Miracle-dz/UniFAR-FTUs huggingface dataset:
Mutant p53 targeting by the low molecular weight compound STIMA‐1

H1299 and H1299-His175 cells were seeded in six-well plates with glass slides, 200 000 cells per well. The next day, cells were treated with 2 lM STIMA-1. After 24-h treatment, cells were washed twice in PBS, fixed for 10 min at room temperature with 4% paraformaldehyde (PFA), permeabilized for 2 min in 0.2% Triton in PBS and washed 3 x 5 min in PBS. Anti-Bax antibody SC6236 (Santa Cruz, CA) was diluted 200 times in 2% BSA and incubated with the slides for 2 h at room temperature. After washing 3 9 10 min with PBS, slides were incubated with Alexa Fluor 594 goat anti-rabbit Ig antibody (Invitrogen/Thermo Fisher Scientific, Sweden), diluted 500 times in 2% BSA, for 1 h, then washed 3 9 10 min in PBS and mounted with Vectashield hard set with DAPI (Vector Laboratories, CA). Images were obtained with a Zeiss Axioplan 2 microscope with an AxioCam HRm Camera.
An Empirical Model of the Medical Match

This paper develops a framework for estimating preferences in a many-to-one matching market using only observed matches. I use pairwise stability and a vertical preference restriction on one side to identify preferences on both sides of the market. Counterfactual simulations are used to analyze the antitrust allegation that the centralized medical residency match is responsible for salary depression. Due to residents' willingness to pay for desirable programs and capacity constraints, salaries in any competitive equilibrium would remain, on average, at least $23,000 below the marginal product of labor. Therefore, the match is not the likely cause of low salaries.
The Mitochondrial Ca2+ Uniporter MCU Is Essential for Glucose-Induced ATP Increases in Pancreatic β-Cells

Glucose induces insulin release from pancreatic β-cells by stimulating ATP synthesis, membrane depolarisation and Ca2+ influx. As well as activating ATP-consuming processes, cytosolic Ca2+ increases may also potentiate mitochondrial ATP synthesis. Until recently, the ability to study the role of mitochondrial Ca2+ transport in glucose-stimulated insulin secretion has been hindered by the absence of suitable approaches either to suppress Ca2+ uptake into these organelles, or to examine the impact on β-cell excitability. Here, we have combined patch-clamp electrophysiology with simultaneous real-time imaging of compartmentalised changes in Ca2+ and ATP/ADP ratio in single primary mouse β-cells, using recombinant targeted (Pericam or Perceval, respectively) as well as entrapped intracellular (Fura-Red), probes. Through shRNA-mediated silencing we show that the recently-identified mitochondrial Ca2+ uniporter, MCU, is required for depolarisation-induced mitochondrial Ca2+ increases, and for a sustained increase in cytosolic ATP/ADP ratio. By contrast, silencing of the mitochondrial Na+-Ca2+ exchanger NCLX affected the kinetics of glucose-induced changes in, but not steady state values of, cytosolic ATP/ADP. Exposure to gluco-lipotoxic conditions delayed both mitochondrial Ca2+ uptake and cytosolic ATP/ADP ratio increases without affecting the expression of either gene. Mitochondrial Ca2+ accumulation, mediated by MCU and modulated by NCLX, is thus required for normal glucose sensing by pancreatic β-cells, and becomes defective in conditions mimicking the diabetic milieu.
Epothilones in epithelial ovarian, fallopian tube, or primary peritoneal cancer: a systematic review

Ovarian cancer is the most lethal gynecologic malignancy; consequently, there is a need for effective therapies. Epothilones are microtubule-stabilizing agents that inhibit cell growth. Currently, patupilone and its four synthetic derivatives ixabepilone, BMS-310705, sagopilone, 20-desmethyl-20-methylsulfanyl epothilone B and epothilone D, as well as its derivative KOS-1584, are under clinical evaluation. This is the first systematic review conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines that synthesizes all available data emerging from trials and evaluates the efficacy and safety of epothilones in epithelial ovarian, primary fallopian tube, and primary peritoneal cancer. Despite the fact that epothilones have proven active in taxane-resistant settings in preclinical models, it is not yet clear from Phase II/III studies reviewed here that their clinical activity is superior to that of taxanes. Nevertheless, responses to epothilones have been observed in platinum-refractory/resistant ovarian cancer patients. Moreover, despite the shared mechanism of action of epothilones, their clinical profile seems clearly different, with diarrhea being the most common dose-limiting toxicity encountered with patupilone, whereas neutropenia and sensory neuropathy are the most common toxic effects observed with the other epothilones. In any case, randomized trials comparing epothilones with standard treatments seem warranted to define further the role of these agents, whereas biomarker analysis might further optimize patient selection.
Standardized Mixed-Meal Tolerance and Arginine Stimulation Tests Provide Reproducible and Complementary Measures of β-Cell Function: Results From the Foundation for the National Institutes of Health Biomarkers Consortium Investigative Series

