macrophages in this model prevents the development of pulmonary hypertension and vascular remodeling. In this study, we specifically investigate the regression of pulmonary hypertension over a four‐week duration after rats were removed from Hb + HX exposure with and without gadolinium chloride administration. Withdrawal of Hb + HX reversed systolic pressures and right ventricular function after Hb + Hx exposure in four weeks. Our data show that depleting circulating monocytes/macrophages during reversal prevents complete recovery of right ventricular systolic pressure and vascular remodeling in this rat model of pulmonary hypertension at four weeks post exposure. The data presented offer a novel insight into the role of macrophages in the processes of pulmonary hypertension regression in a rodent model of Hb + Hx‐driven disease.

3D scaffold-based in vitro cell culturing is a recent technological advancement in cancer research bridging the gap between conventional 2D culture and in vivo tumours. The main challenge in treating neuroblastoma, a paediatric cancer of the sympathetic nervous system, is to combat tumour metastasis and resistance to multiple chemotherapeutic drugs. The aim of this study was to establish a physiologically relevant 3D neuroblastoma tissue-engineered system and explore its therapeutic relevance. Two neuroblastoma cell lines, chemotherapeutic sensitive Kelly and chemotherapeutic resistant KellyCis83 were cultured in a 3D in vitro model on two collagen-based scaffolds containing either glycosaminoglycan (Coll-GAG) or nanohydroxyapatite (Coll-nHA) and compared to 2D cell culture and an orthotopic murine model. Both neuroblastoma cell lines actively infiltrated the scaffolds and proliferated displaying >100-fold increased resistance to cisplatin treatment when compared to 2D cultures, exhibiting chemosensitivity similar to orthotopic xenograft in vivo models. This model demonstrated its applicability to validate miRNA-based gene delivery. The efficacy of liposomes bearing miRNA mimics uptake and gene knockdown was similar in both 2D and 3D in vitro culturing models highlighting the proof-of-principle for the applicability of 3D collagen-based scaffolds cell system for validation of miRNA function. Collectively, this data shows the successful development and characterisation of a physiologically relevant, scaffold-based 3D tissue-engineered neuroblastoma cell model, strongly supporting its value in the evaluation of chemotherapeutics, targeted therapies and investigation of neuroblastoma pathogenesis. While neuroblastoma is the specific disease being focused upon, the platform may have multi-functionality beyond this tumour type. Statement of Significance Traditional 2D cell cultures do not completely capture the 3D architecture of cells and extracellular matrix contributing to a gap in our understanding of mammalian biology at the tissue level and may explain some of the discrepancies between in vitro and in vivo results. Here, we demonstrated the successful development and characterisation of a physiologically relevant, scaffold-based 3D tissue-engineered neuroblastoma cell model, strongly supporting its value in the evaluation of chemotherapeutics, targeted therapies and investigation of neuroblastoma pathogenesis. The ability to test drugs in this reproducible and controllable tissue-engineered model system will help reduce the attrition rate of the drug development process and lead to more effective and tailored therapies. Importantly, such 3D cell models help to reduce and replace animals for pre-clinical research addressing the principles of the 3Rs. [ABSTRACT FROM AUTHOR]

When creating any new anti-parasitic interventions, it is important to evaluate their effects across all life stages. This study had three objectives, which were to evaluate the effect of feeding cranberry vine pellet (CVP) on (1) ewes’ body weights and BCS during late gestation and lactation; (2) ewes’ milk quality during lactation; and (3) lambs’ body weight and growth parameters from birth to 65 days of age. Across two years, 41 Dorset ewes were fed either a 50% CVP or a matching control pellet (CON) from 104 ± 1.60 days of gestation for 62.8 ± 0.68 days of lactation. Measurements were collected from ewes (BW, BCS, and milk) and lambs (BW and body size). Milk from CVP ewes exhibited reduced milk fat and solids (p < 0.01) and increased concentrations of milk urea nitrogen (p = 0.02) when evaluated for the treatment–time. There was no significant difference in the BCS, protein, lamb BW, or growth measurements for treatment–time (p ≥ 0.05). Additional research that targets blood biochemistry and metabolic assessments is needed to fully determine the impact of this pellet on ewes and lambs.

Background: Annotating large medical imaging datasets is an arduous and expensive task, especially when the datasets in question are not organized according to deep learning goals. Here, we propose a method that exploits the hierarchical organization of annotating tasks to optimize efficiency. Methods: We trained a machine learning model to accurately distinguish between one of two classes of lung ultrasound (LUS) views using 2908 clips from a larger dataset. Partitioning the remaining dataset by view would reduce downstream labelling efforts by enabling annotators to focus on annotating pathological features specific to each view. Results: In a sample view-specific annotation task, we found that automatically partitioning a 780-clip dataset by view saved 42 min of manual annotation time and resulted in 55±6 additional relevant labels per hour. Conclusions: Automatic partitioning of a LUS dataset by view significantly increases annotator efficiency, resulting in higher throughput relevant to the annotating task at hand. The strategy described in this work can be applied to other hierarchical annotation schemes.

