Miracle-dz/UniFAR-FTUs huggingface dataset:
A marginalized two-part Beta regression model for microbiome compositional data

In microbiome studies, an important goal is to detect differential abundance of microbes across clinical conditions and treatment options. However, the microbiome compositional data (quantified by relative abundance) are highly skewed, bounded in [0, 1), and often have many zeros. A two-part model is commonly used to separate zeros and positive values explicitly by two submodels: a logistic model for the probability of a specie being present in Part I, and a Beta regression model for the relative abundance conditional on the presence of the specie in Part II. However, the regression coefficients in Part II cannot provide a marginal (unconditional) interpretation of covariate effects on the microbial abundance, which is of great interest in many applications. In this paper, we propose a marginalized two-part Beta regression model which captures the zero-inflation and skewness of microbiome data and also allows investigators to examine covariate effects on the marginal (unconditional) mean. We demonstrate its practical performance using simulation studies and apply the model to a real metagenomic dataset on mouse skin microbiota. We find that under the proposed marginalized model, without loss in power, the likelihood ratio test performs better in controlling the type I error than those under conventional methods.
Fast random pair divisive construction of kNN graph using generic distance measures

We introduce a fast hierarchical method algorithm to construct an approximate kNN-graph. The method is simple to implement and generic, as it works with any type of data for which a symmetric distance function can be provided. We tested the method with text data of 466, 544 English words and an image dataset with one million features. Compared to the O(N2) brute force, the method achieves 140:1 speed-up ratio, on average, and is about twice as fast as the previous state-of-the-art.
An In Vitro Model of Hematotoxicity: Differentiation of Bone Marrow–Derived Stem/Progenitor Cells into Hematopoietic Lineages and Evaluation of Lineage‐Specific Hematotoxicity

Hematotoxicity is a significant issue for drug safety and can result from direct cytotoxicity toward circulating mature blood cell types as well as targeting of immature blood‐forming stem cells/progenitor cells in the bone marrow. In vitro models for understanding and investigating the hematotoxicity potential of new test items/drugs are critical in early preclinical drug development. The traditional method, colony forming unit (CFU) assay, is commonly used and has been validated as a method for hematotoxicity screening. The CFU assay has multiple limitations for its application in investigative work. In this paper, we describe a detailed protocol for a liquid‐culture, microplate‐based in vitro hematotoxicity assay to evaluate lineage‐specific (myeloid, erythroid, and megakaryocytic) hematotoxicity at different stages of differentiation. This assay has multiple advantages over the traditional CFU assay, including being suitable for high‐throughput screening and flexible enough to allow inclusion of additional endpoints for mechanistic studies. Therefore, it is an extremely useful tool for scientists in pharmaceutical discovery and development. © 2018 by John Wiley & Sons, Inc.
Roles of fibronectin isoforms in neonatal vascular development and matrix integrity

Fibronectin (FN) exists in two forms—plasma FN (pFN) and cellular FN (cFN). Although the role of FN in embryonic blood vessel development is well established, its function and the contribution of individual isoforms in early postnatal vascular development are poorly understood. Here, we employed a tamoxifen-dependent cFN inducible knockout (cFN iKO) mouse model to study the consequences of postnatal cFN deletion in smooth muscle cells (SMCs), the major cell type in the vascular wall. Deletion of cFN influences collagen deposition but does not affect life span. Unexpectedly, pFN translocated to the aortic wall in the cFN iKO and in control mice, possibly rescuing the loss of cFN. Postnatal pFN deletion did not show a histological aortic phenotype. Double knockout (dKO) mice lacking both, cFN in SMCs and pFN, resulted in postnatal lethality. These data demonstrate a safeguard role of pFN in vascular stability and the dispensability of the individual FN isoforms in postnatal vascular development. Complete absence of FNs in the dKOs resulted in a disorganized tunica media of the aortic wall. Matrix analysis revealed common and differential roles of the FN isoforms in guiding the assembly/deposition of elastogenic extracellular matrix (ECM) proteins in the aortic wall. In addition, we determined with two cell culture models that that the two FN isoforms acted similarly in supporting matrix formation with a greater contribution from cFN. Together, these data show that pFN exerts a critical role in safeguarding vascular organization and health, and that the two FN isoforms function in an overlapping as well as distinct manner to maintain postnatal vascular matrix integrity.
Indirect Effect of Hopelessness on Depression Symptoms Through Perceived Burdensomeness

