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Abstract Background Children with developmental coordination disorder (DCD) have impaired online motor control. Researchers posit that this impairment could be due to a deficit in utilizing the internal model control process. However, there is little neurological evidence to support this view because few neuroimaging studies have focused specifically on tasks involving online motor control. Therefore, the aim of this study was to investigate the differences in cortical hemodynamic activity during an online movement adjustment task between children with and without DCD. Methods Twenty children with DCD (mean age: 9.88 ± 1.67 years; gender: 14M/6F) and twenty age-and-gender matched children with typical development (TD) (mean age: 9.87 ± 1.59 years; gender: 14M/6F) were recruited via convenience sampling. Participants performed a double-step reaching task under two conditions (with and without online adjustment of reaching). Cortical hemodynamic activity during task in ten regions of interest, including bilateral primary somatosensory cortex, primary motor cortex, premotor cortex, superior parietal cortex, and inferior parietal cortex was recorded using functional near-infrared spectroscopy. In the analyses, change in oxyhemoglobin (ΔHbO) concentration was used to characterize hemodynamic response. Two-way analyses of variance were conducted for each region of interest to compare hemodynamic responses between groups and conditions. Additionally, Pearson’s r correlations between hemodynamic response and task performance were performed. Results Outcome showed that children with DCD required significantly more time to correct their reaching movements compared to the control group (t = 3.948, P

Abstract The microgravity environment aboard the International Space Station (ISS) provides a unique stressor that can help understand underlying cellular and molecular drivers of pathological changes observed in astronauts with the ultimate goals of developing strategies to enable long- term spaceflight and better treatment of diseases on Earth. We used this unique environment to evaluate the effects of microgravity on kidney proximal tubule epithelial cell (PTEC) response to serum exposure and vitamin D biotransformation capacity. To test if microgravity alters the pathologic response of the proximal tubule to serum exposure, we treated PTECs cultured in a microphysiological system (PT-MPS) with human serum and measured biomarkers of toxicity and inflammation (KIM-1 and IL-6) and conducted global transcriptomics via RNAseq on cells undergoing flight (microgravity) and respective controls (ground). Given the profound bone loss observed in microgravity and PTECs produce the active form of vitamin D, we treated 3D cultured PTECs with 25(OH)D3 (vitamin D) and monitored vitamin D metabolite formation, conducted global transcriptomics via RNAseq, and evaluated transcript expression of CYP27B1, CYP24A1, or CYP3A5 in PTECs undergoing flight (microgravity) and respective ground controls. We demonstrated that microgravity neither altered PTEC metabolism of vitamin D nor did it induce a unique response of PTECs to human serum, suggesting that these fundamental biochemical pathways in the kidney proximal tubule are not significantly altered by short-term exposure to microgravity. Given the prospect of extended spaceflight, more study is needed to determine if these responses are consistent with extended (>6 months) exposure to microgravity.

Abstract Determining the physiological effects of microgravity on the human kidney is limited to relatively insensitive tests of biofluids (blood and urine) that do not return abnormal results until more than 50% of kidney function is lost. We have developed an “organ on chip” microphysiological model of the human kidney proximal tubule (PT-MPS) that can recapitulate many kidney functions and disease states and could play a critical role in determining mechanisms of early kidney dysfunction in microgravity. However, the ground-based PT-MPS system is incompatible with spaceflight as it requires a large pneumatic system coupled to a cell incubator for perfusion and intensive hand-on manipulation. Herein, we report the hardware engineering and performance of the Kidney Chip Perfusion Platform (KCPP), a small, advanced, semi-autonomous hardware platform to support kidney microphysiological model experiments in microgravity. The KCPP is composed of five components, the kidney MPS, the MPS housing and valve block, media cassettes, fixative cassettes, and the programable precision syringe pump. The system has been deployed twice to the ISSNL (aboard CRS-17 and CRS-22). From each set of ISSNL experiments and ground-based controls, we were able to recover PT-MPS effluent for biomarker analysis and RNA suitable for transcriptomics analysis demonstrating the usability and functionality of the KCPP.