Previous studies (1) support a role of circadian genes in regulating alcohol intake, and (2) reveal that harmful alcohol use alters circadian rhythms. However, there is minimal knowledge of the effects of chronic alcohol processes on rhythmic circadian gene expression across brain regions important for circadian biology and alcohol intake. Therefore, the present study sought to test the effects of chronic binge-like drinking on diurnal circadian gene expression patterns in the master circadian pacemaker (SCN), the ventral tegmental area (VTA), and the nucleus accumbens (NAc) in High Drinking in the Dark-1 (HDID-1) mice, a unique genetic risk model for drinking to intoxication. Consistent with earlier findings, we found that 8 weeks of binge-like drinking reduced the amplitude of several core circadian clock genes in the NAc and SCN, but not the VTA. To better inform the use of circadian-relevant pharmacotherapies in reducing harmful drinking and ameliorating alcohol’s effects on circadian gene expression, we tested whether the casein kinase-1 inhibitor, PF-67046, or the phosphodiesterase type-4 (an upstream regulator of circadian signalling) inhibitor, apremilast, would reduce binge-like intake and mitigate circadian gene suppression. PF-67046 did not reduce intake but did have circadian gene effects. In contrast, apremilast reduced drinking, but had no effect on circadian expression patterns.

Accurate chromosome segregation depends on bipolar chromosome–microtubule attachment and tension generation on chromosomes. Incorrect chromosome attachment results in chromosome missegregation, which contributes to genome instability. The kinetochore is a protein complex that localizes at the centromere region of a chromosome and mediates chromosome–microtubule interaction. Incorrect chromosome attachment leads to checkpoint activation to prevent anaphase onset. Kinetochore detachment activates the spindle assembly checkpoint (SAC), while tensionless kinetochore attachment relies on both the SAC and tension checkpoint. In budding yeast Saccharomyces cerevisiae, kinesin-5 motor proteins Cin8 and Kip1 are needed to separate spindle pole bodies for spindle assembly, and deletion of CIN8 causes lethality in the absence of SAC. To study the function of Cin8 and Kip1 in chromosome segregation, we constructed an auxin-inducible degron (AID) mutant, cin8-AID. With this conditional mutant, we first confirmed that cin8-AID kip1∆ double mutants were lethal when Cin8 is depleted in the presence of auxin. These cells arrested in metaphase with unseparated spindle pole bodies and kinetochores. We further showed that the absence of either the SAC or tension checkpoint was sufficient to abolish the cell-cycle delay in cin8-AID mutants, causing chromosome missegregation and viability loss. The tension checkpoint-dependent phenotype in cells with depleted Cin8 suggests the presence of tensionless chromosome attachment. We speculate that the failed spindle pole body separation in cin8 mutants could increase the chance of tensionless syntelic chromosome attachments, which depends on functional tension checkpoint for survival.

The P2 purinergic receptor family implicated in many physiological processes, including neurotransmission, mechanical adaptation and inflammation, consists of ATP-gated non-specific cation channels P2XRs and G-protein coupled receptors P2YRs. Different cells, including bone forming osteoblasts, express multiple P2 receptors; however, how P2X and P2Y receptors interact in generating cellular responses to various doses of [ATP] remains poorly understood. Using primary bone marrow and compact bone derived osteoblasts and BMP2-expressing C2C12 osteoblastic cells, we demonstrated conserved features in the P2-mediated Ca2+ responses to ATP, including a transition of Ca2+ response signatures from transient at low [ATP] to oscillatory at moderate [ATP], and back to transient at high [ATP], and a non-monotonic changes in the response magnitudes which exhibited two troughs at 10-4 and 10-2 M [ATP]. We identified P2Y2 and P2X7 receptors as predominantly contributing to these responses and constructed a mathematical model of P2Y2R-induced inositol trisphosphate (IP3) mediated Ca2+ release coupled to a Markov model of P2X7R dynamics to study this system. Model predictions were validated using parental and CRISPR/Cas9-generated P2Y2 and P2Y7 knockouts in osteoblastic C2C12-BMP cells. Activation of P2Y2 by progressively increasing [ATP] induced a transition from transient to oscillatory to transient Ca2+ responses due to the biphasic nature of IP3Rs and the interaction of SERCA pumps with IP3Rs. At high [ATP], activation of P2X7R modulated the response magnitudes through an interplay between the biphasic nature of IP3Rs and the desensitization kinetics of P2X7Rs. Moreover, we found that P2Y2 activity may alter the kinetics of P2X7 towards favouring naïve state activation. Finally, we demonstrated the functional consequences of lacking P2Y2 or P2X7 in osteoblast mechanotransduction. This study thus provides important insights into the biophysical mechanisms underlying ATP-dependent Ca2+ response signatures, which are important in mediating bone mechanoadaptation.

