Miracle-dz/UniFAR-FTUs huggingface dataset:
A self-sustaining process model of inertial layer dynamics in high Reynolds number turbulent wall flows

Field observations and laboratory experiments suggest that at high Reynolds numbers Re the outer region of turbulent boundary layers self-organizes into quasi-uniform momentum zones (UMZs) separated by internal shear layers termed ‘vortical fissures’ (VFs). Motivated by this emergent structure, a conceptual model is proposed with dynamical components that collectively have the potential to generate a self-sustaining interaction between a single VF and adjacent UMZs. A large-Re asymptotic analysis of the governing incompressible Navier–Stokes equation is performed to derive reduced equation sets for the streamwise-averaged and streamwise-fluctuating flow within the VF and UMZs. The simplified equations reveal the dominant physics within—and isolate possible coupling mechanisms among—these different regions of the flow. This article is part of the themed issue ‘Toward the development of high-fidelity models of wall turbulence at large Reynolds number’.
Comparison of the Circulating Metabolite Profile of PF-04991532, a Hepatoselective Glucokinase Activator, Across Preclinical Species and Humans: Potential Implications in Metabolites in Safety Testing Assessment

A previous report from our laboratory disclosed the identification of PF-04991532 [(S)-6-(3-cyclopentyl-2-(4-trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid] as a hepatoselective glucokinase activator for the treatment of type 2 diabetes mellitus. Lack of in vitro metabolic turnover in microsomes and hepatocytes from preclinical species and humans suggested that metabolism would be inconsequential as a clearance mechanism of PF-04991532 in vivo. Qualitative examination of human circulating metabolites using plasma samples from a 14-day multiple ascending dose clinical study, however, revealed a glucuronide (M1) and monohydroxylation products (M2a and M2b/M2c) whose abundances (based on UV integration) were greater than 10% of the total drug-related material. Based on this preliminary observation, mass balance/excretion studies were triggered in animals, which revealed that the majority of circulating radioactivity following the oral administration of [14C]PF-04991532 was attributed to an unchanged parent (>70% in rats and dogs). In contrast with the human circulatory metabolite profile, the monohydroxylated metabolites were not detected in circulation in either rats or dogs. Available mass spectral evidence suggested that M2a and M2b/M2c were diastereomers derived from cyclopentyl ring oxidation in PF-04991532. Because cyclopentyl ring hydroxylation on the C-2 and C-3 positions can generate eight possible diastereomers, it was possible that additional diastereomers may have also formed and would need to be resolved from the M2a and M2b/M2c peaks observed in the current chromatography conditions. In conclusion, the human metabolite scouting study in tandem with the animal mass balance study allowed early identification of PF-04991532 oxidative metabolites, which were not predicted by in vitro methods and may require additional scrutiny in the development phase of PF-04991532.
Hybrid Forecasting of Chaotic Processes: Using Machine Learning in Conjunction with a Knowledge-Based Model

A model-based approach to forecasting chaotic dynamical systems utilizes knowledge of the mechanistic processes governing the dynamics to build an approximate mathematical model of the system. In contrast, machine learning techniques have demonstrated promising results for forecasting chaotic systems purely from past time series measurements of system state variables (training data), without prior knowledge of the system dynamics. The motivation for this paper is the potential of machine learning for filling in the gaps in our underlying mechanistic knowledge that cause widely-used knowledge-based models to be inaccurate. Thus, we here propose a general method that leverages the advantages of these two approaches by combining a knowledge-based model and a machine learning technique to build a hybrid forecasting scheme. Potential applications for such an approach are numerous (e.g., improving weather forecasting). We demonstrate and test the utility of this approach using a particular illustrative version of a machine learning known as reservoir computing, and we apply the resulting hybrid forecaster to a low-dimensional chaotic system, as well as to a high-dimensional spatiotemporal chaotic system. These tests yield extremely promising results in that our hybrid technique is able to accurately predict for a much longer period of time than either its machine-learning component or its model-based component alone.
Enhancement of Swimming Speed Leads to a More-Efficient Chemotactic Response to Repellent