Abstract Excessive bone marrow adipocytes (BMAds) accumulation often occurs under diverse pathophysiological conditions associated with bone deterioration. Estrogen-related receptor α (ESRRA) is a key regulator responding to metabolic stress. Here, we show that adipocyte-specific ESRRA deficiency preserves osteogenesis and vascular formation in adipocyte-rich bone marrow upon estrogen deficiency or obesity. Mechanistically, adipocyte ESRRA interferes with E2/ESR1 signaling resulting in transcriptional repression of secreted phosphoprotein 1 (Spp1); yet positively modulates leptin expression by binding to its promoter. ESRRA abrogation results in enhanced SPP1 and decreased leptin secretion from both visceral adipocytes and BMAds, concertedly dictating bone marrow stromal stem cell fate commitment and restoring type H vessel formation, constituting a feed-forward loop for bone formation. Pharmacological inhibition of ESRRA protects obese mice against bone loss and high marrow adiposity. Thus, our findings highlight a therapeutic approach via targeting adipocyte ESRRA to preserve bone formation especially in detrimental adipocyte-rich bone milieu.

Abstract Previous research on cool-hot executive function (EF) interactions has examined the effects of motivation and emotional distraction on cool EF separately, focusing on one EF component at a time. Although both incentives and emotional distractors have been shown to modulate attention, how they interact and affect cool EF processes is still unclear. Here, we used an experimental paradigm that manipulated updating, inhibition, and shifting demands to determine the interactions of motivation and emotional distraction in the context of cool EF. Forty-five young adults (16 males, 29 females) completed the go/no-go (inhibition), two-back (updating), and task-switching (shifting) tasks. Monetary incentives were implemented to manipulate motivation, and task-irrelevant threatening or neutral faces were presented before the target stimulus to manipulate emotional distraction. We found that incentives significantly improved no-go accuracy, two-back accuracy, and reaction time (RT) switch cost. While emotional distractors had no significant effects on overall task performance, they abolished the incentive effects on no-go accuracy and RT switch cost. Altogether, these findings suggest that motivation and emotional distraction interact in the context of cool EF. Specifically, transient emotional distraction disrupts the upregulation of control activated by incentives. The present investigation has advanced knowledge about the relationship between cool and hot EF and highlights the importance of considering motivation–emotion interactions for a fuller understanding of control.

Summary: Macrophages are critical for maintenance and repair of mucosal tissues. While functionally distinct subtypes of macrophage are known to have important roles in injury response and repair in the lungs, little is known about macrophages in the proximal conducting airways. Single-cell RNA sequencing and flow cytometry demonstrated murine tracheal macrophages are largely monocyte-derived and are phenotypically distinct from lung macrophages at homeostasis. Following sterile airway injury, monocyte-derived macrophages are recruited to the trachea and activate a pro-regenerative phenotype associated with wound healing. Animals lacking the chemokine receptor CCR2 have reduced numbers of circulating monocytes and tracheal macrophages, deficient pro-regenerative macrophage activation and defective epithelial repair. Together, these studies indicate that recruitment and activation of monocyte-derived tracheal macrophages is CCR2-dependent and is required for normal airway epithelial regeneration.

Objectives(1) Compare the cross-sectional thickness (CST) and shear wave speed (SWS) of paraspinal muscles (PSM) in adolescent idiopathic scoliosis (AIS) with and without curve progression; (2) investigate the relationship between CST/SWS and radiographic characteristics in AIS with curve progression; (3) compare the CST/SWS between AIS and non-scoliosis controls.MethodsThis cross-sectional study analyzed the CST and SWS of PSM in 48 AIS with mild to moderate curvature and 24 non-scoliosis participants. Participants with scoliosis greater than 45° of Cobb angles were excluded. The Change of Cobb angles within the last 6-months was retrieved to allocate AIS into progression and non-progression groups. The SWS and CST of multifidus; longissimus and iliocostalis of the major curve were measured using B-mode ultrasound image with an elastography mode. Discrepancies of the SWS (SWS-ratio: SWS on the convex side divided by SWS on the concave side) and CST (CST-ratio: CST on the convex side divided by CST on the concave side) at the upper/lower end and apical vertebrae were studied.ResultsA higher SWS at the apical vertebrae on the concave side of the major curve (multifidus: 3.9 ± 1.0 m/s vs. 3.1 ± 0.6 m/s; p

