Miracle-dz/UniFAR-FTUs huggingface dataset:
GSTP1 polymorphisms sex-specific association with verbal intelligence in survivors of pediatric medulloblastoma tumors

ABSTRACT Glutathione S-transferase (GST) single nucleotide polymorphisms (SNPs) have been associated with a lower intellectual quotient (IQ) in medulloblastoma survivors. We investigated the association of GSTP1 polymorphisms with intellectual, neurocognitive skills (e.g., attention span, working memory, and processing speed), and adaptive outcomes for long-term pediatric medulloblastoma survivors. We hypothesized that genetic risk and sex-specific risk would contribute to significantly lower performances across all measures. Eighteen long-term pediatric medulloblastoma survivors completed the Wechsler Abbreviated Scale Intelligence, California Verbal Learning Test-II, Auditory Consonant Trigrams, and Oral Symbol Digit Modality Test. Informants were interviewed with the Scales of Independent Behavior-Revised (SIB-R). After controlling for the false discovery rate, females with a polymorphism performed significantly worse than females without a polymorphism on verbal IQ (p = .005) and SIB-R (p = .012). There was a significant interaction between sex and polymorphism status for verbal IQ (b = −1.8, SE = 0.827, CI: −3.58, −.036). The main effect of this interaction was significant for females (p = .004) and not for males (p = .557). We found large effect sizes between males with the polymorphism and females with the polymorphism across measures of attention span (g = .877), working memory (g = 1.12), and processing speed (g = 1.53). Female medulloblastoma survivors with a GSTP1 polymorphism may have increased vulnerability to deficits in core cognitive skills, IQ, and everyday functional outcomes. Sex-specific genetic risk contributes to the variability in long-term verbal intelligence for medulloblastoma survivors.
Sleep Intervention for Children with Asthma and their Parents (SKIP): A Novel Web-based Shared Management Pilot Study.

STUDY OBJECTIVES To describe the feasibility, acceptability and preliminary efficacy of a novel Sleep Intervention for Kids and Parents (SKIP). Parent and child primary sleep outcomes were total sleep time (TST), wake after sleep onset (WASO), sleep efficiency (SE), and bedtime range. METHODS Children aged 6-11 years with asthma and one parent, both with behavioral sleep disturbance, enrolled in this single-group pilot. The 8-week shared management intervention included weekly online educational modules, goal setting, and progress reporting. Feasibility was measured by the number of dyads who were eligible, enrolled, and retained. Acceptability was measured by survey and semi-structured interview. TST, WASO, SE and bedtime range were measured by actigraphy at baseline, post-intervention, and 12-week follow-up. Mixed-effects regression models were used to determine change in sleep outcomes from baseline. RESULTS Thirty-three out of 39 eligible dyads enrolled; of 29 dyads that started the intervention, 25 (86%) completed all study visits. SKIP was acceptable for 61% of children and 92% of parents. Compared to baseline, at follow-up children had significantly improved WASO (-37 min [95% CI = -44.5 to -29.7], p<.001), SE (5.4% [4.2 to 6.5], p<.001), and bedtime range (-35.2 min [-42.9 to -27.5], p<.001). Parents also had significantly improved WASO (-13.9 min [-19.5 to -8.2], p<.001), SE (2.7% [1.7 to 3.7], p<.001), and bedtime range (-35.3 min [-51.0 to -19.7], p<.001). CONCLUSIONS SKIP was feasible, acceptable, and we observed improved child and parent sleep outcomes except TST. Following refinements, further testing of SKIP in a controlled clinical trial is warranted.
A common genetic variant rs2821557 in KCNA3 is linked to the severity of multiple sclerosis