ABSTRACT Negative chemotaxis refers to the motion of microorganisms away from regions with high concentrations of chemorepellents. In this study, we set controlled gradients of NiCl2, a chemorepellent, in microchannels to quantify the motion of Escherichia coli over a broad range of concentrations. The experimental technique measured the motion of the bacteria in space and time and further related the motion to the local concentration profile of the repellent. Results show that the swimming speed of bacteria increases with an increasing concentration of repellent, which in turn enhances the drift velocity. The contribution of the increased swimming speed to the total drift velocity was in the range of 20 to 40%, with the remaining contribution coming from the modulation of the tumble frequency. A simple model that incorporates receptor dynamics, including adaptation, intracellular signaling, and swimming speed variation, was able to qualitatively capture the observed trend in drift velocity.
Disease and the Extended Phenotype: Parasites Control Host Performance and Survival through Induced Changes in Body Plan

Background By definition, parasites harm their hosts. However, some forms of parasite-induced alterations increase parasite transmission between hosts, such that manipulated hosts can be considered extensions of the parasite's phenotype. While well accepted in principle, surprisingly few studies have quantified how parasite manipulations alter host performance and survival under field and laboratory conditions. Methodology/Principal Findings By interfering with limb development, the trematode Ribeiroia ondatrae causes particularly severe morphological alterations within amphibian hosts that provide an ideal system to evaluate parasite-induced changes in phenotype. Here, we coupled laboratory performance trials with a capture-mark-recapture study of 1388 Pacific chorus frogs (Pseudacris regilla) to quantify the effects of parasite-induced malformations on host locomotion, foraging, and survival. Malformations, which affected ∼50% of metamorphosing frogs in nature, caused dramatic reductions in all measures of organismal function. Malformed frogs exhibited significantly shorter jumping distances (41% reduction), slower swimming speeds (37% reduction), reduced endurance (66% reduction), and lower foraging success relative to infected hosts without malformations. Furthermore, while normal and malformed individuals had comparable survival within predator-free exclosures, deformed frogs in natural populations had 22% lower biweekly survival than normal frogs and rarely recruited to the adult population over a two-year period. Conclusions/Significance Our results highlight the ability of parasites to deeply alter multiple dimensions of host phenotype with important consequences for performance and survival. These patterns were best explained by malformation status, rather than infection per se, helping to decouple the direct and indirect effects of parasitism on host fitness.
Palliative Care Interventions for Patients with Heart Failure: A Systematic Review and Meta-Analysis.

OBJECTIVE To systematically characterize interventions and effectiveness of palliative care for advanced heart failure (HF) patients. BACKGROUND Patients with advanced heart failure experience a high burden of distressing symptoms and diminished quality of life. Palliative care expertise with symptom management and healthcare decision-making benefits HF patients. METHODS A systematic PubMed search was conducted from inception to June 2016 for studies of palliative care interventions for HF patients. Studies of humans with a HF diagnosis who underwent a palliative care intervention were included. Data were extracted on study design, participant characteristics, intervention components, and in three groups of outcomes: patient-centered outcomes, quality-of-death outcomes, and resource utilization. Study characteristics were examined to determine if meta-analysis was possible. RESULTS The fifteen identified studies varied in design (prospective, n = 10; retrospective, n = 5). Studies enrolled older patients, but greater variability was found for race, sex, and marital status. A majority of studies measuring patient-centered outcomes demonstrated improvements including quality of life and satisfaction. Quality-of-death outcomes were mixed with a majority of studies reporting clarification of care preferences, but less improvement in death at home and hospice enrollment. A meta-analysis in three studies found that home-based palliative care consults in HF patients lower the risk of rehospitalization by 42% (RR = 0.58; 95% Confidence Interval 0.44, 0.77). DISCUSSION Available evidence suggests that home and team-based palliative interventions for HF patients improve patient-centered outcomes, documentation of preferences, and utilization. Increased high quality studies will aid the determination of the most effective palliative care approaches for the HF population.
Determination of Beta-Defensin Genomic Copy Number in Different Populations: A Comparison of Three Methods

