Miracle-dz/UniFAR-FTUs huggingface dataset:
Glucocorticoids and myosin5b loss of function induce heightened PKA signaling in addition to membrane traffic defects

Loss-of-function mutations in the nonconventional myosin Vb (Myo5b) result in microvillus inclusion disease (MVID) and massive secretory diarrhea that often begins at birth. Myo5b mutations disrupt the apical recycling endosome (ARE) and membrane traffic, resulting in reduced surface expression of apical membrane proteins. ARE disruption also results in constitutive phosphoinositide-dependent kinase 1 gain of function. In MVID, decreased surface expression of apical anion channels involved in Cl− extrusion, such as cystic fibrosis transmembrane conductance regulator (CFTR), should reduce fluid secretion into the intestinal lumen. But the opposite phenotype is observed. To explain this contradiction and the onset of diarrhea, we hypothesized that signaling effects downstream from Myo5b loss of function synergize with higher levels of glucocorticoids to activate PKA and CFTR. Data from intestinal cell lines, human MVID, and Myo5b KO mouse intestine revealed changes in the subcellular redistribution of PKA activity to the apical pole, increased CFTR phosphorylation, and establishment of apical cAMP gradients in Myo5b-defective cells exposed to physiological levels of glucocorticoids. These cells also displayed net secretory fluid fluxes and transepithelial currents mainly from PKA-dependent Cl− secretion. We conclude that Myo5b defects result in PKA stimulation that activates residual channels on the surface when intestinal epithelia are exposed to glucocorticoids at birth.
Toward Preventing Enamel Hypoplasia: Modeling Maternal and Neonatal Biomarkers of Human Calcium Homeostasis

Aim: The aim of this study was to assess biomarkers of calcium homeostasis and tooth development, in mothers during pregnancy and their children at birth, for enamel hypoplasia (EH) in the primary maxillary central incisor teeth. Methods: Bayesian methodology was used for secondary data analyses from a randomized, controlled trial of prenatal vitamin D3 supplementation in healthy mothers (N = 350) and a follow-up study of a subset of the children. The biomarkers were serum calcium (Ca), phosphorus (P), intact parathyroid hormone (iPTH), total circulating 25-dihydroxyvitamin D (25(OH)D), and 1,25-dihydroxyvitamin D (1,25(OH)2D). The maternal biomarkers were assayed monthly during pregnancy, and the child’s biomarkers were derived from cord blood. Digital images of the child’s 2 teeth were scored for EH using Enamel Defects Index criteria for each of the incisal, middle, and cervical regions for an EH extent score. Results: The child EH prevalence was 41% (60/145), with most defects present in the incisal and middle tooth regions. Cord blood iPTH and 1,25(OH)2D levels were significantly associated with EH extent after controlling for maternal factors. For every 1 pg/mL increase in cord blood iPTH, the EH extent decreased by approximately 6%. For every 10 pg/mL increase in cord blood 1,25(OH)2D, the EH extent increased by almost 30% (holding all other terms constant and adjusting for subject-level heterogeneity). The relationship between maternal 25(OH)D and maternal mean iPTH varied significantly by EH extent. Conclusion: The results suggest possible modifiable relationships of maternal and neonatal factors of calcium homeostasis during pregnancy and at birth for EH, contributing to the frontier of knowledge regarding sound tooth development for dental caries prevention.
Increasing Physician Assistant Students' Team Communication Skills and Confidence Throughout Clinical Training.

PURPOSE An intervention was designed to increase physician assistant students' team communication skills using the Situation-Background-Assessment-Recommendation (SBAR) tool. METHODS A variety of learning activities were implemented longitudinally over 9 months of clinical education. Instructional activities included an interactive lecture, deliberate practice of SBAR at clinical training sites, self-assessment, and small group discussion. Evaluation involved survey of students' perceived learning outcomes and direct observation of students' proficiency using SBAR during a simulated patient encounter. RESULTS At the beginning of their clinical training, many students (75%) did not have a structured tool for communicating on health care teams. The SBAR tool was readily understood by students following a lecture (89%) and increased their confidence in communicating with preceptors (62%-83%) and nonpreceptors (62%-79%). A majority of students proficiently demonstrated the SBAR components (82%-86%) at the conclusion of the program. CONCLUSION This approach can be adopted and adapted by other programs aiming to teach and evaluate SBAR and other team skills to better prepare new health professionals to effectively communicate on health care teams.
Limitations of cross‐ and multigenerational plasticity for marine invertebrates faced with global climate change