Hopelessness theory of depression posits that hopelessness due to negative inferences may serve as a proximal and sufficient cause of depression, while interpersonal theories suggest that interpersonal stress resulting from relationship problems and social rejection may lead to symptoms of depression. We propose that the two perspectives can be integrated by examining a model in which hopelessness predicts depression symptoms through two specific interpersonal stress constructs, thwarted belongingness and perceived burdensomeness, in a sample of university students from Macau (N = 350). Results of mediation analysis revealed a significant indirect effect of hopelessness on depression symptoms through perceived burdensomeness (indirect effect = .45; 95% confidence interval = .28 to .65), but not thwarted belongingness (indirect effect = .06; 95% confidence interval = −.05 to .18). Alternative models were also tested. When each interpersonal construct was treated as a separate mediator without controlling for the other, significant indirect effects of both perceived burdensomeness and thwarted belongingness were found. Moreover, when hopelessness was assigned as the mediator and interpersonal constructs as independent variables, significant indirect effects were likewise found for perceived burdensomeness and thwarted belongingness. Findings suggest that the two different yet compatible views about depression—hopelessness and interpersonal theories—may be integrated to provide a better understanding of the process of how depression symptoms occur. It also reinforces the importance of considering interpersonal factors in the study of depression, especially in societies where interpersonal relationships are highly valued.
PLINK: Key Functions for Data Analysis

Genetic data analysis of large numbers of single nucleotide variants (SNVs), including genome‐wide association studies (GWAS), exome chips, and whole exome (WES) or whole‐genome (WGS) sequencing data, requires well defined processing steps. As a result, several freely available analytic toolkits have been developed to streamline these processes. Among these, PLINK is the most comprehensive in terms of its quality control and analytic modules, although its focus remains on SNVs. PLINK fulfills two analytic needs—aiding the process of performing quality control (QC) on large data sets and providing basic statistical tools to analyze the variants in genetic models. The current version of PLINK (v1.90b) has incorporated several sophisticated statistical modeling features, such as those that were introduced by GCTA (genome‐wide complex trait analysis), including mixed‐model association analysis and cluster‐based algorithms. Although PLINK is diverse in its applicability to data management and analysis, in some instances, other available tools offer more optimal options. Here we provide a practical overview of major PLINK features with respect to QC, data management, and association mapping, along with learned shortcuts and limitations to be considered. In cases where PLINK features are limited, we provide alternative approaches using additional freely available pipelines. © 2018 by John Wiley & Sons, Inc.
The Polycystic Ovary Syndrome Quality of Life scale (PCOSQOL): Development and preliminary validation

Polycystic ovary syndrome is an endocrine disorder amongst women, which can negatively impact quality of life. Research proposes that a more sensitive PCOS quality of life measure is needed. This study aims to develop and initially validate a quality of life scale for women with the condition in the United Kingdom. Women with PCOS (n = 714) took part in the development and initial validation of the 35-item polycystic ovary syndrome quality of life scale (PCOSQOL)(α = .95). Subscales include Impact of PCOS (α = .95), Infertility (α = .95), Hirsutism (α = .97) and Mood (α = .89). The PCOSQOL scale represents aspects of quality of life important to women with PCOS and may be more sensitive for use in the clinical and research settings.
Switching of the folding-energy landscape governs the allosteric activation of protein kinase A