Background There have been conflicting reports in the literature on association of gene copy number with disease, including CCL3L1 and HIV susceptibility, and β-defensins and Crohn's disease. Quantification of precise gene copy numbers is important in order to define any association of gene copy number with disease. At present, real-time quantitative PCR (QPCR) is the most commonly used method to determine gene copy number, however the Paralogue Ratio Test (PRT) is being used in more and more laboratories. Findings In this study we compare a Pyrosequencing-based Paralogue Ratio Test (PPRT) for determining beta-defensin gene copy number with two currently used methods for gene copy number determination, QPCR and triplex PRT by typing five different cohorts (UK, Danish, Portuguese, Ghanaian and Czech) of DNA from a total of 576 healthy individuals. We found a systematic measurement bias between DNA cohorts revealed by QPCR, but not by the PRT-based methods. Using PRT, copy number ranged from 2 to 9 copies, with a modal copy number of 4 in all populations. Conclusions QPCR is very sensitive to quality of the template DNA, generating systematic biases that could produce false-positive or negative disease associations. Both triplex PRT and PPRT do not show this systematic bias, and type copy number within the correct range, although triplex PRT appears to be a more precise and accurate method to type beta-defensin copy number.
The Immunomodulatory Effects of Macrolides—A Systematic Review of the Underlying Mechanisms

Background The mechanisms underlying the non-antimicrobial immunomodulatory properties of macrolides are not well understood. Objectives To systematically review the evidence for the immunomodulatory properties of macrolides in humans and to describe the underlying mechanism and extent of their influence on the innate and adaptive immune system. Methods A systematic literature search was done in MEDLINE using the OVID interface from 1946 to December 2016 according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA). Original articles investigating the influence of four macrolides (azithromycin, clarithromycin, erythromycin, and roxithromycin) on immunological markers in humans were included. Results We identified 22 randomized, controlled trials, 16 prospective cohort studies, and 8 case–control studies investigating 47 different immunological markers (186 measurements) in 1,834 participants. The most frequently reported outcomes were a decrease in the number of neutrophils, and the concentrations of neutrophil elastase, interleukin (IL)-8, IL-6, IL-1beta, tumor necrosis factor (TNF)-alpha, eosinophilic cationic protein, and matrix metalloproteinase 9. Inhibition of neutrophil function was reported more frequently than eosinophil function. A decrease in T helper (Th) 2 cells cytokines (IL-4, IL-5, IL-6) was reported more frequently than a decrease in Th1 cytokines (IL-2, INF-gamma). Conclusion Macrolides influence a broad range of immunological mechanisms resulting in immunomodulatory effects. To optimize the treatment of chronic inflammatory diseases by macrolides, further studies are necessary, particularly comparing different macrolides and dose effect relationships.
Tandem hnRNP A1 RNA recognition motifs act in concert to repress the splicing of survival motor neuron exon 7

HnRNP A1 regulates many alternative splicing events by the recognition of splicing silencer elements. Here, we provide the solution structures of its two RNA recognition motifs (RRMs) in complex with short RNA. In addition, we show by NMR that both RRMs of hnRNP A1 can bind simultaneously to a single bipartite motif of the human intronic splicing silencer ISS-N1, which controls survival of motor neuron exon 7 splicing. RRM2 binds to the upstream motif and RRM1 to the downstream motif. Combining the insights from the structure with in cell splicing assays we show that the architecture and organization of the two RRMs is essential to hnRNP A1 function. The disruption of the inter-RRM interaction or the loss of RNA binding capacity of either RRM impairs splicing repression by hnRNP A1. Furthermore, both binding sites within the ISS-N1 are important for splicing repression and their contributions are cumulative rather than synergistic. DOI: http://dx.doi. org/10.7554/eLife.25736. 001
Comparison of pMOS and nMOS 28 GHz high efficiency linear power amplifiers in 45 nm CMOS SOI

