Miracle-dz/UniFAR-FTUs huggingface dataset:
Genomic Prediction Within and Across Biparental Families: Means and Variances of Prediction Accuracy and Usefulness of Deterministic Equations

A major application of genomic prediction (GP) in plant breeding is the identification of superior inbred lines within families derived from biparental crosses. When models for various traits were trained within related or unrelated biparental families (BPFs), experimental studies found substantial variation in prediction accuracy (PA), but little is known about the underlying factors. We used SNP marker genotypes of inbred lines from either elite germplasm or landraces of maize (Zea mays L.) as parents to generate in silico 300 BPFs of doubled-haploid lines. We analyzed PA within each BPF for 50 simulated polygenic traits, using genomic best linear unbiased prediction (GBLUP) models trained with individuals from either full-sib (FSF), half-sib (HSF), or unrelated families (URF) for various sizes (Ntrain) of the training set and different heritabilities (h2). In addition, we modified two deterministic equations for forecasting PA to account for inbreeding and genetic variance unexplained by the training set. Averaged across traits, PA was high within FSF (0.41–0.97) with large variation only for Ntrain<50 and h2 <0.6. For HSF and URF, PA was on average ∼40–60% lower and varied substantially among different combinations of BPFs used for model training and prediction as well as different traits. As exemplified by HSF results, PA of across-family GP can be very low if causal variants not segregating in the training set account for a sizeable proportion of the genetic variance among predicted individuals. Deterministic equations accurately forecast the PA expected over many traits, yet cannot capture trait-specific deviations. We conclude that model training within BPFs generally yields stable PA, whereas a high level of uncertainty is encountered in across-family GP. Our study shows the extent of variation in PA that must be at least reckoned with in practice and offers a starting point for the design of training sets composed of multiple BPFs.
Neutral mutations and neutral substitutions in bacterial genomes.

Molecular evolutionary biologists usually assess the underlying spectrum of mutations within a bacterial genome by examining substitutions that occur at sites believed to be under no selective constraints. Alternatively, bacterial mutation rates can also be estimated in a variety of experimental systems. The two classes of changes occurring in DNA sequences-i.e., mutations and neutral substitutions-are, in theory, identical; however, the rates and patterns of mutations in bacteria, as inferred from sequence comparisons, often differ significantly from those derived experimentally. These differences have resulted in conflicting interpretations of the nonselective forces that affect mutation rates.
Serum metabolite concentrations and decreased GFR in the general population.

BACKGROUND Metabolites such as creatinine and urea are established kidney function markers. High-throughput metabolomic studies have not been reported in large general population samples spanning normal kidney function and chronic kidney disease (CKD). STUDY DESIGN Cross-sectional observational studies of the general population. SETTING AND PARTICIPANTS 2 independent samples: KORA F4 (discovery sample, n = 3,011) and Twins UK (validation sample, n = 984). EXPOSURE FACTORS: 151 serum metabolites, quantified by targeted mass spectrometry. OUTCOMES AND MEASUREMENTS Metabolites and their 22,650 ratios were analyzed by multivariable-adjusted linear regression for their association with glomerular filtration rate (eGFR), estimated separately from creatinine and cystatin C levels by CKD-EPI (CKD Epidemiology Collaboration) equations. After correction for multiple testing, significant metabolites (P < 3.3 × 10(-4) for single metabolites; P < 2.2 × 10(-6) for ratios) were meta-analyzed with independent data from the TwinsUK Study. RESULTS Replicated associations with eGFR were observed for 22 metabolites and 516 metabolite ratios. Pooled P values ranged from 7.1 × 10(-7) to 1.8 × 10(-69) for the replicated single metabolites. Acylcarnitines such as glutarylcarnitine were associated inversely with eGFR (-3.73 mL/min/1.73 m(2) per standard deviation [SD] increase, pooled P = 1.8 × 10(-69)). The replicated ratio with the strongest association was the ratio of serine to glutarylcarnitine (P = 3.6 × 10(-81)). Almost all replicated phenotypes associated with decreased eGFR (<60 mL/min/1.73 m(2); n = 172 cases) in KORA F4: per 1-SD increment, ORs ranged from 0.29-2.06. Across categories of a metabolic score consisting of 3 uncorrelated metabolites, the prevalence of decreased eGFR increased from 3% to 53%. LIMITATIONS Cross-sectional study design, GFR was estimated, limited number of metabolites. CONCLUSIONS Distinct metabolic phenotypes were reproducibly associated with eGFR in 2 separate population studies. They may provide novel insights into renal metabolite handling, improve understanding of pathophysiology, or aid in the diagnosis of kidney disease. Longitudinal studies are needed to clarify whether changes in metabolic phenotypes precede or result from kidney function impairment.
Acute Pancreatitis in the Pediatric Intensive Care Unit