The rate of symptom accumulation distinguishes between slowly and rapidly progressing forms of multiple sclerosis (MS). Given that a patient's genetics can affect the rate of disease progression, identification of genetic variants associated with rapid disease progression should provide valuable information for timely prognosis and development of optimal treatment plans. We hypothesized that the polymorphism rs2821557 in the human KCNA3 gene encoding a voltage‐gated potassium channel Kv1.3 might be one of these genetic variants, given the role of Kv1.3 in neuroinflammation, as well as the location and gain‐of‐function effect of this polymorphism. To test this hypothesis we performed an analytic study exploring the relationships between rs2821557 polymorphism and disease progression in a cohort of MS patients. The rs2821557 genotype and the rate of disease progression based on Multiple Sclerosis Severity Score (MSSS) were determined for 101 patients (68 females and 33 males). Peripheral blood CD4+ lymphocyte subpopulations (Tnaive, TCM, TEM) and the expression of chemokine receptors (CXCR5, CXCR3, CCR6, CCR4) were estimated by flow cytometry. The comparisons between groups by genotype (TT, TC, CC) and allelic approach analysis (T vs. C) revealed a significantly higher incidence of the rapid disease course (MSSS ≥ 7.5) among minor C allele carriers (CC and TC) compared to patients with the TT genotype. Furthermore, C allele carriers had higher counts of CXCR3+ TEM cells than homozygous T allele carriers. In conclusion, accelerated MS progression in C allele carriers is likely linked to enhanced Kv1.3‐mediated accumulation of pathogenic CXCR3+ TEM cells and exacerbated neuroinflammation.
Long-range correlation in protein dynamics: Confirmation by structural data and normal mode analysis

Proteins in cellular environments are highly susceptible. Local perturbations to any residue can be sensed by other spatially distal residues in the protein molecule, showing long-range correlations in the native dynamics of proteins. The long-range correlations of proteins contribute to many biological processes such as allostery, catalysis, and transportation. Revealing the structural origin of such long-range correlations is of great significance in understanding the design principle of biologically functional proteins. In this work, based on a large set of globular proteins determined by X-ray crystallography, by conducting normal mode analysis with the elastic network models, we demonstrate that such long-range correlations are encoded in the native topology of the proteins. To understand how native topology defines the structure and the dynamics of the proteins, we conduct scaling analysis on the size dependence of the slowest vibration mode, average path length, and modularity. Our results quantitatively describe how native proteins balance between order and disorder, showing both dense packing and fractal topology. It is suggested that the balance between stability and flexibility acts as an evolutionary constraint for proteins at different sizes. Overall, our result not only gives a new perspective bridging the protein structure and its dynamics but also reveals a universal principle in the evolution of proteins at all different sizes.
Effects of three different diets on the fatty acid profile and sensory properties of fresh Pecorino cheese “Primo Sale”

Objective This study aimed to evaluate and compare the effects of three different diets on the fatty acids (FA) profile and sensory properties of a characteristic Italian fresh cheese: Pecorino “Primo Sale” (PS). Methods Fifty-four sheep were divided into three feeding groups: total mixed ration (TMR) enriched with extruded linseed (TL), control diet with TMR without any integration (TC), and pasture (P). During cheese production, six cheeses per experimental group were produced each week, stored for 10 days at 4°C, and then analyzed for chemical composition, FA profile, and sensory properties. Results Saturated fatty acids (SFA) were significantly higher in PS from group TC (82.11%) than in cheese from other two groups (P 75.48% and TL 66.83%). TL and P groups presented higher values of polyunsaturated fatty acids, 4.35 and 3.65%, respectively, than that of TC group (2.31%). The lowest SFA/unsaturated fatty acid ratio was found in TL and P groups, while the highest was found in the TC group. Vaccenic acid and conjugated linoleic acid (CLA) were higher in group P (p<0.05) than in groups L and TC. Sensory properties of cheese from group P received the highest scores for odor intensity and friability, while control group had a greater chewing consistency. Overall, all cheeses received good scores for acceptability. Conclusion In conclusion, this study showed how the integration of extruded linseed improved the FA profile of fresh pecorino cheese PS preserving its sensory properties. Levels of CLA in the PS group achieved using this approach was not higher than that in a grazing diet. Cheeses from groups P and L contained a higher value of FA, with nutritional implications for humans, when compared with un-supplemented diet. Linseed may be a good feeding strategy when pasture is not available.
Competition between kinesin-1 and myosin-V defines Drosophila posterior determination