OBJECTIVE Standardized, reproducible, and feasible quantification of β-cell function (BCF) is necessary for the evaluation of interventions to improve insulin secretion and important for comparison across studies. We therefore characterized the responses to, and reproducibility of, standardized methods of in vivo BCF across different glucose tolerance states. RESEARCH DESIGN AND METHODS Participants classified as having normal glucose tolerance (NGT; n = 23), prediabetes (PDM; n = 17), and type 2 diabetes mellitus (T2DM; n = 22) underwent two standardized mixed-meal tolerance tests (MMTT) and two standardized arginine stimulation tests (AST) in a test-retest paradigm and one frequently sampled intravenous glucose tolerance test (FSIGT). RESULTS From the MMTT, insulin secretion in T2DM was >86% lower compared with NGT or PDM (P < 0.001). Insulin sensitivity (Si) decreased from NGT to PDM (∼50%) to T2DM (93% lower [P < 0.001]). In the AST, insulin secretory response to arginine at basal glucose and during hyperglycemia was lower in T2DM compared with NGT and PDM (>58%; all P < 0.001). FSIGT showed decreases in both insulin secretion and Si across populations (P < 0.001), although Si did not differ significantly between PDM and T2DM populations. Reproducibility was generally good for the MMTT, with intraclass correlation coefficients (ICCs) ranging from ∼0.3 to ∼0.8 depending on population and variable. Reproducibility for the AST was very good, with ICC values >0.8 across all variables and populations. CONCLUSIONS Standardized MMTT and AST provide reproducible and complementary measures of BCF with characteristics favorable for longitudinal interventional trials use.
The Evolution of Thinking About Poverty: Exploring the Interactions

This paper considers the evolution ofthinking about poverty since Rowntree's classic study ofpoverty in England at the turn ofthe last century. It highlights the progressive broadening ofthe definition and measurement ofpoverty, from command over market-purchased goods (income) to other dimensions ofliving standards such as longevity, literacy and healthiness, and , most recently, to concerns with risk and vulnerability, and powerlessness and lack ofvoice. The paper argues that while there is a correlation between these different dimensions, this broadening changes significantly our thinking about strategies to reduce poverty. A broader definition expands the set ofpolicies that are relevant to the reduction of poverty. But the broadening also emphasizes that poverty reducing strategies must recognize the interactions among the policies--the impact of appropriately designed combinations will be greater than the sum ofthe individual parts.
Influence of Polymorphism in the Genes for the Interleukin (IL)-1 Receptor Antagonist and IL-1β on Tuberculosis

Several lines of evidence suggest that host genetic factors controlling the immune response influence infection by Mycobacterium tuberculosis. The proinflammatory cytokine interleukin (IL)-1β and its antagonist, IL-1Ra (IL-1 receptor agonist), are strongly induced by M. tuberculosis and are encoded by polymorphic genes. The induction of both IL-1Ra mRNA and secreted protein by M. tuberculosis in IL-1Ra allele A2–positive (IL-1Ra A2+) healthy subjects was 1.9-fold higher than in IL-1Ra A2− subjects. The M. tuberculosis–induced expression of mRNA for IL-1β was higher in subjects of the IL-1β (+3953) A1+ haplotype (P = 0.04). The molar ratio of IL-1Ra/IL-1β induced by M. tuberculosis was markedly higher in IL-1Ra A2+ individuals (P < 0.05), with minor overlap between the groups, reflecting linkage between the IL-1Ra A2 and IL-1β (+3953) A2 alleles. In M. tuberculosis–stimulated peripheral blood mononuclear cells, the addition of IL-4 increased IL-1Ra secretion, whereas interferon γ increased and IL-10 decreased IL-1β production, indicative of a differential influence on the IL-1Ra/IL-1β ratio by cytokines. In a study of 114 healthy purified protein derivative–reactive subjects and 89 patients with tuberculosis, the frequency of allelic variants at two positions (−511 and +3953) in the IL-1β and IL-1Ra genes did not differ between the groups. However, the proinflammatory IL-1Ra A2−/IL-1β (+3953) A1+ haplotype was unevenly distributed, being more common in patients with tuberculous pleurisy (92%) in comparison with healthy M. tuberculosis–sensitized control subjects or patients with other disease forms (57%, P = 0.028 and 56%, P = 0.024, respectively). Furthermore, the IL-1Ra A2+ haplotype was associated with a reduced Mantoux response to purified protein derivative of M. tuberculosis: 60% of tuberculin-nonreactive patients were of this type. Thus, the polymorphism at the IL-1 locus influences the cytokine response and may be a determinant of delayed-type hypersensitivity and disease expression in human tuberculosis.
Rab3A Inhibition of Ca2+‐Dependent Dopamine Release From PC12 Cells Involves Interaction With Synaptotagmin I