Aim: The aim of this study is to describe the demographics and outcomes of children with a discharge diagnosis of acute pancreatitis (AP) from the pediatric intensive care unit (PICU). Methods: Data for this retrospective cohort study were obtained from a multisite, clinical PICU database. PICU discharges with a primary or secondary diagnosis of AP (SAP) between 2009 and 2013 from 113 centers were reviewed. We also obtained the Pediatric Index of Mortality 2 Risk of Mortality (PIM2ROM), an indicator of the severity of illness. Results: Of 360,162 PICU discharges, 2026 with a diagnosis of AP were analyzed further (0.56%)—331 had a primary diagnosis of AP, whereas 1695 had a SAP. Among children with primary AP, median PIM2ROM was 1.0% (interquartile range [IQR] 0.8%–1.4%). Fifty-five children with primary AP (16.6%) required mechanical ventilation (MV) for a median of 3.8 days (IQR 1.0–9.3). The length of stay (LOS) in PICU was a median of 2.95 days (IQR 1.53–5.90). Only 1 patient died (mortality 0.3%). Among children with secondary AP, median PIM2ROM was 1.1% (IQR 0.8%–4.0%). A total of 711 children (42.0%) with secondary AP required MV for a median of 5.8 days (IQR 1.8–14.0). PICU LOS was a median of 4.43 days (IQR 1.84–11.22). There were 115 deaths in this group (mortality 6.8%). Median PIM2ROM, PICU LOS, mortality (all P < 0.001), and length of MV (P = 0.035) were significantly greater in children with secondary AP than with primary AP. Conclusions: Unlike in adult series, children with AP rarely die. Patients with secondary AP experience more morbidity and mortality than patients with primary AP.
Computational study of ketosteroid isomerase: insights from molecular dynamics simulation of enzyme bound substrate and intermediate.

Delta(5)-3-Ketosteroid Isomerase (KSI) catalyzes the isomerization of 5,6-unsaturated ketosteroids to their 4,5-unsaturated isomers at a rate approaching the diffusion limit. The isomerization reaction follows a two-step general acid-base mechanism starting with Asp38-CO(2)(-) mediated proton abstraction from a sp(3)-hybridized carbon atom, alpha to carbonyl group, providing a dienolate intermediate. In the second step, Asp38-CO(2)H protonates the C6 of the intermediate providing a 4,5-unsaturated ketosteroid. The details of the mechanism have been highly controversial despite several experimental and computational studies of this enzyme. The general acid-base catalysis has been proposed to involve either a catalytic diad or a cooperative hydrogen bond mechanism. In this paper, we report our results from the 1.5 nanosecond molecular dynamics (MD) simulation of enzyme bound natural substrate (E.S) and enzyme bound intermediate (E. In) solvated in a TIP3P water box. The final coordinates from our MD simulation strongly support the cooperative hydrogen bond mechanism. The MD simulation of E.S and E. In shows that both Tyr14 and Asp99 are hydrogen bonded to the O3 of the substrate or intermediate. The average hydrogen bonding distance between Tyr14-OH and O3 becomes shorter and exhibits less fluctuation on E.S --> E. In. We also observe dynamic motions of water moving in and out of the active site in the E.S structures. This free movement of water disappears in the E. In structures. The active site is shielded by hydrophobic residues, which come together and squeeze out the waters from the active site in the E. In complex.
Colour stability of heat and cold cure acrylic resins.