The educational expectations of students for themselves have been commonly corroborated to directly predict their higher academic performance. Nevertheless, some recent research has reported that the academic performance of students may also contribute to their better development of educational expectations. Moreover, more advanced but limited research has argued that both the educational expectations and academic performance of students are developmental and changeable over time rather than fixed and stable. Due to the importance of students’ science learning performance during the years of secondary school in relation to their later STEM development in adulthood, the current study is intended to investigate how the developmental and growth trajectories of students’ educational expectations and science learning performance reciprocally affect each other directly and inversely in secondary school and then later contribute to their successful completion of a STEM degree in adulthood. Based on the six-wave panel data containing a nationally representative sample of adolescent students from the Longitudinal Study of American Youth (LSAY), the current study was conducted by parallel-process latent growth curve modeling (PP-LGCM) and found that both the developmental and growth trajectories of students’ educational expectations and science learning performance were mutually predictive of each other across the years of secondary school, which then contributed to their later higher likelihood of successful completion of a STEM degree in adulthood. In addition, the conditional direct PP-LGCM model, which is to model the effects of students’ educational expectations on their science learning performance, and the conditional inverse PP-LGCM model, which is to model the effects of students’ science learning performance on their educational expectations, showed significant within- and cross-domain effects differently. The implications of the study findings related to educational reforms and policy designs are discussed.

Abstract Kidney function‐adjusted drug dosing is currently based solely on the estimated glomerular filtration rate (GFR), however, kidney drug handling is accomplished by a combination of filtration, tubular secretion, and re‐absorption. Mechanistic physiologically‐based pharmacokinetic (PBPK) models recapitulate anatomic compartments to predict elimination from estimated perfusion, filtration, secretion, and re‐absorption, but clinical applications are limited by a lack of empiric individual‐level measurements of these functions. We adapted and validated a PBPK model to predict drug clearance from individual biomarker‐based estimates of kidney perfusion and secretory clearance. We estimated organic anion transporter‐mediated secretion via kynurenic acid clearance and kidney blood flow (KBF) via isovalerylglycine clearance in human participants, incorporating these measurements with GFR into the model to predict kidney drug clearance. We compared measured and model‐predicted clearances of administered tenofovir and oseltamivir, which are cleared by both filtration and secretion. There were 27 outpatients (age 55 ± 15 years, mean iohexol‐GFR [iGFR] 76 ± 31 mL/min/1.73 m2) in this drug clearance study. The mean observed and mechanistic model‐predicted tenofovir clearances were 169 ± 102 mL/min and 163 ± 80 mL/min, respectively; estimated mean error of the mechanistic model was 37.1 mL/min (95% confidence interval [CI]: 24–52.9), compared to a mean error of 41.8 mL/min (95% CI: 25–61.6) from regression model. The mean observed and model‐predicted oseltamivir carboxylate clearances were 183 ± 104 mL/min and 179 ± 89 mL/min, respectively; estimated mean error of the mechanistic model was 42.9 mL/min (95% CI: 29.7–56.4), versus error of 48.1 mL/min (95% CI: 31.2–67.3) from the regression model. Individualized estimates of tubular secretion and KBF improved the accuracy of PBPK model‐predicted tenofovir and oseltamivir kidney clearances, suggesting the potential for biomarker‐informed measures of kidney function to refine personalized drug dosing.