High efficiency, compact CMOS power amplifiers (PAs) based on nMOS and pMOS transistors in 45 nm CMOS SOI technology for Ka-band applications are presented. Both the nMOS and pMOS amplifiers use 2-stack power devices in order to increase the maximum output voltage swing. Both the nMOS and pMOS PAs have peak small signal gain of about 13 dB, and demonstrate more than 40% peak PAE, with 18.9 dBm saturated output power for the nMOS and 17.8 dBm for the pMOS (when measured at the same drain bias voltage.) With a 64-QAM OFDM signal with 800MHz bandwidth, the nMOS PA achieves EVM = 5.5% with average output power of Pout = 9.8 dBm and average PAE = 14.8%. We show that the pMOS amplifiers are able to withstand higher drain bias voltages than their nMOS counterparts. The amplifiers have compact dimensions and occupy 0.18 mm2 of active area.
Whole-exome sequencing improves genetic testing accuracy in pulmonary artery hypertension

Sanger sequencing, the traditional “gold standard” for mutation detection, has been wildly used in genetic testing of pulmonary artery hypertension (PAH). However, with the advent of whole-exome sequencing (WES), few studies have compared the accuracy of WES and Sanger sequencing in routine genetic testing of PAH. PAH individuals were enrolled from Fu Wai Hospital and Shanghai Pulmonary Hospital. WES was used to analyze DNA samples from 120 PAH patients whose bone morphogenetic protein receptor type 2 (BMPR2) mutation statuses had been previously studied using Sanger sequencing. The Sanger sequencing and WES agreement was 98.3% (118/120) with near-perfect agreement (κ coefficient = 0.848). There was no significant difference between the two methods on the McNemar–Bowker test (P > 0.05). Twenty-one BMPR2 mutation carriers and 99 non-carriers were detected by Sanger sequencing. Among the 21 BMPR2 carriers detected by Sanger sequencing, one variant (c.1040 T > A) was not found by WES. Among the 99 BMPR2 non-carriers, WES detected an extra mutation carrier (c.76 + 1 G > C) missed by Sanger sequencing. Both false-positive and false-negative results were highly conserved and were re-analyzed by Sanger sequencing. WES improved the accuracy of Sanger sequencing and detected 1% (1/99) false-positive and 4.8% (1/21) false-negative results of Sanger sequencing. No false-positive and false-negative results of WES were identified in our analysis. WES is non-inferior to Sanger sequencing and may play a more important role in genetic testing of PAH patients in the future.
Speech Perception in Quiet and Noise With an Off the Ear CI Processor Enabling Adaptive Microphone Directionality.

OBJECTIVE To investigate the impact of the wearing position of an off-the-ear-processor (OTE) on speech perception in quiet and noise. PATIENTS The study group consisted of 16 adult subjects with bilateral severe-to-profound sensorineural hearing loss, 2 of them unilaterally, and 14 bilaterally provided with cochlear implants. MAIN OUTCOME MEASURES Speech perception in quiet and noise was measured for frontal presentation with the recipients behind-the-ear processor CP810 or CP910 and the OTE processor Kanso (Cochlear Limited, Sydney, Australia). Additionally, speech performance in noise with the OTE for spatially separated signal and noise sources was assessed. RESULTS The recipients showed monosyllabic word recognition scores in quiet between 65 and 95% and speech reception thresholds in noise between 2.4 and -5.5 dB SNR with the OTE. For frontal presentation of speech and noise, application of the adaptive directional microphone (Beam) yielded a slight median decrement of 0.6 dB for the speech reception threshold compared with standard directionality. However, huge median improvements, ranging from -3.7 to -11.6 dB, for the three tested conditions with spatially separated sources (S0NIL, S0NCL, S0N180) were observed. CONCLUSION The beamforming algorithm in the investigated OTE processor provides similar benefits as described in previous studies for behind-the-ear processors in conditions with spatially separated speech and noise sources. Adaptive microphone directionality can be successfully implemented in an OTE processor. The OTE processor's potential to increase usability, comfort, and cosmetics might not be compromised by a deterioration of speech performance.
Protein leucine content is a determinant of shorter- and longer-term muscle protein synthetic responses at rest and following resistance exercise in healthy older women: a randomized, controlled trial.