The spindle assembly checkpoint (SAC) prevents anaphase onset in response to chromosome attachment defects, and SAC silencing is essential for anaphase onset. Following anaphase onset, activated Cdc14 phosphatase dephosphorylates the substrates of cyclin-dependent kinase to facilitate anaphase progression and mitotic exit. In budding yeast, Cdc14 dephosphorylates Fin1, a regulatory subunit of protein phosphatase 1 (PP1), to enable kinetochore localization of Fin1-PP1. We previously showed that kinetochore-localized Fin1-PP1 promotes the removal of the SAC protein Bub1 from the kinetochore during anaphase. We report here that Fin1-PP1 also promotes kinetochore removal of Bub3, the Bub1 partner, but has no effect on another SAC protein Mad1. Moreover, the kinetochore localization of Bub1-Bub3 during anaphase requires Aurora B/Ipl1 kinase activity. We further showed that Fin1-PP1 facilitates the dephosphorylation of kinetochore protein Ndc80, a known Ipl1 substrate. This dephosphorylation reduces kinetochore association of Bub1-Bub3 during anaphase. In addition, we found that untimely Ndc80 dephosphorylation causes viability loss in response to tensionless chromosome attachments. These results suggest that timely localization of Fin1-PP1 to the kinetochore controls the functional window of SAC and is therefore critical for faithful chromosome segregation.

Summary: The accumulation of misfolded proteins is associated with multiple neurodegenerative disorders, but it remains poorly defined how this accumulation causes cytotoxicity. Here, we demonstrate that the Cdc48/p97 segregase machinery drives the clearance of ubiquitinated model misfolded protein Huntingtin (Htt103QP) and limits its aggregation. Nuclear ubiquitin ligase San1 acts upstream of Cdc48 to ubiquitinate Htt103QP. Unexpectedly, deletion of SAN1 and/or its cytosolic counterpart UBR1 rescues the toxicity associated with Cdc48 deficiency, suggesting that ubiquitin depletion, rather than compromised proteolysis of misfolded proteins, causes the growth defect in cells with Cdc48 deficiency. Indeed, Cdc48 deficiency leads to elevated protein ubiquitination levels and decreased free ubiquitin, which depends on San1/Ubr1. Furthermore, enhancing free ubiquitin levels rescues the toxicity in various Cdc48 pathway mutants and restores normal turnover of a known Cdc48-independent substrate. Our work highlights a previously unappreciated function for Cdc48 in ensuring the regeneration of monoubiquitin that is critical for normal cellular function.

The Kv11.1 voltage-gated potassium channel, encoded by the KCNH2 gene, conducts the rapidly activating delayed rectifier current in the heart. KCNH2 pre-mRNA undergoes alternative polyadenylation to generate two C-terminal Kv11.1 isoforms in the heart. Utilization of a poly(A) signal in exon 15 produces the full-length, functional Kv11.1a isoform, while intron 9 polyadenylation generates the C-terminally truncated, nonfunctional Kv11.1a-USO isoform. The relative expression of Kv11.1a and Kv11.1a-USO isoforms plays an important role in the regulation of Kv11.1 channel function. In this study, we tested the hypothesis that the RNA polyadenylate binding protein nuclear 1 (PABPN1) interacts with a unique 22 nt adenosine stretch adjacent to the intron 9 poly(A) signal and regulates KCNH2 pre-mRNA alternative polyadenylation and the relative expression of Kv11.1a C-terminal isoforms. We showed that PABPN1 inhibited intron 9 poly(A) activity using luciferase reporter assays, tandem poly(A) reporter assays, and RNA pulldown assays. We also showed that PABPN1 increased the relative expression level of the functional Kv11.1a isoform using RNase protection assays, immunoblot analyses, and patch clamp recordings. Our present findings suggest a novel role for the RNA-binding protein PABPN1 in the regulation of functional and nonfunctional Kv11.1 isoform expression.

Objective: Health care providers using brief alcohol-related health messaging is an effective manner of reducing risky drinking; however, research is needed to guide the content of such messages. The present study compared current drinkers' and nondrinkers' perspectives on the value of four different alcohol-related messages and the hypothetical impact of the messages on intentions to reduce drinking. Method: Undergraduates (n = 286 current drinkers, n = 101 nondrinkers) from a large, public, Southern Plains university identified primarily as White (82.9%) and female (70%), with a mean age of 19.98 years. They viewed four video recordings containing different alcohol-related messages in random order and were asked to rate how likely they were to change their drinking behaviors after watching each video. Results: All participants generally had a comparably positive appraisal of all four messages. Among current drinkers, one-way analyses of variance revealed significant differences across messages for intention to change drinking frequency, F(3, 260) = 5.69, p = .001, ηp2 = .06, and quantity, F(3, 263) = 4.95, p = .002, ηp2 = .05. Post hoc tests showed that the condition warning students of severe consequences resulted in higher intentions to reduce drinking compared with other conditions describing less severe consequences, drinking norms, or protective behavioral strategies. No significant differences emerged among nondrinkers. Conclusions: Despite mixed research regarding the effectiveness of fear-based warning messages in reducing high-risk drinking, the message containing severe alcohol-related consequences evoked the greatest hypothetical intentions to reduce quantity and frequency of drinking. Future studies should track actual drinking behaviors longitudinally following each message. [ABSTRACT FROM AUTHOR]