Background: In case conservative medical treatment fails or symptoms persist in type B thoracic aortic dissection (TBAD), invasive treatment with thoracic endovascular repair (TEVAR) is recommended. TEVAR aims to prevent aneurysm formation, reduce rupture risk, and improve survival rates if initiated early. However, TEVAR may not always sufficiently remodel the aorta, especially when there are existing tears further down. Some studies suggest extending the stent graft with bare metal stents to enhance aortic remodeling, but the PETTICOAT technique can be complex with incomplete clotting and aortic dilation. This case report introduces the Multilayer Flow Modulator stent (MFM®) as a novel technique that combines stent graft and bare metal stenting advantages while avoiding PETTICOAT limitations. Case report: A 47-year-old male with a history of hypercholesterolemia, smoking, and obesity presented with lower back pain and claudication. A diagnostic CT scan revealed type TBAD with tears at various levels. Initial treatment involved antihypertensive therapy, but the patient later experienced worsened symptoms. A two-stage intervention was performed, utilizing multilayer stents and a Valiant thoracic stent graft to cover the dissected areas. The patient had a successful recovery with improved aortic lining and maintained kidney function. Follow-up scans showed stable aortic diameter and no further complications. Conclusion: This case report presents a successful treatment of a complicated TBAD using a combination of stent grafts and multilayer aortic stents. Follow-up after one year showed significant improvement in aortic remodeling, with thrombosis of the false lumen and patent aortic branches. The patient became asymptomatic with no claudication or thoracic pain. The combined approach appears to be a safe and effective treatment option, but more research is necessary for validation.

Abstract The n-back task is a popular paradigm for studying neurocognitive processing at varying working memory loads. Although much is known about the effects of load on behavior and neural activation during n-back performance, the temporal dynamics of such effects remain unclear. Here, we investigated the within- and between-session stability and consistency of task performance and frontal cortical activation during the n-back task using functional near-infrared spectroscopy (fNIRS). Forty healthy young adults performed the 1-back and 3-back conditions three times per condition. They then undertook identical retest sessions 3 weeks later (M = 21.2 days, SD = 0.9). Over the course of the task, activation in the participants’ frontopolar, dorsomedial, dorsolateral, ventrolateral, and posterolateral frontal cortices was measured with fNIRS. We found significantly improved working memory performance (difference between 1-back and 3-back accuracies) over time both within and between sessions. All accuracy and reaction time measures exhibited good to excellent consistency within and across sessions. Additionally, changes in frontal oxyhemoglobin (HbO) and deoxyhemoglobin (HbR) concentration were maintained over time across timescales, except that load-dependent (3-back > 1-back) HbO changes, particularly in the ventrolateral PFC, diminished over separate sessions. The consistency of fNIRS measures varied greatly, with changes in 3-back dorsolateral and ventrolateral HbO demonstrating fair-to-good consistency both within and between sessions. Overall, this study clarified the temporal dynamics of task performance and frontal activation during the n-back task. The findings revealed the neural mechanisms underlying the change in n-back task performance over time and have practical implications for future n-back research.

Abstract Background Osteogenesis imperfecta (OI) is a rare congenital disorder of the skeletal system, inflicting debilitating physical and psychological distress on patients and caregivers. Over the decades, much effort has been channeled towards understanding molecular mechanisms and developing new treatments. It has recently become more apparent that patient-reported outcome measurements (PROM) during treatment, healing and rehabilitation are helpful in facilitating smoother communication, refining intervention strategies and achieving higher quality of life. To date, systematic analyses of PROM in OI patients remain scarce. Results Here, utilizing a PROM Information System, we report a cross-sectional and longitudinal study in a southern Chinese cohort of 90 OI patients, covering both the child and adult age-groups. In the child group where both self and parental surveys were obtained, we identified two clusters of comparable sizes showing different outlooks in physical mobility and emotional experiences. One cluster (Cluster 1) is more negative about themselves than the other (Cluster 2). A concordance of 84.7% between self and parental assessments was recorded, suggesting the stability and validity of PROM-based stratification. Clinical subtyping, deformity, leg length discrepancy, and limited joint mobility were significantly associated with this stratification, with Cluster 1 showing higher percentages of severe phenotypes than Cluster 2. Since OI is a genetic disorder, we performed genetic testing on 72 of the 90 patients, but found no obvious association between genotypes and the PROM stratification. Analyses of longitudinal data suggested that patients tended to stay in the same psychological state, in both clusters. Adult patients also showed a continuous spectrum of self-evaluation that matches their clinical manifestations. Conclusion By systematically analyzing patient-reported outcomes, our study demonstrated the link between the sociopsychological wellbeing of OI patients, and their clinical manifestations, which may serve as the basis for evaluating clinical interventions and help achieve better patient-centric medical practices. The lack of genotype-PROM association may be due to the diverse mutational spectrum in OI, which warrants further investigation when a larger sample size is available.