Although cross generation (CGP) and multigenerational (MGP) plasticity have been identified as mechanisms of acclimation to global change, the weight of evidence indicates that parental conditioning over generations is not a panacea to rescue stress sensitivity in offspring. For many species, there were no benefits of parental conditioning. Even when improved performance was observed, this waned over time within a generation or across generations and fitness declined. CGP and MGP studies identified resilient species with stress tolerant genotypes in wild populations and selected family lines. Several bivalves possess favourable stress tolerance and phenotypically plastic traits potentially associated with genetic adaptation to life in habitats where they routinely experience temperature and/or acidification stress. These traits will be important to help ‘climate proof’ shellfish ventures. Species that are naturally stress tolerant and those that naturally experience a broad range of environmental conditions are good candidates to provide insights into the physiological and molecular mechanisms involved in CGP and MGP. It is challenging to conduct ecologically relevant global change experiments over the long times commensurate with the pace of changing climate. As a result, many studies present stressors in a shock‐type exposure at rates much faster than projected scenarios. With more gradual stressor introduction over longer experimental durations and in context with conditions species are currently acclimatized and/or adapted to, the outcomes for sensitive species might differ. We highlight the importance to understand primordial germ cell development and the timing of gametogenesis with respect to stressor exposure. Although multigenerational exposure to global change stressors currently appears limited as a universal tool to rescue species in the face of changing climate, natural proxies of future conditions (upwelling zones, CO2 vents, naturally warm habitats) show that phenotypic adjustment and/or beneficial genetic selection is possible for some species, indicating complex plasticity–adaptation interactions.
Nicotinamide Limits Replication of Mycobacterium tuberculosis and Bacille Calmette-Guérin Within Macrophages

Abstract Novel antimicrobials for treatment of Mycobacterium tuberculosis are needed. We hypothesized that nicotinamide (NAM) and nicotinic acid (NA) modulate macrophage function to restrict M. tuberculosis replication in addition to their direct antimicrobial properties. Both compounds had modest activity in 7H9 broth, but only NAM inhibited replication in macrophages. Surprisingly, in macrophages NAM and the related compound pyrazinamide restricted growth of bacille Calmette-Guérin but not wild-type Mycobacterium bovis, which both lack a functional nicotinamidase/pyrazinamidase (PncA) rendering each strain resistant to these drugs in broth culture. Interestingly, NAM was not active in macrophages infected with a virulent M. tuberculosis mutant encoding a deletion in pncA. We conclude that the differential activity of NAM and nicotinic acid on infected macrophages suggests host-specific NAM targets rather than PncA-dependent direct antimicrobial properties. These activities are sufficient to restrict attenuated BCG, but not virulent wild-type M. bovis or M. tuberculosis.
Differences of muscle oxygenation during eccentric and concentric contraction

The aims of the present study were to clarify the differences in muscle oxygen dynamics between eccentric (ECC) and concentric (CON) contractions and to investigate the relationship between muscle oxygen dynamics and the pattern of skeletal muscle recruitment during ECC and CON contractions. Fifteen healthy male subjects (age 21.8 ± 2 yrs) performed isokinetic ECC and CON knee extension and flexion exercise for 1 min at an angular velocity of 180 ◦ /s. Changes in muscle oxygenation (MO) levels in the active muscle were measured using near-infrared spectroscopy (NIRS) whose probe was placed on the rectus femoris. Bipolar surface electrodes recorded the electromyogram (EMG) activity of this muscle. The MO levels during ECC contraction were significantly higher at 10 s and 15 s after the onset of exercise while MO levels during CON contraction were significantly higher 60 s following the onset of exercise. A significant correlation was indicated between MO levels and EMG activity during CON contraction ( p< 0.05). These results reveal that oxygen supply-consumption balance in ECC and CON contraction are different. Moreover, this suggests that muscle activity in CON contraction increases and the oxygen supply to active muscle may exceed the oxygen consumption in active muscle.
Hair cell maturation is differentially regulated along the tonotopic axis of the mammalian cochlea

