Miracle-dz/UniFAR-FTUs huggingface dataset:
Age- and Sex-Related Percentiles of Skinfold Thickness, Waist and Hip Circumference, Waist-to-Hip Ratio and Waist-to-Height Ratio: Results from a Population-Based Pediatric Cohort in Germany (LIFE Child)

Background: Skinfold thickness (ST), waist circumference (WC) and hip circumference (HC) measurements are simple methods for assessing fat tissue at defined body parts. We examined these parameters in a cohort of healthy children and adolescents in Leipzig. Our study provides current percentile curves for biceps, triceps, subscapular and iliac crest ST, plus WC, HC, waist-to-hip ratio and waist-to-height ratio. Methods: 6,344 visits were recorded involving 2,363 individuals from 3 to 16 years in age. Continuous age- and gender-related percentiles (3rd, 10th, median, 90th, 97th percentiles) were estimated using Cole’s LMS method. Results: For biceps and triceps ST, boys show a peak at the beginning of adolescence with a subsequent decrease, while percentile values among girls rise across the age range. Subscapular and iliac crest percentiles also show increasing curves with disproportionately high values for P90 and P97. Boys show higher values of WC, girls have higher levels of HC. WC and HC median percentiles constantly increase in both sexes with a plateau at the age of 16 for girls. Conclusion: Trends for all parameters of body fat are in line with other national and international studies. Unlike the KiGGS study, our study provides circumference data across the whole of our age range, i.e. from 3 to 16 years.
The phenylketonuria-associated substitution R68S converts phenylalanine hydroxylase to a constitutively active enzyme but reduces its stability

The naturally occurring R68S substitution of phenylalanine hydroxylase (PheH) causes phenylketonuria (PKU). However, the molecular basis for how the R68S variant leads to PKU remains unclear. Kinetic characterization of R68S PheH establishes that the enzyme is fully active in the absence of allosteric binding of phenylalanine, in contrast to the WT enzyme. Analytical ultracentrifugation establishes that the isolated regulatory domain of R68S PheH is predominantly monomeric in the absence of phenylalanine and dimerizes in its presence, similar to the regulatory domain of the WT enzyme. Fluorescence and small-angle X-ray scattering analyses establish that the overall conformation of the resting form of R68S PheH is different from that of the WT enzyme. The data are consistent with the substitution disrupting the interface between the catalytic and regulatory domains of the enzyme, shifting the equilibrium between the resting and activated forms ∼200-fold, so that the resting form of R68S PheH is ∼70% in the activated conformation. However, R68S PheH loses activity 2 orders of magnitude more rapidly than the WT enzyme at 37 °C and is significantly more sensitive to proteolysis. We propose that, even though this substitution converts the enzyme to a constitutively active enzyme, it results in PKU because of the decrease in protein stability.
The dynein adaptor Hook2 plays essential roles in mitotic progression and cytokinesis

Hook proteins are evolutionarily conserved dynein adaptors that promote assembly of highly processive dynein–dynactin motor complexes. Mammals express three Hook paralogs, namely Hook1, Hook2, and Hook3, that have distinct subcellular localizations and expectedly, distinct cellular functions. Here we demonstrate that Hook2 binds to and promotes dynein–dynactin assembly specifically during mitosis. During the late G2 phase, Hook2 mediates dynein–dynactin localization at the nuclear envelope (NE), which is required for centrosome anchoring to the NE. Independent of its binding to dynein, Hook2 regulates microtubule nucleation at the centrosome; accordingly, Hook2-depleted cells have reduced astral microtubules and spindle positioning defects. Besides the centrosome, Hook2 localizes to and recruits dynactin and dynein to the central spindle. Dynactin-dependent targeting of centralspindlin complex to the midzone is abrogated upon Hook2 depletion; accordingly, Hook2 depletion results in cytokinesis failure. We find that the zebrafish Hook2 homologue promotes dynein–dynactin association and was essential for zebrafish early development. Together, these results suggest that Hook2 mediates assembly of the dynein–dynactin complex and regulates mitotic progression and cytokinesis.
Genetic Determinants of Glycated Hemoglobin in Type 1 Diabetes