Real-world threatening faces possess both useful and irrelevant attributes with respect to the current goal. How these attributes interact and affect attention, which comprises at least three processes hypothesized to engage the frontal lobes (alerting, orienting, and executive control), remains poorly understood. Here, the neurocognitive effects of threatening facial expressions on the three processes of attention were examined through the emotional Attention Network Test (ANT) and functional near-infrared spectroscopy (fNIRS). Forty-seven (20M, 27F) young adults performed a blocked version of the arrow flanker task with neutral and angry facial cues applied in three cue conditions (no, center, and spatial). Hemodynamic changes occurring in participants' frontal cortices during task performance were recorded by multichannel fNIRS. Behavioral results indicated that alerting, orienting, and executive control processes existed in both the neutral and angry conditions. However, depending on the context, angry facial cues affected these processes differently compared with neutral facial cues. Specifically, the angry face disrupted the classical decrease in reaction time from the no-cue to center-cue condition specifically during the congruent condition. Additionally, fNIRS results revealed significant frontal cortical activation during the incongruent vs. congruent task; neither cue nor emotion significantly affected frontal activation. Thus, the findings suggest that the angry face affects all three attentional processes while exerting context-specific effects on attention. They also imply that during the ANT, the frontal cortex is most involved in executive control. The present study offers essential insights into how various attributes of threatening faces interact and alter attention.

Abstract There has been growing recognition of the utility of combining the verbal fluency test and functional near-infrared spectroscopy (fNIRS) to assess brain functioning and to screen for psychiatric disorders. Recently, an emotional analogue of the semantic fluency test (SFT) has been developed that taps partly different processes from conventional verbal fluency tests. Nevertheless, neural processing during the emotional SFT remains elusive. Here, fNIRS was used to compare frontal cortical activation during emotional and non-emotional SFTs. The goal was to determine whether the emotional SFT activated overlapping yet distinct frontal cortical regions compared with the conventional, non-emotional SFT. Forty-three healthy young adults performed the emotional and non-emotional SFTs while hemodynamic changes in the bilateral frontopolar, dorsomedial, dorsolateral, ventrolateral, and posterolateral frontal cortices were measured by fNIRS. There were significant increases in oxyhemoglobin concentration and significant decreases in deoxyhemoglobin concentration (i.e., activation) in frontopolar, dorsolateral, and ventrolateral frontal regions during both the non-emotional and emotional SFTs. Also, complementary analyses conducted on changes in the two chromophores using classical and Bayesian hypothesis testing suggested that comparable frontal cortical regions were activated while performing the two tests. This similarity in activation occurred in a context where non-emotional and emotional SFT performances exhibited differential relationships with the overall level of negative mood symptoms. In conclusion, frontal cortical activation during the emotional SFT is similar to that during the conventional, non-emotional SFT. Given that there is evidence for discriminant validity for the emotional SFT, the neural mechanisms underlying the uniqueness of this test warrant further investigation.

During human embryonic development, haematopoietic stem cells of the foetal liver undergo expansion, while retaining engraftment capacity. Here the authors apply CITE-seq to profile single cells from a human foetal liver, identifying a molecular signature of engraftment potential

Abstract Midpalatal suture was analysed with cone beam computed tomography to identify its maturation with respect to age and maxillary-complex growth in 72 patients 9- to 21-year-old. Maxillary-complex was divided in premaxillary, maxillary, and palatine segment. Interdigitation and ossification of midpalatal suture, its density relative to hard tissues and soft tissues, and midpalatal suture density ratio were measured for each segment. Correlation of each parameter with age and maxillary-complex length was analysed, and classification trees were developed for staging parameters. Midpalatal suture maturation stages (MPSMS, from A to E) were applied to assess relationship with age and maxillary-complex length. Regarding age, ossification increased in maxillary segment of males (r S = 0.39, p = 0.032), while suture density relative to soft tissues increased in maxillary (r S = 0.37, p = 0.042) and palatine segments (r S = 0.41, p = 0.027) of males and in palatine segment of females (r S = 0.32, p = 0.041). In males, suture density relative to soft tissues discriminated two age-stages (p = 0.024), and the same parameter (p = 0.023) paired with ossification (p = 0.027) discriminated two length-stages. MPSMS identified length-differences between stage A and B in females (p = 0.001). Midpalatal-suture ossification and its density relative to soft tissues showed some relationship with age and maxillary-complex length, especially in males. However, challenging staging and limitations in the imaging method may limit clinical applications.