Significance Mutations, deletions, or gene fusions in protein kinases have been associated with the development of many diseases in humans and have led to the emergence of the protein kinase family as an important therapeutic drug target. In the cell, kinase activity is often turned on and off allosterically by intramolecular regulatory domains, flexible linkers, or other interacting proteins. Here, we use single-molecule optical tweezers to investigate the mechanism of allosteric regulation of the cAMP-dependent PKA. This approach allowed us to determine the thermodynamic driving forces that enable PKA to transduce cAMP-binding signals to turn on its kinase activity. Protein kinases are dynamic molecular switches that sample multiple conformational states. The regulatory subunit of PKA harbors two cAMP-binding domains [cyclic nucleotide-binding (CNB) domains] that oscillate between inactive and active conformations dependent on cAMP binding. The cooperative binding of cAMP to the CNB domains activates an allosteric interaction network that enables PKA to progress from the inactive to active conformation, unleashing the activity of the catalytic subunit. Despite its importance in the regulation of many biological processes, the molecular mechanism responsible for the observed cooperativity during the activation of PKA remains unclear. Here, we use optical tweezers to probe the folding cooperativity and energetics of domain communication between the cAMP-binding domains in the apo state and bound to the catalytic subunit. Our study provides direct evidence of a switch in the folding-energy landscape of the two CNB domains from energetically independent in the apo state to highly cooperative and energetically coupled in the presence of the catalytic subunit. Moreover, we show that destabilizing mutational effects in one CNB domain efficiently propagate to the other and decrease the folding cooperativity between them. Taken together, our results provide a thermodynamic foundation for the conformational plasticity that enables protein kinases to adapt and respond to signaling molecules.
Femtosecond Laser-Based Modification of PDMS to Electrically Conductive Silicon Carbide

In this paper, we experimentally demonstrate femtosecond laser direct writing of conductive structures on the surface of native polydimethylsiloxane (PDMS). Irradiation of femtosecond laser pulses modified the PDMS to black structures, which exhibit electrical conductivity. Fourier-transform infrared (FTIR) and X-ray diffraction (XRD) results show that the black structures were composed of β-silicon carbide (β-SiC), which can be attributed to the pyrolysis of the PDMS. The electrical conductivity was exhibited in limited laser power and scanning speed conditions. The technique we present enables the spatially selective formation of β-SiC on the surface of native PDMS only by irradiation of femtosecond laser pulses. Furthermore, this technique has the potential to open a novel route to simply fabricate flexible/stretchable MEMS devices with SiC microstructures.
Prospective Cohort Study of the Tolerability of Prosthetic Joint Infection Empirical Antimicrobial Therapy

The empirical use of vancomycin in combination with a broad-spectrum beta-lactam is currently recommended after the initial surgery of prosthetic joint infection (PJI). However, the tolerability of such high-dose intravenous regimens is poorly known. ABSTRACT The empirical use of vancomycin in combination with a broad-spectrum beta-lactam is currently recommended after the initial surgery of prosthetic joint infection (PJI). However, the tolerability of such high-dose intravenous regimens is poorly known. Adult patients receiving an empirical antimicrobial therapy (EAT) for a PJI were enrolled in a prospective cohort study (2011 to 2016). EAT-related adverse events (AE) were described according to the common terminology criteria for AE (CTCAE), and their determinants were assessed by logistic regression and Kaplan-Meier curve analysis. The EAT of the 333 included patients (median age, 69.8 years; interquartile range [IQR], 59.3 to 79.1 years) mostly relies on vancomycin (n = 229, 68.8%), piperacillin-tazobactam (n = 131, 39.3%), and/or third-generation cephalosporins (n = 50, 15%). Forty-two patients (12.6%) experienced an EAT-related AE. Ten (20.4%) AE were severe (CTCAE grade ≥ 3). The use of vancomycin (odds ratio [OR], 6.9; 95% confidence interval [95%CI], 2.1 to 22.9), piperacillin-tazobactam (OR, 3.7; 95%CI, 1.8 to 7.2), or the combination of both (OR, 4.1; 95%CI, 2.1 to 8.2) were the only AE predictors. Acute kidney injury (AKI) was the most common AE (n = 25; 51.0% of AE) and was also associated with the use of the vancomycin and piperacillin-tazobactam combination (OR, 6.7; 95%CI, 2.6 to 17.3). A vancomycin plasma overexposure was noted in nine (37.5%) of the vancomycin-related AKIs only. Other vancomycin-based therapies were significantly less at risk for AE and AKI. The EAT of PJI is associated with an important rate of AE, linked with the use of the vancomycin and the piperacillin-tazobactam combination. These results corroborate recent findings suggesting a synergic toxicity of these drugs in comparison to vancomycin-cefepime, which remains to be evaluated in PJI. (This study has been registered at ClinicalTrials.gov under identifier NCT03010293.)
Dissecting recipient from donor contribution in experimental kidney transplantation: focus on endothelial proliferation and inflammation

