Miracle-dz/UniFAR-FTUs huggingface dataset:
The convergent evolution of snake‐like forms by divergent evolutionary pathways in squamate reptiles *

Convergent evolution of phenotypes is considered evidence that evolution is deterministic. Establishing if such convergent phenotypes arose through convergent evolutionary pathways is a stronger test of determinism. We studied the evolution of snake‐like body shapes in six clades of lizards, each containing species ranging from short‐bodied and pentadactyl to long‐bodied and limbless. We tested whether body shapes that evolved in each clade were convergent, and whether clades evolved snake‐like body shapes following convergent evolutionary pathways. Our analyses showed that indeed species with the same numbers of digits in each clade evolved convergent body shapes. We then compared evolutionary pathways among clades by considering patterns of evolutionary integration and shape of relationship among body parts, patterns of vertebral evolution, and models of digit evolution. We found that all clades elongated their bodies through the addition, not elongation, of vertebrae, and had similar patterns of integration. However, patterns of integration, the body parts that were related by a linear or a threshold model, and patterns of digit evolution differed among clades. These results showed that clades followed different evolutionary pathways. This suggests an important role of historical contingency as opposed to determinism in the convergent evolution of snake‐like body shapes.
Dynamic transcriptomic analysis reveals suppression of PGC1α/ERRα drives perturbed myogenesis in facioscapulohumeral muscular dystrophy

Abstract Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable myopathy, linked to epigenetic derepression of D4Z4 repeats on chromosome 4q, leading to ectopic DUX4 expression. FSHD patient myoblasts have defective myogenic differentiation, forming smaller myotubes with reduced myosin content. However, molecular mechanisms driving such disrupted myogenesis in FSHD are poorly understood. We performed high-throughput morphological analysis describing FSHD and control myogenesis, revealing altered myogenic differentiation results in hypotrophic myotubes. Employing polynomial models and an empirical Bayes approach, we established eight critical time points during which human healthy and FSHD myogenesis differ. RNA-sequencing at these eight nodal time points in triplicate, provided temporal depth for a multivariate regression analysis, allowing assessment of interaction between progression of differentiation and FSHD disease status. Importantly, the unique size and structure of our data permitted identification of many novel FSHD pathomechanisms undetectable by previous approaches. For further analysis here, we selected pathways that control mitochondria: of interest considering known alterations in mitochondrial structure and function in FSHD muscle, and sensitivity of FSHD cells to oxidative stress. Notably, we identified suppression of mitochondrial biogenesis, in particular via peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α), the cofactor and activator of oestrogen-related receptor α (ERRα). PGC1α knock-down caused hypotrophic myotubes to form from control myoblasts. Known ERRα agonists and safe food supplements biochanin A, daidzein or genistein, each rescued the hypotrophic FSHD myotube phenotype. Together our work describes transcriptomic changes in high resolution that occur during myogenesis in FSHD ex vivo, identifying suppression of the PGC1α-ERRα axis leading to perturbed myogenic differentiation, which can effectively be rescued by readily available food supplements.
A Surface Protein From Lactobacillus plantarum Increases the Adhesion of Lactobacillus Strains to Human Epithelial Cells

Adhesion to epithelial cells is considered important for Lactobacillus to exert probiotic effects. In this study, we found that trypsin treatment decreased the adhesion ability of Lactobacillus plantarum AR326 and AR269, which exhibit good adhesion ability, and surface proteins extracts increased the adhesion of the strains with poor adhesion ability. By SDS–polyacrylamide gel electrophoresis and mass spectrometry analysis, the main component of the surface proteins was detected and identified as a protein of approximately 37 kDa. It was 100% homologous with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from L. plantarum WCFS1. The adhesion of AR326 and AR269 was decreased significantly by blocking with the anti-GAPDH antibody, and GAPDH restored the adhesion of AR326 and AR269 treated with trypsin. In addition, purified GAPDH significantly increased the adhesion of the strains with poor adhesion ability. These results indicated that GAPDH mediates the adhesion of these highly adhesive lactobacilli to epithelial cells and can be used to improve the adhesion ability of probiotics or other bacteria of interest.
Hormones and Hearing: Central Auditory Processing in Women