Abstract Background Exosomes derived from stem cells have been widely studied for promoting regeneration and reconstruction of multiple tissues as “cell-free” therapies. However, the applications of exosomes have been hindered by limited sources and insufficient therapeutic potency. Results In this study, a stem cell-mediated gene therapy strategy is developed in which mediator mesenchymal stem cells are genetically engineered by bone morphogenetic protein-2 gene to produce exosomes (MSC-BMP2-Exo) with enhanced bone regeneration potency. This effect is attributed to the synergistic effect of the content derived from MSCs and the up-regulated BMP2 gene expression. The MSC-BMP2-Exo also present homing ability to the injured site. The toxic effect of genetical transfection vehicles is borne by mediator MSCs, while the produced exosomes exhibit excellent biocompatibility. In addition, by plasmid tracking, it is interesting to find a portion of plasmid DNA can be encapsulated by exosomes and delivered to recipient cells. Conclusions In this strategy, engineered MSCs function as cellular factories, which effectively produce exosomes with designed and enhanced therapeutic effects. The accelerating effect in bone healing and the good biocompatibility suggest the potential clinical application of this strategy. Graphical Abstract

The delinquency of female adolescents at risk has increased conspicuously, much to the concern of human service and public health practitioners. Nevertheless, prior findings of pertinent research have commonly been based on samples of male or gender-mixed participants, especially general youths in the community. These cannot adequately explicate the impacts of different contextual systems on at-risk female adolescents, who are, in fact, more vulnerable to developing delinquency. Based on cross-sectional data collected from a sample of 236 at-risk female adolescents with the help of a large social work organization, the present study investigated and compared the effects of family, school, and peer systems on different forms of delinquency among at-risk female adolescents. The results show that positive family functioning, constructive school experiences, and deviant peer influence were predictive of both self-destructive and other-destructive delinquency in at-risk adolescent girls, respectively, but the effects were significantly different depending on which contextual systems influenced what forms of delinquency. Furthermore, the relationships between positive family functioning and both forms of delinquency were significantly mediated by the effects of constructive school experiences and deviant peer influence, giving support to the distal role of family and the proximal functions of school and peers in adolescence. Implications for policy prevention and interventions to strengthen the contextual supports in different social systems to help female adolescents at risk are discussed.

Abstract The use of microphysiological systems (MPS) to support absorption, distribution, metabolism, and elimination (ADME) sciences has grown substantially in the last decade, in part driven by regulatory demands to move away from traditional animal‐based safety assessment studies and industry desires to develop methodologies to efficiently screen and characterize drugs in the development pipeline. The past decade of MPS development has yielded great user‐driven technological advances with the collective fine‐tuning of cell culture techniques, fluid delivery systems, materials engineering, and performance enhancing modifications. The rapid advances in MPS technology have now made it feasible to evaluate critical ADME parameters within a stand‐alone organ system or through interconnected organ systems. This review surveys current MPS developed for liver, kidney, and intestinal systems as stand‐alone or interconnected organ systems, and evaluates each system for specific performance criteria recommended by regulatory authorities and MPS leaders that would render each system suitable for evaluating drug ADME. Whereas some systems are more suitable for ADME type research than others, not all system designs were intended to meet the recently published desired performance criteria and are reported as a summary of initial proof‐of‐concept studies.