ABSTRACT Kidney transplantation (Tx) is considered the only definite treatment for end-stage kidney disease (ESKD) patients. The increasing prevalence of ESKD has necessitated the introduction of transplantation with kidneys from suboptimal donors. There is, however, still a lack of fundamental and longitudinal research on suboptimal kidney transplants. Specifically, there is a demand for accurate pre-Tx predictors of donor kidney function and injury to predict post-Tx outcome. In the present study, we combine rat models of chronic kidney disease (CKD) and renal Tx to dissect the effects of healthy and CKD renal grafts on healthy and CKD recipients. We show that renal function at 6 weeks post-Tx is exclusively determined by donor graft quality. Using cell tracking within enhanced green fluorescent protein-positive (eGFP+) recipients, we furthermore show that most inflammatory cells within the donor kidney originate from the donor. Oxidative and vascular extra-renal damage were, in contrast, determined by the recipient. Post- versus pre-Tx evaluation of grafts showed an increase in glomerular and peritubular capillary rarefaction in healthy but not CKD grafts within a CKD environment. Proliferation of glomerular endothelium was similar in all groups, and influx of eGFP+ recipient-derived cells occurred irrespective of graft or recipient status. Glomerular and peritubular capillary rarefaction, severity of inflammation and macrophage subtype data post-Tx were, however, determined by more complicated effects, warranting further study. Our experimental model could help to further distinguish graft from recipient environment effects, leading to new strategies to improve graft survival of suboptimal Tx kidneys. This article has an associated First Person interview with the first author of the paper. Summary: Using experimental kidney transplantation, we dissected donor graft from recipient environment effects, focusing on the endothelium and inflammation. These results can direct strategies to improve graft survival after suboptimal transplantation.
Evaluation of the Effectiveness and Safety of Olanzapine as an Adjunctive Treatment for Anorexia Nervosa in Adolescents: An Open-Label Trial.

Objectives To evaluate the effectiveness and safety of adjunctive olanzapine treatment for low weight adolescents with anorexia nervosa (AN). Methods A non-randomized open-label trial was conducted between 2010 and 2014. Participants received standard treatment and were invited to take olanzapine at study enrollment. Participants could accept, continue, or discontinue olanzapine as treatment progressed. Weight and psychological outcomes were monitored. Results Of 239 adolescents assessed, 65 met inclusion criteria, 38 enrolled in the study, and 32 were retained for analysis. Twenty-two participants took olanzapine (medication group) and ten participants did not (comparison group). Participants in the medication group demonstrated a higher rate of weight gain compared to those who did not receive olanzapine (p = .012). No serious adverse events were noted, although seven participants (31.8%) discontinued olanzapine due to a side effect. Conclusion Preliminary results suggest that olanzapine may help facilitate weight gain in adolescents with AN. The importance of medical monitoring over the course of treatment is discussed. Evaluation of the Efficacy and Safety of Olanzapine for Anorexia Nervosa in Children and Adolescents; http://clinicaltrials.gov; NCT01184443.
Random Sampling Applied to the MST Problem in the Node Congested Clique Model