Abstract Background: Estrogen has been identified as playing a key role in many organ systems. Recently, estrogen has been found to be produced in the human brain and is believed contribute to central auditory processing. After menopause, a low estrogen state, many women report hearing loss but demonstrate no deficits in peripheral hearing sensitivity, which support the notion that estrogen plays an effect on central auditory processing. Although animal research on estrogen and hearing loss is extensive, there is little in the literature on the human model. Purpose: The aim of this study was to evaluate relationships between hormonal changes and hearing as it relates to higher auditory function in pre- and postmenopausal (Post-M) females. Research Design: A prospective, group comparison study. Study Sample: Twenty eight women between the ages of 18 and 70 at the University of Kentucky were recruited. Data Collection and Analysis: Participants were separated into premenopausal and peri-/Post-M groups. Participants had normal peripheral hearing sensitivity and underwent a behavioral auditory processing battery and electrophysiological evaluation. An analysis of variance was performed to address the aims of the study. Results: Results from the study demonstrated statistically significant difference between groups, where Post-M females had difficulties in spatial hearing abilities as reflected on the Listening in Spatialized Noise Test–Sentences test. In addition, measures on the auditory brainstem response and the middle latency response reflected statistically significant differences between groups with Post-M females having longer latencies. Conclusions: Results from the present study demonstrated significant differences between groups, particularly listening in noise. Females who present with auditory complaints in spite of normal hearing thresholds should have a more extensive audiological evaluation to further evaluate possible central deficits.
Start-Stop Assembly: a functionally scarless DNA assembly system optimized for metabolic engineering

DNA assembly allows individual DNA constructs or designed mixtures to be assembled quickly and reliably. Most methods are either: (i) Modular, easily scalable and suitable for combinatorial assembly, but leave undesirable ‘scar’ sequences; or (ii) bespoke (non-modular), scarless but less suitable for construction of combinatorial libraries. Both have limitations for metabolic engineering. To overcome this trade-off we devised Start-Stop Assembly, a multi-part, modular DNA assembly method which is both functionally scarless and suitable for combinatorial assembly. Crucially, 3 bp overhangs corresponding to start and stop codons are used to assemble coding sequences into expression units, avoiding scars at sensitive coding sequence boundaries. Building on this concept, a complete DNA assembly framework was designed and implemented, allowing assembly of up to 15 genes from up to 60 parts (or mixtures); monocistronic, operon-based or hybrid configurations; and a new streamlined assembly hierarchy minimising the number of vectors. Only one destination vector is required per organism, reflecting our optimisation of the system for metabolic engineering in diverse organisms. Metabolic engineering using Start-Stop Assembly was demonstrated by combinatorial assembly of carotenoid pathways in E. coli resulting in a wide range of carotenoid production and colony size phenotypes indicating the intended exploration of design space. GRAPHICAL ABSTRACT
Systemic and local hepcidin as emerging and important peptides in renal homeostasis and pathology

Recent data suggest that the importance of hepcidin goes beyond its classical role in controlling systemic iron metabolism. Local hepcidins are emerging as important peptides for organ homeostasis in the brain, heart, blood vessels, and in cancer as well. Similarly, accumulating data indicate that hepcidin does seem to be an important factor in renal homeostasis. This review encompasses present knowledge concerning the role of hepcidin in renoprotection and its use as a biomarker of kidney diseases. Understanding the role of hepcidin in kidneys is important due to its relevance for kidney physiology and its potential therapeutic application in kidney pathologies. © 2018 BioFactors, 45(2):118–134, 2019
Adherence of Newborn-Specific Antibiotic Stewardship Programs to CDC Recommendations