Seismic data-sets are extremely large and are broken into data files, ranging in size from 100s of GiBs to 10s of TiBs and larger. The parallel I/O for these files is complex due to the amount of data along with varied and multiple access patterns within individual files. Properties of legacy file formats, such as the de-facto standard SEG-Y, also contribute to the decrease in developer productivity while working with these files. SEG-Y files embed their own internal layout which could lead to conflict with traditional, file-system-level layout optimization schemes. Additionally, as seismic files continue to increase in size, memory bottlenecks will be exacerbated, resulting in the need for smart I/O optimization not only to increase the efficiency of read/writes, but to manage memory usage as well. The ExSeisDat (Extreme-Scale Seismic Data) set of libraries addresses these problems through the development and implementation of easy to use, object oriented libraries that are portable and open source with bindings available in multiple languages. The lower level parallel I/O library, ExSeisPIOL (Extreme-Scale Seismic Parallel I/O Library), targets SEG-Y and other proprietary formats, simplifying I/O by internally interfacing MPI-I/O and other I/O interfaces. The I/O is explicitly handled; end users only need to define the memory limits, decomposition of I/O across processes, and data access patterns when reading and writing data. ExSeisPIOL bridges the layout gap between the SEG-Y file structure and file system organization. The higher level parallel seismic workflow library, ExSeisFlow (Extreme-Scale Seismic workFlow), leverages ExSeisPIOL, further simplifying I/O by implicitly handling all I/O parameters, thus allowing geophysicists to focus on domain-specific development. Operations in ExSeisFlow focus on prestack processing and can be performed on single traces, individual gathers, and across entire surveys, including out of core sorting, binning, filtering, and transforming. To optimize memory management, the workflow only reads in data pertinent to the operations being performed instead of an entire file. A smart caching system manages the read data, discarding it when no longer needed in the workflow. As the libraries are optimized to handle spatial and temporal locality, they are a natural fit to burst buffer technologies, particularly DDN’s Infinite Memory Engine (IME) system. With appropriate access semantics or through the direct exploitation of the low-level interfaces, the ExSeisDat stack on IME delivers a significant improvement to I/O performance over standalone parallel file systems like Lustre.

This article revises the spatial and temporal boundaries of the Casas Grandes tradition associated with northwest Chihuahua, Mexico, based on new data collected in neighboring northeastern Sonora. The Casas Grandes tradition attained its greatest extent during the Medio period (AD 1200–1450/1500) followed by a dramatic demographic and political collapse. Hunter-gatherer groups subsequently occupied most of northwest Chihuahua. Data from the Fronteras Valley, Sonora, presents an alternative scenario, with a clear pattern of cultural continuity from the eleventh century to the colonial period in which sedentary farmers occupied the same landscapes and occasionally the same villages. These observations contribute to our understanding of the spread and subsequent demise of the Casas Grandes tradition in hinterland regions. For the Fronteras Valley, we infer that immigrant groups originally introduced Casas Grandes traditions and that uneven participation in a suite of shared religious beliefs and practices was common to all the hinterlands. [ABSTRACT FROM AUTHOR]