Local accumulation of oskar (osk) mRNA in the Drosophila oocyte determines the posterior pole of the future embryo. Two major cytoskeletal components, microtubules and actin filaments, together with a microtubule motor, kinesin-1, and an actin motor, myosin-V, are essential for osk mRNA posterior localization. In this study, we use Staufen, an RNA-binding protein that colocalizes with osk mRNA, as a proxy for posterior determination. We demonstrate that posterior localization of osk/Staufen is determined by competition between kinesin-1 and myosin-V. While kinesin-1 removes osk/Staufen from the cortex along microtubules, myosin-V anchors osk/Staufen at the cortex. Myosin-V wins over kinesin-1 at the posterior pole due to low microtubule density at this site, while kinesin-1 wins it at anterior and lateral positions because they have high density of cortically-anchored microtubules. As a result, posterior determinants are removed from the anterior and lateral cortex but retained at the posterior pole. Thus, posterior determination of Drosophila oocyte is defined by kinesin-myosin competition, whose outcome is primarily determined by cortical microtubule density.
Cultural Differences in Tweeting about Drinking Across the US

Excessive alcohol use in the US contributes to over 88,000 deaths per year and costs over $250 billion annually. While previous studies have shown that excessive alcohol use can be detected from general patterns of social media engagement, we characterized how drinking-specific language varies across regions and cultures in the US. From a database of 38 billion public tweets, we selected those mentioning “drunk”, found the words and phrases distinctive of drinking posts, and then clustered these into topics and sets of semantically related words. We identified geolocated “drunk” tweets and correlated their language with the prevalence of self-reported excessive alcohol consumption (Behavioral Risk Factor Surveillance System; BRFSS). We then identified linguistic markers associated with excessive drinking in different regions and cultural communities as identified by the American Community Project. “Drunk” tweet frequency (of the 3.3 million geolocated “drunk” tweets) correlated with excessive alcohol consumption at both the county and state levels (r = 0.26 and 0.45, respectively, p < 0.01). Topic analyses revealed that excessive alcohol consumption was most correlated with references to drinking with friends (r = 0.20), family (r = 0.15), and driving under the influence (r = 0.14). Using the American Community Project classification, we found a number of cultural markers of drinking: religious communities had a high frequency of anti-drunk driving tweets, Hispanic centers discussed family members drinking, and college towns discussed sexual behavior. This study shows that Twitter can be used to explore the specific sociocultural contexts in which excessive alcohol use occurs within particular regions and communities. These findings can inform more targeted public health messaging and help to better understand cultural determinants of substance abuse.
Editorial for focused issue "Neurological Diseases".

In this special issue of Annals of Translational Medicine , experienced physicians and academic researchers contribute their original works in the field of neurological diseases. The burden of neurological diseases is one of the leading causes of disability and death globally and continues to increase. Luckily, the knowledges of this field continue to update with advances in technology at the meantime. Neurology is becoming a rapidly developing field and we need to rethink and redefine some traditional concepts in this new environment.
Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU: Cardiovascular, Endocrine, Hematologic, Pulmonary and Renal Considerations: Executive Summary

Critical Care Medicine www.ccmjournal. org 415 16Division of Pulmonary and Critical Care Medicine, University of Kentucky College of Medicine, Lexington, KY. 17Department of Medicine, Kansas University Medical Center, Kansas City, KS. 18Medical College of Wisconsin, Milwaukee, WI. 19Department of Anesthesiology, University of California Los Angeles Medical Center, Los Angeles, CA. 20Barnes Jewish Hospital, St. Louis, MO. Conflicts of interest were reviewed and adjudicated by the co-chairs and co-vice chairs of the guidelines. In the event an individual disclosed a conflict or potential conflict by submitted form or verbally during the process of guidelines, those individuals abstained from voting on related questions. The taskforce followed all procedures as documented in the American College of Critical Care Medicine/Society of Critical Care Medicine (SCCM) Standard Operating Procedures Manual. Drs. Nanchal, Subramanian, Karvellas, Singbartl, Truwit, Killian, and Olson disclosed authorship on several related manuscripts with potential intellectual conflicts explored and adjudicated. Dr. Dionne described volunteer service for Canadian Association of Gastroenterology, American College of Gastroenterology, American Gastroenterological Association, and European Society of Intensive Care Medicine. Dr. Hyzy described volunteer service for American Thoracic Society, Quality Improvement and Implementation Committee, and the SCCM Finance Committee as well as service as an expert witness in a previous medical case involving this subject matter. Dr. Taylor advised of service as an author on the SCCM/American Society of Parenteral DOI: 10.1097/CCM.0000000000004193 1Division of Pulmonary and Critical Care Medicine, Medical College of Wisconsin, Milwaukee, WI. 2Emory University Hospital, Atlanta, GA. 3Department of Critical Care Medicine and Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, AB, Canada. 4Hackensack University Medical Center, Hackensack, NJ. 5Froedtert and the Medical College of Wisconsin, Milwaukee, WI. 6Mayo Clinic, Phoenix, AZ. 7Division of Pulmonary and Critical Care Medicine, Medical College of Wisconsin, Waukesha, WI. 8Department of Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA. 9GUIDE Group, McMaster University, Hamilton, ON, Canada. 10Department of Medicine, McMaster University, Hamilton, ON, Canada. 11Mayo Clinic, Rochester, MN. 12Department of Anesthesiology, Henry Ford Health System, Detroit, MI. 13University of Michigan Hospitals, Ann Arbor, MI. 14Northeast Georgia Medical Center, Gainesville, GA. 15Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada. Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU: Cardiovascular, Endocrine, Hematologic, Pulmonary and Renal Considerations: Executive Summary
Sparse hand-held probe for optoacoustic ultrasound volumetric imaging: an experimental proof-of-concept study.