In this cross-sectional study of neonatal antibiotic usage, we identify the baseline prevalence of ASPs in the newborn setting. BrightcoveDefaultPlayer10.1542/6138648370001PEDS-VA_2017-4322 Video Abstract BACKGROUND: The Centers for Disease Control and Prevention (CDC) published the Core Elements of Hospital Antibiotic Stewardship Programs (ASPs), while the Choosing Wisely for Newborn Medicine Top 5 list identified antibiotic therapy as an area of overuse. We identify the baseline prevalence and makeup of newborn-specific ASPs and assess the variability of NICU antibiotic use rates (AURs). METHODS: Data were collected using a cross-sectional audit of Vermont Oxford Network members in February 2016. Unit measures were derived from the 7 domains of the CDC’s Core Elements of Hospital ASPs, including leadership commitment, accountability, drug expertise, action, tracking, reporting, and education. Patient-level measures included patient demographics, indications, and reasons for therapy. An AUR, defined as the number of infants who are on antibiotic therapy divided by the census that day, was calculated for each unit. RESULTS: Overall, 143 centers completed structured self-assessments. No center addressed all 7 core elements. Of the 7, only accountability (55%) and drug expertise (62%) had compliance >50%. Centers audited 4127 infants for current antibiotic exposure. There were 725 infants who received antibiotics, for a hospital median AUR of 17% (interquartile range 10%–26%). Of the 412 patients on >48 hours of antibiotics, only 26% (107 out of 412) had positive culture results. CONCLUSIONS: Significant gaps exist between CDC recommendations to improve antibiotic use and antibiotic practices during the newborn period. There is wide variation in point prevalence AURs. Three-quarters of infants who received antibiotics for >48 hours did not have infections proven by using cultures.
Apo-Opsin Exists in Equilibrium Between a Predominant Inactive and a Rare Highly Active State

Bleaching adaptation in rod photoreceptors is mediated by apo-opsin, which activates phototransduction with effective activity 105- to 106-fold lower than that of photoactivated rhodopsin (meta II). However, the mechanism that produces such low opsin activity is unknown. To address this question, we sought to record single opsin responses in mouse rods. We used mutant mice lacking efficient calcium feedback to boosts rod responses and generated a small fraction of opsin by photobleaching ∼1% of rhodopsin. The bleach produced a dramatic increase in the frequency of discrete photoresponse-like events. This activity persisted for hours, was quenched by 11-cis-retinal, and was blocked by uncoupling opsin from phototransduction, all indicating opsin as its source. Opsin-driven discrete activity was also observed in rods containing non-activatable rhodopsin, ruling out transactivation of rhodopsin by opsin. We conclude that bleaching adaptation is mediated by opsin that exists in equilibrium between a predominant inactive and a rare meta II-like state. SIGNIFICANCE STATEMENT Electrophysiological analysis is used to show that the G-protein-coupled receptor opsin exists in equilibrium between a predominant inactive and a rare highly active state that mediates bleaching adaptation in photoreceptors.
Influence of follicle-stimulating hormone concentrations on the integrity and development of bovine follicles cultured in vitro

Summary This study investigated the in vitro culture of bovine follicles included in ovarian tissue for 2 or 6 days (D2 or D6), with the addition of different concentrations of follicle-stimulating hormone (FSH) (0, 10, 50, 100 or 200 ng/ml). Data were compared for follicular development, morphological integrity and diameter of follicles and oocytes. Ovaries (n = 10) from Nelore cows (n = 5) were divided into fragments (n = 11 per ovary) and were immediately fixed in Bouin’s solution (D0) or were individually cultured for 2 or 6 days in one of the described concentrations of FSH and then processed for histology. Compared with the rates of follicular development at D2 for minimal essential medium (MEM) (75.0%) and 50 ng/ml of FSH (71.1%), the best rates of follicular development at D2 were obtained with 10 (84.7%), 100 (87.5%) and 200 ng/ml of FSH (85.0%; P<0.05). After 6 days of cultivation, there were no differences among treatments regarding follicular growth. The morphological integrity of preantral follicles was better maintained by 100 ng/ml FSH for 2 and 6 days of cultivation (51.2 and 40.4%, respectively; P<0.05) than that for MEM (D2: 30.9%, D6: 20.8%), 10 (D2: 39.2%, D6: 22.8%), 50 (D2: 30.4%, D6: 28.8%) and 200 ng/ml FSH (D2: 45.2%, D6: 36.8%). FSH at 100 ng/ml provided the highest mean diameter averages: 34.5±10.8 µm at D2 and 33.2±12.5 µm at D6 (P<0.05). We concluded that the medium supplemented with 100 ng/ml FSH during in vitro culture provided appropriate conditions for the development and morphological integrity of preantral follicles in cattle.
Veterans Health Administration's Physician Assistant Primary Care Residency: An Evaluation of the First 3 Years