Abstract Individuals with autism spectrum disorder (ASD) perform poorly in working memory (WM) tasks, with some literature suggesting that their impaired performance is modulated by WM load. While some neuroimaging and neurophysiological studies have reported altered functional connectivity during WM processing in individuals with autism, it remains largely unclear whether such alterations are moderated by WM load. The present study aimed to examine the effect of WM load on functional connectivity within the prefrontal cortex (PFC) in ASD using functional near-infrared spectroscopy (fNIRS). Twenty-two children with high-functioning ASD aged 8–12 years and 24 age-, intelligent quotient (IQ)-, sex- and handedness-matched typically developing (TD) children performed a number n-back task with three WM loads (0-back, 1-back, and 2-back). Hemodynamic changes in the bilateral lateral and medial PFC during task performance were monitored using a multichannel NIRS device. Children with ASD demonstrated slower reaction times, specifically during the “low load” condition, than TD children. In addition, the ASD and TD groups exhibited differential load-dependent functional connectivity changes in the lateral and medial PFC of the right but not the left hemisphere. These findings indicate that WM impairment in high-functioning ASD is paralleled by load-dependent alterations in right, but not left, intrahemispheric connectivity during WM processing in children with ASD. A disruption of functional neural connections that support different cognitive processes may underlie poor performance in WM tasks in ASD.

Mechanisms underlying bone formation induced by divalent metal cations remain largely unknown. Here the authors show that these cations can activate the skeleton interoceptive circuit through the immune-neural axis to initiate new bone formation.

IntroductionFollicle stimulating hormone (FSH) is identified to play a role in postmenopausal disease and hypothesized to affect abdominal aortic aneurysm (AAA) onset/progression in postmenopausal women. We aimed to detect FSHR gene expression in AAA tissue and cell types involved in AAA formation.MethodsFSH stimulation of human umbilical cord endothelial cells (HUVECs), smooth muscle cells (HUCs) and PMA-differentiated macrophages to assess gene expression of FSHR and various markers. Human macrophages activated with various stimuli were assessed for FSHR gene expression. AAA dataset, AAA tissue samples and AAA-derived smooth muscle cells (SMC) obtained from elderly female donors were assessed for FSHR gene expression. AAA-SMCs were stimulated with FSH to assess its effect on gene expression. Lastly, oxidized low-density-lipoprotein (ox-LDL) uptake and abundance of cell surface protein markers were assessed by flow cytometry after FSH stimulation of human monocytes.ResultsFSH stimulation showed similar levels of gene expression in HUVECs and HUCs. Only ACTA2 was downregulated in HUCs. In PMA-differentiated macrophages, gene expression of inflammation markers was unchanged after FSH stimulation. FSHR gene expression was found to be low in the AAA datasets. Female AAA-SMCs show occasional FSHR gene expression at a very low level, yet stimulation with FSH did not affect gene expression of SMC- or inflammation markers. FSH stimulation did not impact ox-LDL uptake or alter cell surface protein expression in monocytes. While FSHR gene expression was detected in human testis tissue, it was below quantification level in all other investigated cell types, even upon activation of macrophages with various stimuli.ConclusionDespite previous reports, we did not detect FSHR gene expression in various extragonadal cell types, except in occasional female AAA-SMCs. No clear effect on cell activation was observed upon FSH stimulation in any cell type. Our data suggest that a direct effect of FSH in AAA-related extragonadal cells is unlikely to influence AAA.

While forecasting football match results has long been a popular topic, a practical model for football participants, such as coaches and players, has not been considered in great detail. In this study, we propose a generalized and interpretable machine learning model framework that only requires coaches' decisions and player quality features for forecasting. By further allowing the model to embed historical match statistics, features that consist of significant information, during the training process the model was practical and achieved both high performance and interpretability. Using five years of data (over 1,700 matches) from the English Premier League, our results show that our model was able to achieve high performance with an F1-score of 0.47, compared to the baseline betting odds prediction, which had an F1-score of 0.39. Moreover, our framework allows football teams to adapt for tactical decision-making, strength and weakness identification, formation and player selection, and transfer target validation. The framework in this study would have proven the feasibility of building a practical match result forecast framework and may serve to inspire future studies.