INTRODUCTION To evaluate the colour stability of heat and cold cure acrylic resins under simulated oral conditions with different colorants. MATERIALS AND METHODS Three different brands of heat cure acrylic resin and two rapid cure auto polymerizing acrylic resin of commercial products such as Trevelon Heat Cure (THC), DPI Heat cure (DHC), Pyrax Heat Cure (PHC), DPI Cold cure (DCC) and Acralyn-R-Cold cure (ACC) have been evaluated for discoloration and colour variation on subjecting it to three different, commonly employed food colorants such as Erythrosine, Tartarizine and Sunset yellow. In order to simulate the oral condition the food colorants were diluted with artificial saliva to the samples taken up for the study. These were further kept in an incubator at 37°C ± 1°C. The UV-visible spectrophotometer has been utilized to evaluate the study on the basis of CIE L* a* b* system. The prepared samples for standard evaluation have been grouped as control group, which has been tested with a white as standard, which is applicable for testing the colour variants. RESULTS The least colour changes was found to be with Sunset Yellow showing AE* value of 3.55 with heat cure acrylic resin branded as PHC material and the highest colour absorption with Tartarizine showing AE* value of 12.43 in rapid cure autopolymerzing acrylic resin material branded as ACC material. CONCLUSION ACC which is a self cure acrylic resin shows a higher colour variation to the tartarizine food coloration. There were not much of discoloration values shown on the denture base resins as the food colorants are of organic azodyes.
Reduced Expression of Cytoskeletal and Extracellular Matrix Genes in Human Adult Retinal Pigment Epithelium Cells Exposed to Simulated Microgravity

Background/Aims: Microgravity (µg) has adverse effects on the eye of humans in space. The risk of visual impairment is therefore one of the leading health concerns for NASA. The impact of µg on human adult retinal epithelium (ARPE-19) cells is unknown. Methods: In this study we investigated the influence of simulated µg (s-µg; 5 and 10 days (d)), using a Random Positioning Machine (RPM), on ARPE-19 cells. We performed phase-contrast/fluorescent microscopy, qRT-PCR, Western blotting and pathway analysis. Results: Following RPM-exposure a subset of ARPE-19 cells formed multicellular spheroids (MCS), whereas the majority of the cells remained adherent (AD). After 5d, alterations of F-actin and fibronectin were observed which reverted after 10d-exposure, suggesting a time-dependent adaptation to s-µg. Gene expression analysis of 12 genes involved in cell structure, shape, adhesion, migration, and angiogenesis suggested significant changes after a 10d-RPM-exposure. 11 genes were down-regulated in AD and MCS 10d-RPM-samples compared to 1g, whereas FLK1 was up-regulated in 5d- and 10d-RPM-MCS-samples. Similarly, TIMP1 was up-regulated in 5d-RPM-samples, whereas the remaining genes were down-regulated in 5d-RPM-samples. Western blotting revealed similar changes in VEGF, β-actin, laminin and fibronectin of 5d-RPM-samples compared to 10d, whereas different alterations of β-tubulin and vimentin were observed. The pathway analysis showed complementing effects of VEGF and integrin β-1. Conclusions: These findings clearly show that s-µg induces significant alterations in the F-actin-cytoskeleton and cytoskeleton-related proteins of ARPE-19, in addition to changes in cell growth behavior and gene expression patterns involved in cell structure, growth, shape, migration, adhesion and angiogenesis.
Visually Driven Neuropil Activity and Information Encoding in Mouse Primary Visual Cortex

Cortical neuropil modulations recorded by calcium imaging reflect the activity of large aggregates of axo-dendritic processes and synaptic compartments from a large number of neurons. The organization of this activity impacts neuronal firing but is not well understood. Here we used in vivo 2-photon imaging with Oregon Green Bapta (OGB) and GCaMP6s to study neuropil visual responses to moving gratings in layer 2/3 of mouse area V1. We found neuropil responses to be strongly modulated and more reliable than neighboring somatic activity. Furthermore, stimulus independent modulations in neuropil activity, i.e., noise correlations, were highly coherent across the cortical surface, up to distances of at least 200 μm. Pairwise neuropil-to-neuropil-patch noise correlation strength was much higher than cell-to-cell noise correlation strength and depended strongly on brain state, decreasing in quiet wakefulness relative to light anesthesia. The profile of neuropil noise correlation strength decreased gently with distance, dropping by ~11% at a distance of 200 μm. This was comparatively slower than the profile of cell-to-cell noise correlations, which dropped by ~23% at 200 μm. Interestingly, in spite of the “salt & pepper” organization of orientation and direction encoding across mouse V1 neurons, populations of neuropil patches, even of moderately large size (radius ~100 μm), showed high accuracy for discriminating perpendicularly moving gratings. This was commensurate to the accuracy of corresponding cell populations. The dynamic, stimulus dependent, nature of neuropil activity further underscores the need to carefully separate neuropil from cell soma activity in contemporary imaging studies.
The distribution of adenosine A1 receptors and 5′‐nucleotidase in the hippocampal formation of several mammalian species