Purpose Results from an evaluation of a 12-month postgraduate Veterans Health Administration (VHA) residency in primary care for physician assistants (PAs). Methods Descriptive and open-ended data were collected to describe the experience of faculty and trainees participating in the first 3 years of this pilot residency. Quantitative data were summarized using descriptive statistics. Text data were transcribed and reviewed for common themes across residency sites and respondents. Data were collected at 2 time points—the end of the first year and the beginning of year 4. Results In the first 3 years of the program, 18 residents were enrolled at 6 sites, with 89% completing the residency. At the second time point, 8 more residents were enrolled. Residents were primarily female (69%). Of the residents completing the program, 56% obtained VHA employment, and 75% of the current residents planned to work for the VHA upon completing the program. Program infrastructure, such as written curriculum, a dedicated administrative staff, and written evaluations for trainees, was more common at the second time point. Recurring themes included the importance of establishing relationships with potential applicants, preceptors, medical center leadership, and trainees to support the program and the importance of securing resources such as space and protected time for faculty. Conclusions Although postgraduate residency programs are less common for PAs than for some other health professions, our data suggest that a one-year residency can provide training for new graduates to help solidify their clinical experience and facilitate their transition to practice.
Four model variants within a continuous forensic DNA mixture interpretation framework: Effects on evidential inference and reporting

Continuous mixture interpretation methods that employ probabilistic genotyping to compute the Likelihood Ratio (LR) utilize more information than threshold-based systems. The continuous interpretation schemes described in the literature, however, do not all use the same underlying probabilistic model and standards outlining which probabilistic models may or may not be implemented into casework do not exist; thus, it is the individual forensic laboratory or expert that decides which model and corresponding software program to implement. For countries, such as the United States, with an adversarial legal system, one can envision a scenario where two probabilistic models are used to present the weight of evidence, and two LRs are presented by two experts. Conversely, if no independent review of the evidence is requested, one expert using one model may present one LR as there is no standard or guideline requiring the uncertainty in the LR estimate be presented. The choice of model determines the underlying probability calculation, and changes to it can result in non-negligible differences in the reported LR or corresponding verbal categorization presented to the trier-of-fact. In this paper, we study the impact of model differences on the LR and on the corresponding verbal expression computed using four variants of a continuous mixture interpretation method. The four models were tested five times each on 101, 1-, 2- and 3-person experimental samples with known contributors. For each sample, LRs were computed using the known contributor as the person of interest. In all four models, intra-model variability increased with an increase in the number of contributors and with a decrease in the contributor’s template mass. Inter-model variability in the associated verbal expression of the LR was observed in 32 of the 195 LRs used for comparison. Moreover, in 11 of these profiles there was a change from LR > 1 to LR < 1. These results indicate that modifications to existing continuous models do have the potential to significantly impact the final statistic, justifying the continuation of broad-based, large-scale, independent studies to quantify the limits of reliability and variability of existing forensically relevant systems.
Outcome of patients aged 80 years or older treated for chronic lymphocytic leukaemia