Outer hair cells (OHCs) enhance the sensitivity and the frequency tuning of the mammalian cochlea. Similar to the primary sensory receptor, the inner hair cells (IHCs), the mature functional characteristics of OHCs are acquired before hearing onset. We found that OHCs, like IHCs, fire spontaneous Ca2+‐induced action potentials (APs) during immature stages of development, which are driven by CaV1.3 Ca2+ channels. We also showed that the development of low‐ and high‐frequency hair cells is differentially regulated during pre‐hearing stages, with the former cells being more strongly dependent on experience‐independent Ca2+ action potential activity.
Social proximity in dairy calves is affected by differences in pessimism

Negative social interactions have been extensively studied in dairy cattle, but little is known about the establishment of positive (preferential) relationships. Adult dairy cows are known to spend more time at close proximity to specific social partners, indicating that they establish stronger bonds with these animals, but few studies have explored what happens in socially housed calves. In this study, we explored whether calves that spent their entire life in the same social group established social preferences (i.e. pairs of individuals that interact more) that are stable over time (two 48-h periods, separated by three days), across two types of behavior (standing and lying) and across contexts (change in environment and housing design). When housed in an open pack, calves showed consistent proximity patterns when standing (but not when lying). These preferential relationships persisted even after calves were moved into a new pen fitted with free stalls. At the individual level, calves varied in how selective they were in their social relationships, with some calves spending much more time with specific partners than did others. This degree of selectivity was not associated to Sociability, marginally associated to Fearfulness, but was associated with Pessimism (more pessimistic calves were more selective in their social relationships). In conclusion, calves can form selective relationships that appeared to be consistent over time and across context, and the degree to which calves were selective varied in relation to individual differences in Pessimism.
Concurrent impact of bilateral multiple joint functional electrical stimulation and treadmill walking on gait and spasticity in post-stroke survivors: a pilot study

ABSTRACT Background: Stroke causes multi-joint gait deficits, so a major objective of post-stroke rehabilitation is to regain normal gait function. Design and Setting: A case series completed at a neuroscience institute. Aim: The aim of the study was to determine the concurrent impact of functional electrical stimulation (FES) during treadmill walking on gait speed, knee extensors spasticity and ankle plantar flexors spasticity in post-stroke survivors. Participants: Six post-stroke survivors with altered gait patterns and ankle plantar flexors spasticity (4 = male; age 56.8 ± 4.8 years; Body Mass Index (BMI) 26.2 ± 4.3; since onset of stroke: 30.8 ± 10.4 months; side of hemiplegia [L/R]: 3:3) were recruited. Intervention: Nine treatment sessions using FES bilaterally while walking on a treadmill. Main Outcome Measures: Primary outcome measures included the Modified Modified Ashworth Scale (MMAS), Timed Up and Go test (TUG), 10-m walking test, gait speed, and Functional ambulation category (FAC). Secondary outcome measures included the Step Length Test (SLT), and active range of motion (ROM) of the affected ankle and the knee. Measurements were taken at baseline (T0), at the end of last treatment (T1), and 1 month after the final treatment session (T2). Results: The TUG, 10-m walking test, gait speed, FAC, active ROM, and SLT all significantly improved following treatment (P< .05), while ankle plantar flexors spasticity (P = .135), and knee extensors spasticity (P = .368) did not show any significant decrease. Conclusions: A short duration of bilateral FES in conjugation with treadmill walking contributed to significant improvement in gait speed, functional mobility, functional ambulation, range of motion and step length in post-stroke survivors. In contrast, no significant decreases were identified in the spasticity of the ankle plantar flexors and knee extensors muscles.
Gas-directed production of noble metal-magnetic heteronanostructures in continuous fashion: Application in catalysis.