5-Methyldeoxycytidine (5mC) is a major epigenetic marker that regulates cellular functions in mammals. Endogenous lipid peroxidation can convert 5mC into 3,N4-etheno-5-methylcytosine (ϵ5mC). ϵ5mC is structurally similar to the mutagenic analog 3,N4-ethenocytosine (ϵC), which is repaired by AlkB family enzymes in the direct reversal repair (DRR) pathway and excised by DNA glycosylases in the base excision repair (BER) pathway. However, the repair of ϵ5mC has not been reported. Here, we examined the activities against ϵ5mC by DRR and BER enzymes and TET1-3, enzymes that modify the 5-methyl group in 5mC. We found that the etheno modification of 5mC blocks oxidation by TET1-3. Conversely, three human homologs in the AlkB family, ALKBH2, 3 and FTO were able to repair ϵ5mC to 5mC, which was subsequently modified by TET1 to 5-hydroxymethylcytosine. We also demonstrated that ALKBH2 likely repairs ϵ5mC in MEF cells. Another homolog, ALKBH5, could not repair ϵ5mC. Also, ϵ5mC is not a substrate for BER glycosylases SMUG1, AAG, or TDG. These findings indicate DRR committed by ALKBH2, 3 and FTO could reduce the detrimental effects of ϵ5mC in genetics and epigenetics and may work together with TET enzymes to modulate epigenetic regulations., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Neighborhood safety is defined inconsistently across epidemiologic studies - a conceptual problem that results in incomparable measurements, hampering the design of health interventions. Using child behavior problems (measured via the Child Behavior Checklist) as the outcome of interest, this study directly compared four measures of neighborhood safety: two of experienced safety and two of perceived safety, with each one measured at family and community levels. These included children's direct experience of harm, parental perceptions, community crime statistics, and community perceptions. In a sample of 3291 ten-year-olds from the Generation R cohort (living in municipal Rotterdam, Netherlands, 2013), all four measures were correlated (χ2 ≥ 9.2, P < 0.002 in pairwise chi-square comparisons), but ultimately identified different levels of risk for behavioral health. Direct experiences of harm, parental perceptions, and community crime statistics were all associated with increased child internalizing behaviors (β = 3.12, β = 2.10, and β = 1.77, respectively), while only experiences of harm and parental perceptions were associated with increased externalizing behaviors (β = 2.75 and β = 1.31, respectively). These results provide novel evidence that the conceptual distinctions underlying different measures of neighborhood safety are meaningful for child mental health and should be considered in intervention design., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Purpose: There is widespread recognition of the importance and complexity of measuring neighborhood contexts within research on child psychopathology. In this study, we assessed the cross-sectional associations between two measures of neighborhood quality and internalizing and externalizing behaviors in preadolescence., Methods: Drawing on baseline data from the Adolescent Brain Cognitive Development Study (n = 10,577 preadolescents), we examined two multi-component assessments of neighborhood quality in relation to children's internalizing and externalizing symptoms: the Area Deprivation Index (ADI), which measures socioeconomic adversity, and the Child Opportunity Index 2.0 (COI), which measures economic, educational, and environmental opportunity. Both measures were categorized into quintiles. We then used mixed-effects linear regression models to examine bivariate and adjusted associations., Results: The bivariate associations displayed strong inverse associations between the COI and ADI and externalizing symptoms, with a graded pattern of fewer externalizing behaviors with increasing neighborhood quality. Only the ADI was associated with externalizing behaviors in models adjusted for child and family characteristics. We did not observe a clear association between either measure of neighborhood quality and internalizing behaviors in bivariate or adjusted models., Conclusions: Neighborhood quality, as measured by the COI and ADI, was associated with externalizing behaviors in preadolescent children. The association using the ADI persisted after adjustment for family-level characteristics, including financial strain. Our results indicate that different assessments of neighborhood quality display distinct associations with preadolescent behavioral health. Future research is needed to assess the association between neighborhood quality and behavior trajectories and to identify place-based intervention strategies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Air pollution causes premature death and disease and disproportionately harms non-white and lower-income groups in the United States. Government policies are responsible for the racial disparity in air pollution exposure and related health outcomes. Investigating complex relationships between policies, air pollution, and health requires (i) harmonized data connecting policies, environmental exposures, socioeconomic characteristics, and health at the individual and area level; (ii) interpretable estimands accounting for the complex interplay between policies and disparities in exposures and health outcomes; and (iii) data science approaches that can elucidate direct and indirect policy effects on disparities to identify effective interventions. We review statistical considerations and new data science approaches needed to scrutinize the policy impacts on disparities in air pollution exposure and health outcomes.

Background and Objectives: Amyotrophic lateral sclerosis (ALS) is predominantly associated with motor cortex, corticospinal tract (CST), brainstem, and spinal cord degeneration, and cerebellar involvement is much less well characterized. However, some of the cardinal clinical features of ALS, such as dysarthria, dysphagia, gait impairment, falls, and impaired dexterity, are believed to be exacerbated by coexisting cerebellar pathology. Cerebellar pathology may also contribute to cognitive, behavioral, and pseudobulbar manifestations. Our objective was to systematically assess both intracerebellar pathology and cerebrocerebellar connectivity alterations in a genetically stratified cohort of ALS., Methods: A prospective, multimodal neuroimaging study was conducted to evaluate the longitudinal evolution of intracerebellar pathology and cerebrocerebellar connectivity, using structural and functional measures., Results: A total of 113 healthy controls and 212 genetically stratified individuals with ALS were included: (1) C9orf72 hexanucleotide carriers ("C9POS"), (2) sporadic patients who tested negative for ALS-associated genetic variants, and (3) intermediate-length CAG trinucleotide carriers in ATXN2 ("ATXN2"). Flocculonodular lobule ( p adj = 0.014, 95% CI -5.06e-5 to -3.98e-6) and crura ( p adj = 0.031, 95% CI -1.63e-3 to -5.55e-5) volume reductions were detected at baseline in sporadic patients. Cerebellofrontal and cerebelloparietal structural connectivity impairment was observed in both C9POS and sporadic patients at baseline, and both projections deteriorated further over time in sporadic patients ( p adj = 0.003, t (249) = 3.04 and p adj = 0.05, t (249) = 1.93). Functional cerebelloparietal uncoupling was evident in sporadic patients at baseline ( p adj = 0.004, 95% CI -0.19 to -0.03). ATXN2 patients exhibited decreased cerebello-occipital functional connectivity at baseline ( p adj = 0.004, 95% CI -0.63 to -0.06), progressive cerebellotemporal functional disconnection ( p adj = 0.025, t (199) = -2.26), and progressive flocculonodular lobule degeneration ( p adj = 0.017, t (249) = -2.24). C9POS patients showed progressive ventral dentate atrophy ( p adj = 0.007, t (249) = -2.75). The CSTs ( p adj < 0.001, 95% CI 4.89e-5 to 1.14e-4) and transcallosal interhemispheric fibers ( p adj < 0.001, 95% CI 5.21e-5 to 1.31e-4) were affected at baseline in C9POS and exhibited rapid degeneration over the 4 time points. The rate of decline in CST and corpus callosum integrity was faster than the rate of cerebrocerebellar disconnection ( p adj = 0.001, t (190) = 6.93)., Discussion: ALS is associated with accruing intracerebellar disease burden as well as progressive corticocerebellar uncoupling. Contrary to previous suggestions, we have not detected evidence of compensatory structural or functional changes in response to supratentorial degeneration. The contribution of cerebellar disease burden to dysarthria, dysphagia, gait impairment, pseudobulbar affect, and cognitive deficits should be carefully considered in clinical assessments, monitoring, and multidisciplinary interventions.