Glycated hemoglobin (HbA1c) is an important measure of glycemia in diabetes. HbA1c is influenced by environmental and genetic factors both in people with and in people without diabetes. We performed a genome-wide association study (GWAS) for HbA1c in a Finnish type 1 diabetes (T1D) cohort, FinnDiane. Top results were examined for replication in T1D cohorts DCCT/EDIC, WESDR, CACTI, EDC, and RASS, and a meta-analysis was performed. Three SNPs in high linkage disequilibrium on chromosome 13 near relaxin family peptide receptor 2 (RXFP2) were associated with HbA1c in FinnDiane at genome-wide significance (P < 5 × 10−8). The minor alleles of rs2085277 and rs1360072 were associated with higher HbA1c also in the meta-analysis with RASS (P < 5 × 10−8), where these variants had minor allele frequencies ≥1%. Furthermore, these SNPs were associated with HbA1c in an East Asian population without diabetes (P ≤ 0.013). A weighted genetic risk score created from 55 HbA1c-associated variants from the literature was associated with HbA1c in FinnDiane but explained only a small amount of variation. Understanding the genetic basis of glycemic control and HbA1c may lead to better prevention of diabetes complications.
Fecal microbiota changes associated with dehorning and castration stress primarily affects light-weight dairy calves

Gastrointestinal tract (GIT) microbiota and stress can impact animal health. Studies have shown that perturbations in the GIT microbiota can influence host health and productivity by affecting physiological homeostasis, metabolism, hematopoiesis and inflammation. The present study aimed to evaluate possible effects of dehorning and castration stress on the GIT microbiota of dairy calves. Dehorning and castration are routinely performed on over 90% of dairy farms, and analgesics like flunixin meglumine (FLU) are given at the time of these procedures to reduce pain. We analyzed fecal microbiota of 24 weaned male dairy calves at two different stages in their life (at 10 weeks for dehorning and 36 weeks age for castration) to determine any GIT microbiota changes due to these stressful procedures and the FLU treatment. Dehorning was performed using an electrocautery dehorner applied to the horn for 10 seconds, and surgical castration was used as the castration method. Our analysis showed that the Shannon diversity index was significantly higher in animals that were not dehorned compared to dehorned animals. Castration stress also resulted in a significant decrease in Shannon diversity index, which was more pronounced in lower weight calves. Body weight and stress had significant effects on the taxonomic profiles of the GIT microbiota. There was a significant difference in the GIT bacterial community structure between heavy- and light-weight calves at Day 3 after castration but not at Day 0 (prior to castration). Our results indicate that dehorning and castration stress reduced microbial diversity of the GIT microbiota, but only in light-weight calves. This work is important for elucidating biological effects of stress on dairy calves and identifying potential modulation points in the microbiota of these food-producing animals to improve animal health and production.
The multiple faces of CD5

Since its discovery, over 30 years ago, CD5 has been used as a marker to identify T cells, B1‐a cells, and B cell chronic lymphocytic leukemia cells. Throughout the years, many studies have described the functional relevance of CD5 as a modulator of T and B cell receptor signaling. However, it has not been until recent years that CD5 has emerged as a functional receptor in other areas of the immune system. Here, we review some of the most important aspects of CD5 as a modulator of TCR and BCR signaling, cell survival receptor both in T and B cells during health and disease, as well as the newly discovered roles of this receptor in thymocyte selection, T cell effector differentiation, and immune tolerance. CD5 was found to promote T cell survival by protecting autoreactive T cell from activation‐induced cell death, to promote de novo induction of regulatory T cells in the periphery, to modulate Th17 and Th2 differentiation, and to modulate immune responses by modulating dendritic cell functions. CD5 is overexpressed in Tregs and Bregs, which are fundamental to maintain immune homeostasis. The newly established roles of CD5 in modulating different aspects of immune responses identify this receptor as an immune checkpoint modulator, and therefore it could be used as a target for immune intervention in different pathologies such as cancer, autoimmune diseases or infections.
Increasing availability of ω‐3 fatty acid in the early‐life diet prevents the early‐life stress‐induced cognitive impairments without affecting metabolic alterations