Abstract Opioid overdose, dependence, and addiction are a major public health crisis. Patients with chronic kidney disease (CKD) are at high risk of opioid overdose, therefore novel methods that provide accurate prediction of renal clearance (CLr) and systemic disposition of opioids in CKD patients can facilitate the optimization of therapeutic regimens. The present study aimed to predict renal clearance and systemic disposition of morphine and its active metabolite morphine-6-glucuronide (M6G) in CKD patients using a vascularized human proximal tubule microphysiological system (VPT-MPS) coupled with a parent-metabolite full body physiologically-based pharmacokinetic (PBPK) model. The VPT-MPS, populated with a human umbilical vein endothelial cell (HUVEC) channel and an adjacent human primary proximal tubular epithelial cells (PTEC) channel, successfully demonstrated secretory transport of morphine and M6G from the HUVEC channel into the PTEC channel. The in vitro data generated by VPT-MPS were incorporated into a mechanistic kidney model and parent-metabolite full body PBPK model to predict CLr and systemic disposition of morphine and M6G, resulting in successful prediction of CLr and the plasma concentration–time profiles in both healthy subjects and CKD patients. A microphysiological system together with mathematical modeling successfully predicted renal clearance and systemic disposition of opioids in CKD patients and healthy subjects.

Children with autism spectrum disorder (ASD) show marked difficulties in reading comprehension, a complex cognitive skill fundamental to successful daily functioning that is associated with core executive functions. However, the neurophysiological mechanisms underlying reading comprehension deficits in these children remain elusive. Twenty-one right-handed males with high-functioning ASD (mean age = 10.24 years) and 23 age-, IQ-, educational level-, sex- and handedness-matched typically developing (TD; mean age = 10.14 years) individuals underwent a reading comprehension test and the semantic verbal fluency test that tapped core executive functions underlying reading comprehension during concurrent prefrontal functional near-infrared spectroscopy (fNIRS) measurement. Participants’ information processing efficiency was also assessed. High-functioning ASD children exhibited general reading comprehension [main effect of group: F(1,40) = 7.58, p = 0.009], selective verbal fluency deficits [Group × category interaction: F(1,42) = 4.90, p = 0.032] and slower processing speed (t42 = 2.36, p = 0.023). Regarding the hemodynamics of the prefrontal cortex (PFC), although ASD individuals showed comparable patterns of PFC brain activation to their healthy counterparts, lower PFC intrahemispheric [main effect of group: F(1,42) = 11.36, p = 0.002] and interhemispheric [main effect of group: F(1,42) = 7.79, p = 0.008] functional connectivity were evident during the semantic verbal fluency test. At the whole-group level, poorer reading comprehension performance was associated with poorer performance in the semantic verbal fluency test (r42 = 0.508, p < 0.001). Moreover, poorer semantic verbal fluency test performance was associated with slower information processing speed (r42 = –0.312, p = 0.044), which is associated with reduced left medial PFC functional connectivity (r42 = –0.319, p = 0.040). Abnormal intrahemispheric and interhemispheric prefrontal hypoconnectivity is associated with deficits in executive processes essential for reading comprehension in ASD. Our study has provided important implications for the neuropsychological and neurophysiological mechanisms underlying reading comprehension deficits in ASD.

Thermochromic window coatings represent a promising technology to improve the energy efficiency of buildings in intermediate climates. With the technology approaching market introduction it is important to investigate its performance limits within smart windows and to identify existing development challenges. Here we analyze the theoretical maximum performance of thermochromic window coatings that modulate IR transmission whilst retaining high visible transparency. The set limitations lead to a theoretical maximum solar modulation of 39.1%. Within an insulated glazing unit (IGU), where at least 2 glass panes and a conventional low-e coating are required, this value is further reduced to 12.9%. We show that by carefully selecting a low-e coating with the highest compatibility to a thermochromic coated glass and by allowing 10% of modulation in the visible spectral range, the theoretical maximum can be increased to 23.1%, illustrating the importance to codesign and match both coatings within a smart window to reach optimum performance. Furthermore, we compared our current best-performing VO2:SiO2 composite coating within an IGU to the theoretical maximum. The analysis shows that with a solar modulation of 13.4%, the coating is currently at 59% of the theoretical maximum. Finally, we propose and discuss several strategies to proceed further toward the theoretical maximum.