Background : While frontotemporal involvement is increasingly recognized in Amyotrophic lateral sclerosis (ALS), the degeneration of limbic networks remains poorly characterized, despite growing evidence of amnestic deficits, impaired emotional processing and deficits in social cognition. Methods : A prospective neuroimaging study was conducted with 204 individuals with ALS and 111 healthy controls. Patients were stratified for hexanucleotide expansion status in C9orf72 . A deep-learning-based segmentation approach was implemented to segment the nucleus accumbens, hypothalamus, fornix, mammillary body, basal forebrain and septal nuclei. The cortical, subcortical and white matter components of the Papez circuit were also systematically evaluated. Results : Hexanucleotide repeat expansion carriers exhibited bilateral amygdala, hypothalamus and nucleus accumbens atrophy, and C9orf72 negative patients showed bilateral basal forebrain volume reductions compared to controls. Both patient groups showed left rostral anterior cingulate atrophy, left entorhinal cortex thinning and cingulum and fornix alterations, irrespective of the genotype. Fornix, cingulum, posterior cingulate, nucleus accumbens, amygdala and hypothalamus degeneration was more marked in C9orf72 -positive ALS patients. Conclusions : Our results highlighted that mesial temporal and parasagittal subcortical degeneration is not unique to C9orf72 carriers. Our radiological findings were consistent with neuropsychological observations and highlighted the importance of comprehensive neuropsychological testing in ALS, irrespective of the underlying genotype.

Purpose: Positive dimensions of psychological well-being in adolescence may help youth preserve cardiometabolic health (CMH) as they age, but little is known about which aspects of well-being matter most and for whom. This study examines the differential impact of five dimensions of adolescent psychological well-being on CMH maintenance in adulthood and considers social patterning in both their distribution and respective health benefits., Methods: Data were from the National Longitudinal Study of Adolescent Health (N = 3,464), five dimensions of psychological well-being were identified at baseline (1994-1995; mean age = 15 years): happiness, optimism, self-esteem, belonging, and feeling loved. CMH was measured using seven biomarkers related to chronic disease risk in 2008 (mean age = 28 years) and 2016-2018 (mean age = 38 years): high-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, systolic blood pressure, diastolic blood pressure, hemoglobin A1c, C-reactive protein, and body mass index. CMH maintenance in adulthood was characterized as having healthy levels of ≥6 biomarkers at each follow-up., Results: Youth who reported higher levels of belonging in the teen years were more likely to maintain CMH across young adulthood than those who reported lower levels, regardless of one's social standing (OR per 1- standard deviation  = 1.23, 95% CI = 1.03-1.46). Associations with other dimensions of well-being were heterogeneous by sex and race and ethnicity, while differences by socioeconomic factors were less apparent., Discussion: Fostering belonging through supportive social environments may help set youth on positive health trajectories and prevent chronic disease across the lifespan., (Copyright © 2024 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Cadherin-17 (CDH17) is a calcium-dependent cell adhesion protein that is overexpressed in several adenocarcinomas, including gastric, colorectal, and pancreatic adenocarcinoma. High levels of CDH17 have been linked to metastatic disease and poor prognoses in patients with these malignancies, fueling interest in the protein as a target for diagnostics and therapeutics. Herein, we report the synthesis, in vitro validation, and in vivo evaluation of a CDH17-targeted 89 Zr-labeled immunoPET probe., Methods: The CDH17-targeting mAb D2101 was modified with an isothiocyanate-bearing derivative of desferrioxamine (DFO) to produce a chelator-bearing immunoconjugate - DFO-D2101 - and flow cytometry and surface plasmon resonance (SPR) were used to interrogate its antigen-binding properties. The immunoconjugate was then radiolabeled with zirconium-89 (t 1/2 ~ 3.3 days), and the serum stability and immunoreactive fraction of [ 89 Zr]Zr-DFO-D2101 were determined. Finally, [ 89 Zr]Zr-DFO-D2101's performance was evaluated in a trio of murine models of pancreatic ductal adenocarcinoma (PDAC): subcutaneous, orthotopic, and patient-derived xenografts (PDX). PET images were acquired over the course of 5 days, and terminal biodistribution data were collected after the final imaging time point., Results: DFO-D2101 was produced with a degree of labeling of ~ 1.1 DFO/mAb. Flow cytometry with CDH17-expressing AsPC-1 cells demonstrated that the immunoconjugate binds to its target in a manner similar to its parent mAb, while SPR with recombinant CDH17 revealed that D2101 and DFO-D2101 exhibit nearly identical K D values: 8.2 × 10 -9 and 6.7 × 10 -9 M, respectively. [ 89 Zr]Zr-DFO-D2101 was produced with a specific activity of 185 MBq/mg (5.0 mCi/mg), remained >80% stable in human serum over the course of 5 days, and boasted an immunoreactive fraction of >0.85. In all three murine models of PDAC, the radioimmunoconjugate yielded high contrast images, with high activity concentrations in tumor tissue and low uptake in non-target organs. Tumoral activity concentrations reached as high as >60 %ID/g in two of the cohorts bearing PDXs., Conclusion: Taken together, these data underscore that [ 89 Zr]Zr-DFO-D2101 is a highly promising probe for the non-invasive visualization of CDH17 expression in PDAC. We contend that this radioimmunoconjugate could have a significant impact on the clinical management of patients with both PDAC and gastrointestinal adenocarcinoma, most likely as a theranostic imaging tool in support of CDH17-targeted therapies., (© 2024. The Author(s).)