Exposure to early‐life stress (ES) is associated with cognitive and metabolic deficits in adulthood. The role of early nutrition in programming these long‐term effects is largely unknown. We focused on essential ω‐3 and ω‐6 long‐chain polyunsaturated fatty acids (LCPUFA) and investigated whether ES affects central and peripheral FA profiles, as well as if and how an early diet with increased availability of ω‐3 LCPUFA (via lowering ω‐6/ω‐3 ratio) protects against ES‐induced impairments. ES exposure [limited nesting and bedding paradigm from postnatal day (P)2 to P9] altered central and peripheral FA profiles in mice. An early diet with low ω‐6/ω‐3 ratio from P2 to P42 notably prevented the ES‐induced cognitive impairments, and the alterations in hippocampal newborn cell survival and in CD68+ microglia, without affecting the ES‐induced metabolic alterations. Other markers for hippocampal plasticity, apoptosis, and maternal care were unaffected by ES or diet. Our findings highlight the importance of early dietary lipid quality for later cognition in ES‐exposed populations. —Yam, K. ‐Y. , Schipper, L. , Reemst, K. , Ruigrok, S. R. , Abbink, M. R. , Hoeijmakers, L. , Naninck, E. F. G. , Zarekiani, P., Oosting, A. , Van der Beek, E. M. , Lucassen, P. J., Korosi, A. Increasing availability of ω‐3 fatty acid in the early‐life diet prevents the early‐life stress‐induced cognitive impairments without affecting metabolic alterations. FASEB J. 33, 5729–5740 (2019). www.fasebj. org
Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) With Susceptibility to Testicular Germ Cell Tumors

Importance Approximately 50% of the risk for the development of testicular germ cell tumors (TGCTs) is estimated to be heritable, but no mendelian TGCT predisposition genes have yet been identified. It is hypothesized that inherited pathogenic DNA repair gene (DRG) alterations may drive susceptibility to TGCTs. Objective To systematically evaluate the enrichment of germline pathogenic variants in the mendelian cancer predisposition DRGs in patients with TGCTs vs healthy controls. Design, Setting, and Participants A case-control enrichment analysis was performed from January 2016 to May 2018 to screen for 48 DRGs in 205 unselected men with TGCT and 27 173 ancestry-matched cancer-free individuals from the Exome Aggregation Consortium cohort in the discovery stage. Significant findings were selectively replicated in independent cohorts of 448 unselected men with TGCTs and 442 population-matched controls, as well as 231 high-risk men with TGCTs and 3090 ancestry-matched controls. Statistical analysis took place from January to May 2018. Main Outcomes and Measures Gene-level enrichment analysis of germline pathogenic variants in individuals with TGCTs relative to cancer-free controls. Results Among 205 unselected men with TGCTs (mean [SD] age, 33.04 [9.67] years), 22 pathogenic germline DRG variants, one-third of which were in CHEK2 (OMIM 604373), were identified in 20 men (9.8%; 95% CI, 6.1%-14.7%). Unselected men with TGCTs were approximately 4 times more likely to carry germline loss-of-function CHEK2 variants compared with cancer-free individuals from the Exome Aggregation Consortium cohort (odds ratio [OR], 3.87; 95% CI, 1.65-8.86; nominal P = .006; q = 0.018). Similar enrichment was also seen in an independent cohort of 448 unselected Croatian men with TGCTs (mean [SD] age, 31.98 [8.11] years) vs 442 unselected Croatian men without TGCTs (at least 50 years of age at time of sample collection) (OR, >1.4; P = .03) and 231 high-risk men with TGCTs (mean [SD] age, 31.54 [9.24] years) vs 3090 men (all older than 50 years) from the Penn Medicine Biobank (OR, 6.30; 95% CI, 2.34-17.31; P = .001). The low-penetrance CHEK2 variant (p.Ile157Thr) was found to be a Croatian founder TGCT risk variant (OR, 3.93; 95% CI, 1.53-9.95; P = .002). Individuals with the pathogenic CHEK2 loss-of-function variants developed TGCTs 6 years earlier than individuals with CHEK2 wild-type alleles (5.95 years; 95% CI, 1.48-10.42; P = .009). Conclusions and Relevance This multicenter case-control analysis of men with or without TGCTs provides evidence for CHEK2 as a novel moderate-penetrance TGCT susceptibility gene, with potential clinical utility. In addition to highlighting DNA-repair deficiency as a potential mechanism driving TGCT susceptibility, this analysis also provides new avenues to explore management strategies and biological investigations for high-risk individuals.
Dietary supplementation of Scutellaria baicalensis extract during early lactation decreases milk somatic cells and increases whole lactation milk yield in dairy cattle