We present an experimental proof-of-concept study on the performance of a sparse segmented annular array for optoacoustic imaging. A capacitive micromachined ultrasonic transducer was equipped with a negatively focused acoustic lens and scanned in an annular fashion to exploit the performance of the sparse array geometry proposed in our recent numerical studies [Biomed. Opt. Express10, 1545 (2019)BOEICL2156-708510.1364/BOE.10. 001545; J. Biomed. Opt.23, 025004 (2018)JBOPFO1083-366810.1117/1.JBO. 23.2. 025004]. A dedicated water tank was made using a 3D printer for light delivery and mounting the sample. A phantom experiment was carried out to showcase the possibility of full-field optoacoustic ultrasound (OPUS) imaging and confirm the earlier numerical results. This proof of concept opens the door towards a prototype of OPUS imaging for (pre-) clinical studies.
Proton Pump Inhibitors, But Not H2-receptor Antagonists, Are Associated With Incident Fractures Among Kidney Transplant Recipients

Background. Fractures are a common and burdensome problem among kidney transplant recipients (KTRs). Proton pump inhibitors (PPIs) are frequently used after kidney transplantation and have been associated with increased fracture risk in the general population. This study aimed to determine whether PPI use is associated with incidence of major fractures in KTRs. Methods. Using the Wisconsin Allograft Recipient Database, we identified 155 KTRs with a major fracture that occurred at least 12 months after transplantation. Controls were selected using incidence-density sampling. Use of PPIs and histamine 2-receptor antagonists (H2RA) during the year before the index date were identified. Results. A total of 155 cases were matched to 685 controls. Within 1 year before the index date, 68% of cases and 52% of controls used a PPI, and 16% of cases and 11% of controls used an H2RA. PPI use was associated with higher incidence of major fractures in unadjusted analysis (odds ratio [OR], 2.4; 95% CI, 1.6-3.5) and in adjusted analyses controlling for demographic and transplant-related covariates and use of corticosteroids, bisphosphonates, vitamin D and calcium supplements (OR, 1.9; 95% CI, 1.2-3.1). H2RA use was not associated with incidence of major fractures in adjusted analyses (OR, 1.0; 95% CI, 0.5-1.8). The associations between PPI use and fractures remained similar in analyses limited to spine and hip fractures. Conclusions. Use of PPIs, but not H2RAs, is associated with a higher risk of major fractures among KTRs. Clinicians should individualize PPI use in KTRs, evaluating the risks and benefits of prescribing and continuing PPIs in KTRs.
Clinical Trial Generalizability Assessment in the Big Data Era: A Review