Introduction: The potential role of pathogens, particularly vector-transmitted infectious agents, as a cause of psychosis has not been intensively investigated. We have reported a potential link between Bartonella spp. bacteremia and neuropsychiatric symptoms, including pediatric acute onset neuropsychiatric syndrome and schizophrenia. The purpose of this study was to further assess whether Bartonella spp. exposure or infection are associated with psychosis., Methods: In a blinded manner, we assessed the presence of anti- Bartonella antibodies by indirect immunofluorescence assays (IFA), and infection by amplification of bacterial DNA from blood by quantitative polymerase chain reaction (qPCR), digital PCR (dPCR), and droplet digital PCR (ddPCR) in 116 participants. Participants were categorized into one of five groups: 1) controls unaffected by psychosis ( n = 29); 2) prodromal participants ( n = 16); 3) children or adolescents with psychosis ( n = 7); 4) adults with psychosis ( n = 44); and 5) relatives of a participant with psychosis ( n = 20)., Results: There was no significant difference in Bartonella spp. IFA seroreactivity between adults with psychosis and adult controls unaffected by psychosis. There was a higher proportion of adults with psychosis who had Bartonella spp. DNA in the bloodstream (43.2%) compared to adult controls unaffected by psychosis (14.3%, p = 0.021). The Bartonella species was determined for 18 of the 31 bacteremic participants, including infection or co-infection with Bartonella henselae (11/18), Bartonella vinsonii subsp. b erkhoffii (6/18), Bartonella quintana (2/18), Bartonella alsatica (1/18), and Bartonella rochalimae (1/18)., Discussion: In conjunction with other recent research, the results of this study provide justification for a large national or international multi-center study to determine if Bartonella spp. bacteremia is more prevalent in adults with psychosis compared to adults unaffected by psychosis. Expanding the investigation to include a range of vector-borne and other microbial infections with potential CNS effects would enhance knowledge on the relationship between psychosis and infection., Competing Interests: In conjunction with Dr. S. Sontakke and North Carolina State University, EB holds US Patent No. 7,115,385 Media and Methods for Cultivation of Microorganisms, which was issued on October 3rd, 2006. He is a co-founder, shareholder and Chief Scientific Officer for Galaxy Diagnostics, a company that provides advanced diagnostic testing for the detection of Bartonella spp. infections. RM is a co-founder and the Chief Technical Officer for Galaxy Diagnostics Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Delaney, Robveille, Maggi, Lashnits, Kingston, Liedig, Murray, Fallon and Breitschwerdt.)

Background: Primary lateral sclerosis (PLS) is traditionally solely associated with progressive upper motor neuron dysfunction manifesting in limb spasticity, gait impairment, bulbar symptoms and pseudobulbar affect. Recent studies have described frontotemporal dysfunction in some patients resulting in cognitive manifestations. Cerebellar pathology is much less well characterised despite sporadic reports of cerebellar disease., Methods: A multi-timepoint, longitudinal neuroimaging study was conducted to characterise the evolution of both intra-cerebellar disease burden and cerebro-cerebellar connectivity. The volumes of deep cerebellar nuclei, cerebellar cortical volumes, cerebro-cerebellar structural and functional connectivity were assessed longitudinally in a cohort of 43 individuals with PLS., Results: Cerebello-frontal, -temporal, -parietal, -occipital and cerebello-thalamic structural disconnection was detected at baseline based on radial diffusivity (RD) and cerebello-frontal decoupling was also evident based on fractional anisotropy (FA) alterations. Functional connectivity changes were also detected in cerebello-frontal, parietal and occipital projections. Volume reductions were identified in the vermis, anterior lobe, posterior lobe, and crura. Among the deep cerebellar nuclei, the dorsal dentate was atrophic. Longitudinal follow-up did not capture statistically significant progressive changes. Significant primary motor cortex atrophy and inter-hemispheric transcallosal degeneration were also captured., Conclusions: PLS is not only associated with upper motor neuron dysfunction, but cerebellar cortical volume loss and deep cerebellar nuclear atrophy can also be readily detected. In addition to intra-cerebellar disease burden, cerebro-cerebellar connectivity alterations also take place. Our data add to the evolving evidence of widespread neurodegeneration in PLS beyond the primary motor regions. Cerebellar dysfunction in PLS is likely to exacerbate bulbar, gait and dexterity impairment and contribute to pseudobulbar affect., (© 2024. The Author(s).)