Background Older women may not be consuming enough protein to maintain muscle mass. Augmentation of protein intake with leucine may enhance the muscle protein synthetic response in older women to aid in maintaining muscle mass. Objective We measured the acute (hourly) and integrated (daily) myofibrillar protein synthesis (myoPS) response to consumption of a high-quality mixed protein beverage compared with an isonitrogenous protein beverage with added leucine. Design In a parallel design, free-living, healthy older women (aged 65-75 y, n = 11/group) consumed a fixed, weight-maintaining diet with protein at 1.0 g · kg-1 · d-1 and were randomly assigned to twice-daily consumption of either 15 g milk protein beverage containing 4.2 g leucine (LEU) or 15 g mixed protein (milk and soy) beverage containing 1.3 g leucine (CON). Unilateral leg resistance exercise allowed a determination of acute ([13C6]-phenylalanine infusion, hourly rate) and integrated (deuterated water ingestion, daily rate) exercised and rested myoPS responses. Results Acute myoPS increased in response to feeding in the rested (CON: 13% ± 4%; LEU: 53% ± 5%) and exercised (CON: 30% ± 4%; LEU: 87% ± 7%) leg in both groups, but the increase was greater in LEU (P < 0.001). Integrated myoPS increased during the supplementation period in both legs (rested: 9% ±1%; exercised: 17% ± 2%; P < 0.001) in LEU, but in the exercised leg only (7% ± 2%; P < 0.001) in CON. Conclusions A 15-g protein-containing beverage with ∼4 g leucine induced greater increases in acute and integrated myoPS than did an isonitrogenous, isoenergetic mixed-protein beverage. Declines in muscle mass in older women may be attenuated with habitual twice-daily consumption of a protein beverage providing 15 g protein and higher (4.2 g/serving) amounts of leucine. This trial was registered at clinicaltrials.gov as NCT02282566.
miRNA-mRNA Integrated Analysis Reveals Roles for miRNAs in Primary Breast Tumors

Introduction Few studies have performed expression profiling of both miRNA and mRNA from the same primary breast carcinomas. In this study we present and analyze data derived from expression profiling of 799 miRNAs in 101 primary human breast tumors, along with genome-wide mRNA profiles and extensive clinical information. Methods We investigate the relationship between these molecular components, in terms of their correlation with each other and with clinical characteristics. We use a systems biology approach to examine the correlative relationship between miRNA and mRNAs using statistical enrichment methods. Results We identify statistical significant differential expression of miRNAs between molecular intrinsic subtypes, and between samples with different levels of proliferation. Specifically, we point to miRNAs significantly associated with TP53 and ER status. We also show that several cellular processes, such as proliferation, cell adhesion and immune response, are strongly associated with certain miRNAs. We validate the role of miRNAs in regulating proliferation using high-throughput lysate-microarrays on cell lines and point to potential drivers of this process. Conclusion This study provides a comprehensive dataset as well as methods and system-level results that jointly form a basis for further work on understanding the role of miRNA in primary breast cancer.
Methane Output of Tortoises: Its Contribution to Energy Loss Related to Herbivore Body Mass

An increase in body mass (M) is traditionally considered advantageous for herbivores in terms of digestive efficiency. However, recently increasing methane losses with increasing M were described in mammals. To test this pattern in non-mammal herbivores, we conducted feeding trails with 24 tortoises of various species (M range 0.52–180 kg) fed a diet of grass hay ad libitum and salad. Mean daily dry matter and gross energy intake measured over 30 consecutive days scaled to M0.75 (95%CI 0.64–0.87) and M0.77 (95%CI 0.66–0.88), respectively. Methane production was measured over two consecutive days in respiration chambers and scaled to M1.03 (95%CI 0.84–1.22). When expressed as energy loss per gross energy intake, methane losses scaled to 0.70 (95%CI 0.47–1.05) M0.29 (95%CI 0.14–0.45). This scaling overlaps in its confidence intervals to that calculated for nonruminant mammals 0.79 (95%CI 0.63–0.99) M0.15 (95%CI 0.09–0.20), but is lower than that for ruminants. The similarity between nonruminant mammals and tortoises suggest a common evolution of the gut fauna in ectotherms and endotherms, and that the increase in energetic losses due to methane production with increasing body mass is a general allometric principle in herbivores. These findings add evidence to the view that large body size itself does not necessarily convey a digestive advantage.