Systemic inflammation is common in early lactation dairy cows and is associated with decreased milk production. The Scutellaria baicalensis plant contains flavonoids with anti-inflammatory and anti-oxidative properties, which may counteract the inflammatory state in early lactation dairy cows. The objective of this experiment was to determine whether Scutellaria baicalensis extract (SBE), a source of bioactive flavonoids, would alter the adaptation to lactation. Multiparous Holstein cows (n = 122) were used in a randomized block design to determine the effect of short-term and long-term postpartum administration of SBE on 305-d milk yield, 120-d milk component yield, and early lactation milk markers of inflammation and metabolic function. Treatments were 1) control, 2) short term (5-d) administration of the SBE (SBE5), and 3) long term (60-d) administration of the SBE (SBE60). Treatments were included in a treatment pellet that was identical to a control pellet in ingredient source and composition except for the extract (10 g/d SBE providing 3.3 g/d of the flavonoid baicalin), both provided via an automated milking system beginning on d 1 of lactation. Milk samples were collected on d 1, 3, and once during d 5–12 of lactation, followed by weekly sampling until 120 days in milk (DIM). Milk samples collected in the first 2 wk were used for biomarker analysis (haptoglobin, β-hydroxybutyrate [BHB], and glucose-6-phosphate [G6P]), and all samples were used for composition analysis. Cows were body condition scored every 2 wk prepartum and postpartum. Milk production, programmed pellet allocation, and actual provision of both pelleted feeds were recorded daily. Treatment effects were evaluated by contrasts between control and SBE5 and control and SBE60 for both the treatment (TP; wk 1–9) and carryover periods (CP; wk 10–37). Total pellet offered was greater for SBE60 in both the TP (P < 0.01) and CP (P = 0.02) but was not different for SBE5 during either period (P ≥ 0.13). No treatment effects were observed for body condition score (BCS), milk haptoglobin, BHB, or G6P. SBE5 did not alter milk yield or milk components. SBE60 increased whole-lactation milk yield by 1,419 kg (13%; P = 0.03). SBE60 increased milk lactose and fat yields (P ≤ 0.04) and tended to increase milk protein yield (P = 0.09) during TP, and each increased during CP (P ≤ 0.04). Somatic cell count decreased by 10% in SBE60 during TP (P = 0.02) but not CP (P = 0.13). Mastitis incidence tended to differ by treatment, being lesser for both SBE5 and SBE60 vs. control (14 and 15% vs. 33%). SBE supplementation did not impact time to pregnancy or hazard of leaving the herd. In conclusion, despite no detected treatment effects on BCS or milk biomarkers of inflammation and metabolic status, supplementation of postpartum dairy cows with Scutellaria baicalensis extract for 60 d was effective at increasing whole lactation milk yield.
Wnt/β-Catenin Inhibitor Dickkopf 1.

β (glycogen synthase kinase 3 β ), axin, APC (adenoma-tous polyposis coli), and CK-1 (casein kinase-1), followed by degradation of the phosphorylated β -catenin via the ubiquitin proteasome system. B , Binding of the Wnt protein to a frizzled receptor leads to co-activation of LRP5/6, followed by phosphorylation of the intramembrane part of LRP5/6 and leading to recruitment of DVL (disheveled) protein. This results in inactivation of the β -catenin destruction complex and leads to the accumulation of β -catenin and its translocalization to the nucleus where it forms a complex with the TCF/LEF (T-cell factor/lymphoid enhancer factor) and induces transcription of several target genes. C , Binding of DKK1 to LRP5/6 leads to a complex formation with the Kremen receptor (Kre), followed by endocytosis and degradation of the LRP5/6 receptor, resulting in the inhibition of Wnt/ β -catenin signaling.
Cent ans après : Politiques scolaires et la vitalité des langues en danger le cas de l'arménien occidental