Complex nanomaterials produced by scale-up batch processes suffer from irreproducibility of shape, size distribution, chemical composition and quality because heat and mass transfer are seriously affected as the reactor volume increases. Here we use a novel continuous synthesis procedure, the active gas-liquid segmented flow, to produce noble metal-magnetic heteronanostructures with enormous interest in the fields of catalysis, biomedicine, sensors environmental and food monitoring and chemical analysis. The microreactor technology proposed scales-down the reaction volume to gain advantage of the large surface area to volume ratio with respect to conventional batch type reactors, improving heat and mass transport, and consequently promoting a uniform heating and mixing. The gas phase was introduced in the chemical reactor as gas slugs of nanoliter scale with a dual role: 1) passive mixing and 2) chemical directing agent to tune the crystallization of nanostructures in a continuous fashion. The shape, size and magnetic properties of the resulting heteronanostructures, as well as the density size and composition of noble metal nanoparticles were tuned to show the versatility of the proposed approach in a timeline of 4 minutes. We demonstrated that the produced nanostructures provide excellent catalytic properties in the catalyzed hydrogenation of nitrophenols to aminophenols. Electron microscopy, UV-Vis spectroscopy and cyclic voltammetry studies showed the remarkable catalytic performance of the produced heteronanostructures.
Dopaminergic gene analysis indicates influence of inattention but not IQ in executive dysfunction of Indian ADHD probands

Abstract Organizational inefficiency and inattention are speculated to be the reason for executive deficit (ED) of ADHD probands. Even with average IQ, probands often perform poorly due to higher inattention. Pharmacotherapy, cognitive behavioural therapy, and counselling provide only symptomatic relief. Several candidate genes showed involvement with ADHD; the most consistent are dopamine receptor 4 (DRD4) and solute carrier family 6 member 3 (SLC6A3). We analyzed association of rarely investigated DRD4 and SLC6A3 variants with ADHD core traits in Indo-Caucasoid probands. ED, inattention, organizational efficiency, and IQ were measured by Barkley Deficit in Executive Functioning-Child & Adolescent scale, DSM-IV-TR, Conners’ Parent Rating Scale-revised, and WISC respectively. Target sites were analyzed by PCR, RFLP, and/or Sanger sequencing of genomic DNA. DRD4 variants mostly affected inattention while SLC6A3 variants showed association with IQ. Few DRD4 and SLC6A3 variants showed dichotomous association with IQ and inattention. DRD4 Exon3 VNTR >4R showed negative impact on all traits excepting IQ. Inattention showed correlation with attention span, organizational efficiency, and ED, while IQ failed to do so. We infer that IQ and attention could be differentially regulated by dopaminergic gene variants affecting functional efficiency in ADHD and the two traits should be considered together for providing better rehabilitation.
Policy Options for Long-Term Care

This paper examines the effect of government nursing home policies on institutionalization rates and support for the elderly in the community. We combine data from the National Long Term Care Survey with information on state policies to estimate these effects. We examine two state policies for nursing home care: the ability of some high income elderly to receive Medicaid support, and the price differential between Medicaid and the private market. Both policies strongly affect aggregate nursing home utilization. as well as the composition of nursing home residents. In states with more liberal Medicaid rules. the high income elderly are more likely to use a nursing home. while in states with larger underpayments. the poor suffer reduced access. The marginal source of community care for the institutionalized elderly appears to be support from children or other helpers, rather than living alone. Almost all of the elderly in nursing homes would have lived with children or others had they been in the community. In addition, as the ease of acquiring Medicaid increases or Medicaid payments become more generous, fewer elderly receive substantial day-to-day help from their children.
Drug Abuse Treatment and Comprehensive Services for Adolescents

Data from two national studies of treatment spanning two decades—Treatment Outcome Prospective Study (TOPS), 1979 to 1981, and Drug Abuse Treatment Outcome Studies for Adolescents (DATOS-A), 1993 to 1995—provided a comparison of treatment and services provided to 261 TOPS and 1,519 DATOS-A intreatment adolescent patients in a cross-modality sample of 24 TOPS and 31 DATOS-A programs. The authors used patient self-reports of treatment needs and services received to compare unmet needs for six services. Findings showed a general decline over treatment eras in services received that was only partially offset by significant decreases in some self-reported service needs in DATOS-A. Unmet needs increased significantly over treatment eras for specific services, including psychological, family, employment, and financial services. Potential explanations include changes in treatment access and decreases in program resources for services.
Functional analysis of RPS27 mutations and expression in melanoma