Lay Abstract: Existing research has identified an increased risk of depression among autistic adults, which can negatively impact their adaptive functioning abilities and socioeconomic outcomes. Mobile app-based meditation is a feasible, accessible, and effective self-care solution for depression among neurotypical adults, but there is limited evidence for the long-term benefits of app-based meditation among autistic adults. Habits are a key behavioral strategy for maintaining behavior change, and anchoring is one effective habit formation intervention that has yet to be tested among autistic adults. This study demonstrates that it is both feasible and effective to integrate the anchoring habit formation strategy into an app-based meditation intervention for establishing meditation habits among autistic adults. In addition, the study shows that app-based meditation habits were successful at maintaining reductions in depressive symptoms over 6 months. These results demonstrate the power of anchoring-based habit formation interventions for establishing healthy habits among autistic adults, which offers a promising behavioral intervention technique for establishing other healthy habits among autistic adults. The study also shows that app-based meditation habits are an effective long-term self-care solution for managing depressive symptoms among autistic adults that should be used by mental health providers and policymakers. Future research should test this combined anchoring and app-based meditation intervention technique among larger samples of autistic adults and over longer durations to better understand the mechanisms underlying the success of this intervention., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Decisions about how to divide resources have profound social and practical consequences. Do explanations regarding the source of existing inequalities influence how children and adults allocate new resources? When 3- to 6-year-old children (N = 201) learned that inequalities were caused by structural forces (stable external constraints affecting access to resources) as opposed to internal forces (effort), they rectified inequalities, overriding previously documented tendencies to perpetuate inequality or divide resources equally. Adults (N = 201) were more likely than children to rectify inequality spontaneously; this was further strengthened by a structural explanation but reversed by an effort-based explanation. Allocation behaviors were mirrored in judgments of which allocation choices by others were appropriate. These findings reveal how explanations powerfully guide social reasoning and action from childhood through adulthood., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: While the impacts of social and environmental exposure on cardiovascular risks are often reported individually, the combined effect is poorly understood., Methods and Results: Using the 2022 Environmental Justice Index, socio-environmental justice index and environmental burden module ranks of census tracts were divided into quartiles (quartile 1, the least vulnerable census tracts; quartile 4, the most vulnerable census tracts). Age-adjusted rate ratios (RRs) of coronary artery disease, strokes, and various health measures reported in the Prevention Population-Level Analysis and Community Estimates data were compared between quartiles using multivariable Poisson regression. The quartile 4 Environmental Justice Index was associated with a higher rate of coronary artery disease (RR, 1.684 [95% CI, 1.660-1.708]) and stroke (RR, 2.112 [95% CI, 2.078-2.147]) compared with the quartile 1 Environmental Justice Index. Similarly, coronary artery disease 1.057 [95% CI,1.043-1.0716] and stroke (RR, 1.118 [95% CI, 1.102-1.135]) were significantly higher in the quartile 4 than in the quartile 1 environmental burden module. Similar results were observed for chronic kidney disease, hypertension, diabetes, obesity, high cholesterol, lack of health insurance, sleep <7 hours per night, no leisure time physical activity, and impaired mental and physical health >14 days., Conclusions: The prevalence of CVD and its risk factors is highly associated with increased social and environmental adversities, and environmental exposure plays an important role independent of social factors.

Introduction: Ambient air temperature may affect birth outcomes adversely, but little is known about their impact on foetal growth throughout pregnancy. We evaluated the association between temperature exposure during pregnancy and foetal size and growth in three European birth cohorts., Methods: We studied 23,408 pregnant women from the English Born in Bradford cohort, Dutch Generation R Study, and Spanish INMA Project. Using the UrbClim TM model, weekly ambient air temperature exposure at 100x100m resolution at the mothers' residences during pregnancy was calculated. Estimated foetal weight, head circumference, and femur length at mid and late pregnancy and weight, head circumference, and length at birth were converted into standard deviation scores (SDS). Foetal growth from mid to late pregnancy was calculated (grams or centimetres/week). Cohort/region-specific distributed lag non-linear models were combined using a random-effects meta-analysis and results presented in reference to the median percentile of temperature (14 °C)., Results: Weekly temperatures ranged from -5.6 (Bradford) to 30.3 °C (INMA-Sabadell). Cold and heat exposure during weeks 1-28 were associated with a smaller and larger head circumference in late pregnancy, respectively (e.g., for 9.5 °C: -1.6 SDS [95 %CI -2.0; -0.4] and for 20.0 °C: 1.8 SDS [0.7; 2.9]). A susceptibility period from weeks 1-7 was identified for cold exposure and a smaller head circumference at late pregnancy. Cold exposure was associated with a slower head circumference growth from mid to late pregnancy (for 5.5 °C: -0.1 cm/week [-0.2; -0.04]), with a susceptibility period from weeks 4-12. No associations that survived multiple testing correction were found for other foetal or any birth outcomes., Conclusions: Cumulative exposure to cold and heat during pregnancy was associated with changes in foetal head circumference throughout gestation, with susceptibility periods for cold during the first pregnancy trimester. No associations were found at birth, suggesting potential recovery. Future research should replicate this study across different climatic regions including varying temperature profiles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)