The distributions of adenosine Al receptors, as demonstrated by 3H‐cyclohexyladenosine (3H‐CHA) binding, and the adenosine‐producing enzyme 5′‐nucleotidase were examined in the hippocampal formation of the rat, mouse, gerbil, cat, hamster, rabbit, and guinea pig. The enzyme and binding sites were restricted to subregions and often individual layers of this structure. The distribution of 3H‐CHA binding was consistent among the species with the strata radiatum and oriens of fields CA1 and CA3 exhibiting the highest levels of binding. A distinct band of 3H‐CHA binding was observed in the stratum moleculare of the dentate gyrus; and in most species, this band was restricted to the inner one‐third of the stratum moleculare (i.e., proximal to the stratum granulosum). The strata pyramidale, granulosum, and lucidum were in general only weakly positive for 3H CHA binding. The binding to the stratum lacunosum/moleculare (or the distinct strata lacunosum and moleculare in the rabbit and cat) was moderate. In contrast to the relative consistency of the patterns of 3H‐CHA binding in these species, 5′‐nucleotidase exhibited wide variations in both the absolute amount of activity and its localization. In all species, the strata granulosum and pyramidale appeared devoid of 5′‐nucleotidase activity. The only clear exception to this rule was the CA3 region of the cat where activity was seen between the cell bodies of stratum pyramidale. The strata radiatum and oriens of CAI were strongly positive in the rat and hamster but only low to moderately stained in the other species examined. The stratum lucidum of CA3 showed high amounts of staining in the hamster and moderate to high in the rat and rabbit. The cat, mouse, gerbil, and guinea pig exhibited only low to moderate 5′‐nucleotidase activity in the stratum lucidum of CA3. The stratum oriens of CA3 was low to moderate in all species except the cat, in which a dense band was observed near the stratum pyramidale. The only evidence of distinct binding in field CA2 was observed in the mouse and gerbil, in which all strata were moderately labeled except the stratum pyramidale. The dentate gyrus presented a variety of patterns with the stratum moleculare being low to moderate and relatively homogeneously stained in the mouse, rat, guinea pig, and rabbit. In the cat and gerbil, a dense band of enzymatic activity was seen in the outer one‐third (i.e., distal to the stratum granulosum) of the stratum moleculare near the obliterated hippocampal fissure. The gerbil exhibited an additional dense band in the inner third of the stratum moleculare of the dentate gyrus. The hamster, in constrast to the other species, showed dense 5′‐nucleotidase activity throughout the stratum moleculare.
Molecular and clinical characterization of cardio‐facio‐cutaneous (CFC) syndrome: Overlapping clinical manifestations with Costello syndrome

Cardio‐facio‐cutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by heart defects, a distinctive facial appearance, ectodermal abnormalities and mental retardation. Clinically, it overlaps with both Noonan syndrome and Costello syndrome, which are caused by mutations in two genes, PTPN11 and HRAS, respectively. Recently, we identified mutations in KRAS and BRAF in 19 of 43 individuals with CFC syndrome, suggesting that dysregulation of the RAS/RAF/MEK/ERK pathway is a molecular basis for CFC syndrome. The purpose of this study was to perform comprehensive mutation analysis in 56 patients with CFC syndrome and to investigate genotype–phenotype correlation. We analyzed KRAS, BRAF, and MAP2K1/2 (MEK1/2) in 13 new CFC patients and identified five BRAF and one MAP2K1 mutations in nine patients. We detected one MAP2K1 mutation in three patients and four new MAP2K2 mutations in four patients out of 24 patients without KRAS or BRAF mutations in the previous study [Niihori et al., 2006 ]. No mutations were identified in MAPK3/1 (ERK1/2) in 21 patients without any mutations. In total, 35 of 56 (62.5%) patients with CFC syndrome had mutations (3 in KRAS, 24 in BRAF, and 8 in MAP2K1/2). No significant differences in clinical manifestations were found among 3 KRAS‐positive patients, 16 BRAF‐positive patients, and 6 MAP2K1/2‐positive patients. Wrinkled palms and soles, hyperpigmentation and joint hyperextension, which have been commonly reported in Costello syndrome but not in CFC syndrome, were observed in 30–40% of the mutation‐positive CFC patients, suggesting a significant clinical overlap between these two syndromes. © 2007 Wiley‐Liss, Inc.
Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome

Many currently used and candidate vaccine adjuvants are particulate in nature, but their mechanism of action is not well understood. Here, we show that particulate adjuvants, including biodegradable poly(lactide-co-glycolide) (PLG) and polystyrene microparticles, dramatically enhance secretion of interleukin-1β (IL-1β) by dendritic cells (DCs). The ability of particulates to promote IL-1β secretion and caspase 1 activation required particle uptake by DCs and NALP3. Uptake of microparticles induced lysosomal damage, whereas particle-mediated enhancement of IL-1β secretion required phagosomal acidification and the lysosomal cysteine protease cathepsin B, suggesting a role for lysosomal damage in inflammasome activation. Although the presence of a Toll-like receptor (TLR) agonist was required to induce IL-1β production in vitro, injection of the adjuvants in the absence of TLR agonists induced IL-1β production at the injection site, indicating that endogenous factors can synergize with particulates to promote inflammasome activation. The enhancement of antigen-specific antibody production by PLG microparticles was independent of NALP3. However, the ability of PLG microparticles to promote antigen-specific IL-6 production by T cells and the recruitment and activation of a population of CD11b+Gr1− cells required NALP3. Our data demonstrate that uptake of microparticulate adjuvants by DCs activates the NALP3 inflammasome, and this contributes to their enhancing effects on innate and antigen-specific cellular immunity.
Downward Nominal Wage Rigidity in the United States: New Evidence From Worker-Firm Linked Data

This paper examines the extent and consequences of Downward Nominal Wage Rigidity (DNWR) using administrative worker-firm linked data from the Longitudinal Employer Household Dynamics (LEHD) program for a large representative U.S. state. Prior to the Great Recession, only 7-8% of job stayers are paid the same nominal hourly wage rate as one year earlier - substantially less than previously found in survey-based data - and about 20% of job stayers experience a wage cut. During the Great Recession, the incidence of wage cuts increases to 30%, followed by a large rise in the proportion of wage freezes to 16% as the economy recovers. Total earnings of job stayers exhibit even fewer zero changes and a larger incidence of reductions than hourly wage rates, due to systematic variations in hours worked. The results are consistent with concurrent findings in the literature that reductions in base pay are exceedingly rare but that firms use different forms of non-base pay and variations in hours worked to flexibilize labor cost. We then exploit the worker-firm link of the LEHD and find that during the Great Recession, firms with indicators of DNWR reduced employment by about 1.2% more per year. This negative effect is driven by significantly lower hiring rates and persists into the recovery. Our results suggest that despite the relatively large incidence of wage cuts in the aggregate, DNWR has sizable allocative consequences.
PROPHYLACTIC USE OF 15(S)15 METHYL PGF2α BY INTRAMUSCULAR ROUTE FOR CONTROL OF POSTPARTUM BLEEDING — A COMPARATIVE TRIAL WITH METHYLERGOMETRINE

In a multicentre trial (3 centres) the safety and efficacy of an intramuscular injection of 125 µg of 15(S)15 methyl PGF2α (Prostin 15M, Upjohn) was compared with methylergometrine for prophylactic control of bleeding during the third stage of labour. Three hundred patients were recruited for the study — 150 to each treatment group. The duration of the third stage was shorter in the patients (4.4 minutes) treated with Prostin 15M compared to the methylergometrine group (8.6 minutes). Similarly the blood loss during the third stage was reduced by 50% of that observed in the methylergometrine group (72 ml vs 145 ml). Prostin 15M, when used prophylactically was better than methylergometrine in controlling the blood loss during the third stage of labour.