Clinical management of chronic lymphocytic leukaemia (CLL) in patients aged ≥80 years is based on limited evidence due to the lack of published information. Therefore, we analysed CLL patients aged ≥80 years using data from seven phase III clinical trials of the German CLL Study Group. Among 3552 participants, 152 were ≥80 years old at initiation of first‐line study treatment. Median age was 82 years (range 80–90). Concomitant diseases were present in 99% of the patients, with a median cumulative illness rating scale score of 8 (0–18). Chemoimmunotherapy with chlorambucil‐obinutuzumab (CLB‐OB) or chlorambucil‐rituximab (CLB‐R) was administered to 61 (40%) and 56 (37%) patients. The remaining patients received CLB (n = 19) or fludarabine (F, n = 10), F/cyclophosphamide (FC, n = 1), FC/rituximab (FCR, n = 2) or bendamustine/rituximab (BR, n = 3). Rates of grade 3 or 4 neutropenia and infections were 35% and 13%. Overall response rate was 77% with 13% complete remissions. Median progression‐free survival and treatment‐free survival were 17·2 and 32·3 months, respectively. Median overall survival was 48·3 months; adverse events (22%) and progressive CLL (16·4%) were the most frequent causes of death. These findings suggest that anti‐leukaemic treatment including chemoimmunotherapy is feasible and efficacious in ≥80‐year‐old CLL patients. However, this group of patients lives for a shorter time than age‐matched controls of the general population.
The application of Hadoop in Structural Bioinformatics

The paper reviews the use of the Hadoop platform in Structural Bioinformatics applications. Specifically, we review a number of implementations using Hadoop of high-throughput analyses, e.g. ligand-protein docking and structural alignment, and their scalability in comparison with other batch schedulers and MPI. We find that these deployments for the most part use known executables called from MapReduce rather than rewriting the algorithms. The scalability exhibits a variable behaviour in comparison with other batch schedulers, particularly as direct comparisons on the same platform are generally not available. We do note there is some evidence that MPI implementations scale better than Hadoop. A significant barrier to the use of the Hadoop ecosystem is the difficulty of the interface and configuration of a resource to use Hadoop. This will improve over time as interfaces to Hadoop e.g. Spark improve, usage of cloud platforms (e.g. Azure and AWS) increases and approaches such as the Workflow Definition Language are taken up.
Phthalates Exposure as Determinant of Albuminuria in Subjects With Type 2 Diabetes: A Cross-Sectional Study.

CONTEXT Recent epidemiological observations have reported an association among phthalates exposure and insulin resistance, obesity, and diabetes but have not related exposure to these environmental pollutants with microvascular complications of diabetes. OBJECTIVE To explore the relationship between phthalates and renal function in subjects with diabetes. DESIGN Cross-sectional, case-only study. Concentrations of three urinary metabolites of di-2-ethylhexylphthalate were quantified in a spot morning urine sample, normalized for creatinine urinary excretion, and related to clinical parameters and phenotype, adjusting for confounders. PATIENTS Two hundred and nine patients with diabetes consecutively referred to our clinic. MAIN OUTCOME MEASURES Relationship between phthalates and renal function [evaluated with estimated glomerular filtration rate (eGFR) and albuminuria]. RESULTS Creatinine-adjusted urinary concentrations of mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP), and mono-2-ethyl-5-hydroxyhexyl phthalate were 7.53 µg/g (range, 4.84 to 12.60), 3.04 µg/g (range, 1.03 to 5.14), and 10.70 µg/g (7.02 to 17.40), respectively. Age, sex, body mass index, diabetes duration, smoking, blood pressure, glycated Hb, and eGFR did not influence their levels. Exposure to MEHP and MEOHP was greater in individuals with microalbuminuria/macroalbuminuria (MEHP, P = 0.0173; MEOHP, P = 0.0306). The fourth vs first quartile showed a greater risk of albuminuria (MEHP: OR, 4.83; 95% CI, 1.45 to 16.06; P = 0.0297; MEOHP: OR, 3.29; 95% CI, 1.08 to 10.04); P = 0.0352). MEOHP was greater (P = 0.034) in subjects with cardiovascular events; MEHP showed a positive trend (P = 0.061). CONCLUSION Our findings have revealed an association between exposure to di-2-ethylhexylphthalate metabolites and the degree of albuminuria in subjects with diabetes; the lack of a relationship with eGFR suggests their urinary levels are independent of renal function.