Clinical studies, especially randomized, controlled trials, are essential for generating evidence for clinical practice. However, generalizability is a long‐standing concern when applying trial results to real‐world patients. Generalizability assessment is thus important, nevertheless, not consistently practiced. We performed a systematic review to understand the practice of generalizability assessment. We identified 187 relevant articles and systematically organized these studies in a taxonomy with three dimensions: (i) data availability (i.e., before or after trial (a priori vs. a posteriori generalizability)); (ii) result outputs (i.e., score vs. nonscore); and (iii) populations of interest. We further reported disease areas, underrepresented subgroups, and types of data used to profile target populations. We observed an increasing trend of generalizability assessments, but < 30% of studies reported positive generalizability results. As a priori generalizability can be assessed using only study design information (primarily eligibility criteria), it gives investigators a golden opportunity to adjust the study design before the trial starts. Nevertheless, < 40% of the studies in our review assessed a priori generalizability. With the wide adoption of electronic health records systems, rich real‐world patient databases are increasingly available for generalizability assessment; however, informatics tools are lacking to support the adoption of generalizability assessment practice.
Discovery of 9O-Substituted Palmatine Derivatives as a New Class of Anti-COL1A1 Agents Via Repressing TGF-β1/Smads and JAK1/STAT3 Pathways

Twenty 9O-substituted palmatine derivatives were prepared and tested for their biological effect against collagen α1 (I) (COL1A1) promotor in human hepatic stellate LX-2 cells. The structure−activity relationship (SAR) indicated that the introduction of a benzyl motif on the 9O atom was favorable for activity. Among them, compound 6c provided the highest inhibitory effect against COL1A1 with an IC50 value of 3.98 μM, and it also dose-dependently inhibited the expression of fibrogenic COL1A1, α-soomth muscle actin (α-SMA), matrix metalloprotein 2 (MMP2) in both mRNA and protein levels, indicating extensive inhibitory activity against fibrogenesis. A further primary mechanism study indicated that it might repress the hepatic fibrogenesis via inhibiting both canonical transforming growth factor-beta 1 (TGF-β1)/Smads and non-canonical janus-activated kinase 1 (JAK1)/singal transducer and activator of transcription 3 (STAT3) signaling pathways. Additionally, 6c owned a high safety profile with the LD50 value of over 1000 mg·kg−1 in mice. These results identified palmatine derivatives as a novel class of anti-fibrogenic agents, and provided powerful information for further structure optimization.
Junctional Adhesion Molecule-C Mediates the Recruitment of Embryonic-Endothelial Progenitor Cells to the Perivascular Niche during Tumor Angiogenesis

The homing of Endothelial Progenitor Cells (EPCs) to tumor angiogenic sites has been described as a multistep process, involving adhesion, migration, incorporation and sprouting, for which the underlying molecular and cellular mechanisms are yet to be fully defined. Here, we studied the expression of Junctional Adhesion Molecule-C (JAM-C) by EPCs and its role in EPC homing to tumor angiogenic vessels. For this, we used mouse embryonic-Endothelial Progenitor Cells (e-EPCs), intravital multi-fluorescence microscopy techniques and the dorsal skin-fold chamber model. JAM-C was found to be expressed by e-EPCs and endothelial cells. Blocking JAM-C did not affect adhesion of e-EPCs to endothelial monolayers in vitro but, interestingly, it did reduce their adhesion to tumor endothelium in vivo. The most striking effect of JAM-C blocking was on tube formation on matrigel in vitro and the incorporation and sprouting of e-EPCs to tumor endothelium in vivo. Our results demonstrate that JAM-C mediates e-EPC recruitment to tumor angiogenic sites, i.e., coordinated homing of EPCs to the perivascular niche, where they cluster and interact with tumor blood vessels. This suggests that JAM-C plays a critical role in the process of vascular assembly and may represent a potential therapeutic target to control tumor angiogenesis.
Central cardiovascular system limits to aerobic capacity

What is the topic of this review? The limits to maximal aerobic capacity. What advances does it highlight? A synthesis of data and ideas about what limits maximal aerobic capacity demonstrates the central roles of cardiac output, stroke volume and red blood cell mass in the complex physiological responses to maximal exercise. In healthy humans these factors, along with skeletal muscle blood flow, dominate systemic delivery of oxygen to the contracting muscles and set the upper limit of aerobic energy production by skeletal muscles. In elite athletes and patients with pulmonary disease the lungs can also limit oxygen uptake and delivery.