Next‐generation sequencing has enabled genetic and genomic characterization of melanoma to an unprecedent depth. However, the high mutational background plus the limited depth of coverage of whole‐genome sequencing performed on cutaneous melanoma samples make the identification of novel driver mutations difficult. We sought to explore the somatic mutation portfolio in exonic and gene regulatory regions in human melanoma samples, for which we performed targeted sequencing of tumors and matched germline DNA samples from 89 melanoma patients, identifying known and novel recurrent mutations. Two recurrent mutations found in the RPS27 promoter associated with decreased RPS27 mRNA levels in vitro. Data mining and IHC analyses revealed a bimodal pattern of RPS27 expression in melanoma, with RPS27‐low patients displaying worse prognosis. In vitro characterization of RPS27‐high and RPS27‐low melanoma cell lines, as well as loss‐of‐function experiments, demonstrated that high RPS27 status provides increased proliferative and invasive capacities, while low RPS27 confers survival advantage in low attachment and resistance to therapy. Additionally, we demonstrate that 10 other cancer types harbor bimodal RPS27 expression, and in those, similarly to melanoma, RPS27‐low expression associates with worse clinical outcomes. RPS27 promoter mutation could thus represent a mechanism of gene expression modulation in melanoma patients, which may have prognostic and predictive implications.
Suboptimal compliance to aerosol therapy in pediatric asthma: A prospective cohort study from Eastern India

Background: Suboptimal compliance to aerosol medication is common in pediatric asthma. Accordingly, the objective of this study is to assess noncompliance to aerosol therapy in childhood asthma and determine contributory factors. Materials and Methods: A prospective cohort study was conducted among pediatric patients attending asthma clinic. Patients (n = 215) having “mild” and “moderate” asthma severity rating were included. The total study duration was 12 months (June 2016–June 2017), with an active recruitment phase of 6 months. The minimum period for follow-up was 90 days. Caregivers were instructed to maintain an “asthma diary” for daily dosages of inhalers. At follow-up, the diary entries were corroborated with the amount of inhaler medication unused. Subsequently, medication compliance ratio (CR) was calculated according to the following formula: CR = number of medication doses taken/number of medication doses prescribed. CR% >80 was considered as “good compliance”. Results: A total of 169 patients (78.6%) returned for follow-up. The mean compliance to asthma medication was suboptimal (75.3%). The children were primarily prescribed inhaled corticosteroids and short-acting beta-agonist (SABA)-based regimens on index visit. Leukotriene receptor antagonist was added in select cases (67.9%). Nearly 45.6% of the patients had “good compliance. ” CR correlated with the sociodemographic profile and disease severity. Higher socioeconomic status and proper inhaler technique reflected better symptom control. Fear of side effects, behavioral difficulties, and economic restrictions were the identified causes of medication default. Conclusion: In the Eastern part of India, compliance to aerosol therapy in pediatric asthma is suboptimal. Sociodemographics, disease severity, and inhaler technique are important determinants.
Kv2.1 mediates spatial and functional coupling of L-type calcium channels and ryanodine receptors in mammalian neurons

The voltage-gated K+ channel Kv2.1 serves a major structural role in the soma and proximal dendrites of mammalian brain neurons, tethering the plasma membrane (PM) to endoplasmic reticulum (ER). Although Kv2.1 clustering at neuronal ER-PM junctions (EPJs) is tightly regulated and highly conserved, its function remains unclear. By identifying and evaluating proteins in close spatial proximity to Kv2.1-containing EPJs, we discovered that a significant role of Kv2.1 at EPJs is to promote the clustering and functional coupling of PM L-type Ca2+ channels (LTCCs) to ryanodine receptor (RyR) ER Ca2+ release channels. Kv2.1 clustering also unexpectedly enhanced LTCC opening at polarized membrane potentials. This enabled Kv2.1-LTCC-RyR triads to generate localized Ca2+ release events (i.e., Ca2+ sparks) independently of action potentials. Together, these findings uncover a novel mode of LTCC regulation and establish a unique mechanism whereby Kv2.1-associated EPJs provide a molecular platform for localized somatodendritic Ca2+ signals in mammalian brain neurons.