The Congested Clique model, proposed by Lotker et al. [SPAA'03, SICOMP'05], was introduced in order to provide a simple abstraction for overlay networks. Congested Clique is a model of distributed (or parallel) computing, in which there are $n$ players (nodes) with unique identifiers from set {1, . , n}, which perform computations in synchronous rounds. Each round consists of the phase of unlimited local computation and the communication phase. While communicating, each pair of nodes is allowed to exchange a single message of size $\mathcal{O}(\log n)$ bits. Since, in a single round, each player can communicate with even $\Theta(n)$ other players, the model seems to be to powerful to imitate bandwidth restriction emerging from the underlying network. In this paper we study a restricted version of the Congested Clique model, the Node Congested Clique model, proposed by Augustine et al. [arxiv1805]. The additional restriction is that in a single communication phase, a player is allowed to send / receive only $\mathcal{O}(\log n)$ messages. In this paper, we provide communication primitives that improve the round complexity of the MST (Minimum Spanning Tree) algorithm by Augustine et al. [arxiv1805] to $\mathcal{O}(\log^3 n)$ rounds. Moreover, we propose a different approach to this problem that requires only $\mathcal{O}(\log^3 n / \log \log n)$ rounds, and has smaller dependence on the weights of the edges. Besides the faster MST algorithm, we consider the key contributions to be: - an efficient implementation of some basic protocols, - a tighter analysis of a special case of the sampling approach by Karger, Klein and Tarjan [JACM'95] (and related results by Pemmaraju and Sardeshmukh [FSTTCS'16]), - an application of sparse recovery techniques going slightly beyond the standard usage of linear graph sketching by Ahn, Guha and McGregor [SODA'12]
Time Course of Recovery From Resistance Exercise With Different Set Configurations.

Pareja-Blanco, F, Rodríguez-Rosell, D, Aagaard, P, Sánchez-Medina, L, Ribas-Serna, J, Mora-Custodio, R, Otero-Esquina, C, Yáñez-García, JM, and González-Badillo, JJ. Time course of recovery from resistance exercise with different set configurations. J Strength Cond Res XX(X): 000-000, 2018-This study analyzed the response to 10 resistance exercise protocols differing in the number of repetitions performed in each set (R) with respect to the maximum predicted number (P). Ten males performed 10 protocols (R(P): 6(12), 12(12), 5(10), 10(10), 4(8), 8(8), 3(6), 6(6), 2(4), and 4(4)). Three sets with 5-minute interset rests were performed in each protocol in bench press and squat. Mechanical muscle function (countermovement jump height and velocity against a 1 m·s load, V1-load) and biochemical plasma profile (testosterone, cortisol, growth hormone, prolactin, IGF-1, and creatine kinase) were assessed at several time points from 24-hour pre-exercise to 48-hour post-exercise. Protocols to failure, especially those in which the number of repetitions performed was high, resulted in larger reductions in mechanical muscle function, which remained reduced up to 48-hour post-exercise. Protocols to failure also showed greater increments in plasma growth hormone, IGF-1, prolactin, and creatine kinase concentrations. In conclusion, resistance exercise to failure resulted in greater fatigue accumulation and slower rates of neuromuscular recovery, as well as higher hormonal responses and greater muscle damage, especially when the maximal number of repetitions in the set was high.
Standardized reporting of the costs of management interventions for biodiversity conservation

Effective conservation management interventions must combat threats and deliver benefits at costs that can be achieved within limited budgets. Considerable effort has focused on measuring the potential benefits of conservation interventions, but explicit quantification of the financial costs of implementation is rare. Even when costs have been quantified, haphazard and inconsistent reporting means published values are difficult to interpret. This reporting deficiency hinders progress toward a collective understanding of the financial costs of management interventions across projects and thus limits the ability to identify efficient solutions to conservation problems or attract adequate funding. We devised a standardized approach to describing financial costs reported for conservation interventions. The standards call for researchers and practitioners to describe the objective and outcome, context and methods, and scale of costed interventions, and to state which categories of costs are included and the currency and date for reported costs. These standards aim to provide enough contextual information that readers and future users can interpret the cost data appropriately. We suggest these standards be adopted by major conservation organizations, conservation science institutions, and journals so that cost reporting is comparable among studies. This would support shared learning and enhance the ability to identify and perform cost‐effective conservation.