L’armenien occidental est classe comme langue en danger depuis 2010, mais il est enseigne dans un reseau d’ecoles armeniennes a travers une diaspora mondiale, cree par un genocide en 1915. Les inscriptions sont en declin dans les ecoles du Moyen-Orient depuis quatre decennies, alors qu’en France on observe un developpement des ecoles privees. Toutes les ecoles sont confrontees a une culture educative en evolution. Les donnees sont collectees a Beyrouth, Amman, Paris et Marseille, et des participants venant d’Alep. L’approche est interdisciplinaire, poststructuraliste et constructiviste, dans le but de comprendre le role des politiques scolaires dans l’attractivite des ecoles et dans la transmission linguistique et dans la promotion de la vitalite de la langue dans chaque contexte. L’analyse de discours est employee pour analyser les representations de la langue et des ecoles aux niveaux personnel et structurel. Les theories de la vitalite ethnolinguistique et de la socialisation linguistique aident a eclairer les liens entre la politique, le choix des parents, et la vitalite de la langue. Le choix des parents est approche du point de vue de la psychologie de la consommation, et finalement c’est la notion de l’habitus (de Bourdieu) qui eclaire le mieux les dynamiques de ce choix et pourquoi il constitue souvent une rupture definitive avec l’institution. L’etude montre que les politiques au-dela de l’institutionnel ont moins d’influence sur le maintien de la langue que l’inscription a l’ecole et les discours dominants. Des preconisations sont formulees pour des changements de la politique scolaire et de la pedagogie.
Baloxavir Marboxil: The First Cap-Dependent Endonuclease Inhibitor for the Treatment of Influenza

Objective: To review the pharmacology, pharmacokinetics, clinical trials, and clinical implications of baloxavir marboxil. Data Sources: A MEDLINE search was conducted using the terms baloxavir, baloxavir marboxil, cap-dependent endonuclease inhibitor, and polymerase acidic endonuclease inhibitor. Additional data were obtained from the prescribing information and relevant guidelines. Study Selection and Data Extraction: All clinical trials were included. Data Synthesis: Baloxavir marboxil exploits a new mechanism of action of inhibiting cap-dependent endonuclease. Baloxavir was shown to be superior compared with placebo and noninferior compared with oseltamivir with regard to the primary end point. Baloxavir was well tolerated in the trials. A second phase III study investigating high-risk patients was completed with positive results. However, the full article is not yet published. Relevance to Patient Care and Clinical Practice: The small amount of literature limits baloxavir’s use in certain patient populations. Baloxavir offers advantages such as single-dose regimen, eliminating adherence concerns and lack of cross-resistance, making it an alternative for resistant viruses. Several uncertainties remain. Baloxavir has not been studied in hospitalized patients, patients with symptoms for >48 hours, or in combination with other antiviral agents. Furthermore, resistance to baloxavir can develop after 1 dose. Clinical studies are ongoing to evaluate baloxavir in young pediatric patients, hospitalized patients, and in combination therapy with neuraminidase inhibitors to further elucidate baloxavir’s place in therapy. Conclusion: Baloxavir is a new antiviral medication for the treatment of influenza. Given the new mechanism of action, baloxavir may be useful in treating patients with resistant viruses.
Atypical Clinical Presentations of Pediatric Acute Immune-Mediated Polyneuropathy

Guillain-Barré syndrome (GBS) is the most common cause of acute flaccid paralysis in children. During the acute phase, the disorder can be life-threatening by involving the respiratory muscles and the autonomic nervous system. Nevertheless, the prognosis is good, and most children achieve full recovery. The aim of this study was to characterize the clinical and electrophysiologic findings in children with Guillain-Barré syndrome referred to a tertiary center in Israel. A retrospective database review from 2009 to 2015 identified 39 children. Data on clinical presentation, respiratory complications, and long-term neurologic outcomes were collected. Atypical clinical findings at admission included asymmetric weakness in 23%, nonascending weakness in 30%, and normal deep tendon reflexes in 28%. Eight children were later diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Electrophysiologic findings, available in 12 patients with Guillain-Barré syndrome, revealed acute inflammatory demyelinating polyradiculoneuropathy (AIDP) in 4 (33.5%), AIDP with secondary axonal changes in 3 (25%), and acute motor axonal neuropathy (AMAN) subtype in 4 (33.5%); 8% had no abnormal findings. On follow-up, 71% of the children with Guillain-Barré syndrome fully recovered compared to 14% of the children with CIDP. Corresponding rates of neurologic sequelae were 29% and 86%. Clinicians should be alert to the atypical presenting symptoms of Guillain-Barré syndrome, which occur in a significant proportion of children.