Rab3 and synaptotagmin have been suggested to play important roles in the regulation of neurotransmitter release and, however, the molecular mechanism has not been completely clear. Here, we studied the effects of Rab3A and synaptotagmin I (Syt I) on dopamine release using PC12 cells as a model system. Rab3A was demonstrated to have effects on both Ca2+‐independent and Ca2+‐dependent dopamine releases from the PC12 cells. Application of Rab3A (up to 2500 nM) gradually decreased the amount of Ca2+‐dependently released dopamine, indicating that Rab3A is a negative modulator that was further supported by the increase in dopamine release caused by Rab3A knockdown. Syt I knockdown weakened the Ca2+‐dependent dopamine release, suggesting that Syt I plays a positive regulatory role in the cellular process. Treatment of the Syt I‐knocked down PC12 cells with Rab3A further decreased Ca2+‐dependent dopamine release and, however, the decrease magnitude was significantly reduced compared with that before Syt I knockdown, thus for the first time demonstrating that the inhibitory effect of Rab3A on Ca2+‐dependent dopamine release involves the interaction with Syt I. This work has shed new light on the molecular mechanism for Rab3 and synaptotamin regulation of neurotransmitter release. J. Cell. Biochem. 118: 3696–3705, 2017. © 2017 Wiley Periodicals, Inc.
Handling missing data in propensity score estimation in comparative effectiveness evaluations: a systematic review

Aim Even though systematic reviews have examined how aspects of propensity score methods are used, none has reviewed how the challenge of missing data is addressed with these methods. This review there-fore describes how missing data are addressed with propensity score methods in observational comparative effectiveness studies. Methods Published articles on observational comparative effectiveness studies were extracted from MEDLINE and EMBASE databases. Results Our search yielded 167 eligible articles. Majority of these studies (114; 68%) conducted complete case analysis with only 53 of them stating this in the methods. Only 16 articles reported use of multiple imputation. Conclusion Few researchers use correct methods for handling missing data or reported missing data methodology which may lead to reporting biased findings.
Is physical activity a cause of longevity? It is not as straightforward as some would believe. A critical analysis

There are discrepant findings between (A) observational follow-ups and (B) interventional studies that investigate possible causal association between high physical activity and low mortality. Participation in vigorous physical activity at a specific time-point is an indicator of good fitness and health, and is associated with a reduced risk of death. However, neither randomised controlled trials nor experimental animal studies have provided conclusive evidence to show that physical activity started during adulthood extends lifespan. Consequently, the undisputed health-related benefits of exercise have yet to translate into any proven causal relationship with longevity. Physical activity improves fitness and physical function, and confers other health-related effects. These outcomes have a greater basis in evidence-based data than any claims of a reduced risk of death, especially when recommending physical activity for previously physically inactive middle-aged and elderly adults.
Cellular and Molecular Properties of Neurons Systems-based analysis of dendritic nonlinearities reveals temporal feature extraction in mouse L 5 cortical neurons

Kalmbach BE, Gray R, Johnston D, Cook EP. Systems-based analysis of dendritic nonlinearities reveals temporal feature extraction in mouse L5 cortical neurons. J Neurophysiol 117: 2188–2208, 2017. First published March 1, 2017; doi:10.1152/jn.00951. 2016. —What do dendritic nonlinearities tell a neuron about signals injected into the dendrite? Linear and nonlinear dendritic components affect how time-varying inputs are transformed into action potentials (APs), but the relative contribution of each component is unclear. We developed a novel systems-identification approach to isolate the nonlinear response of layer 5 pyramidal neuron dendrites in mouse prefrontal cortex in response to dendritic current injections. We then quantified the nonlinear component and its effect on the soma, using functional models composed of linear filters and static nonlinearities. Both noise and waveform current injections revealed linear and nonlinear components in the dendritic response. The nonlinear component consisted of fast Na spikes that varied in amplitude 10-fold in a single neuron. A functional model reproduced the timing and amplitude of the dendritic spikes and revealed that they were selective to a preferred input dynamic (~4.5 ms rise time). The selectivity of the dendritic spikes became wider in the presence of additive noise, which was also predicted by the functional model. A second functional model revealed that the dendritic spikes were weakly boosted before being linearly integrated at the soma. For both our noise and waveform dendritic input, somatic APs were dependent on the somatic integration of the stimulus, followed a subset of large dendritic spikes, and were selective to the same input dynamics preferred by the dendrites. Our results suggest that the amplitude of fast dendritic spikes conveys information about high-frequency features in the dendritic input, which is then combined with low-frequency somatic integration.
Polymer-Bioglass Composite Coatings: A Promising Alternative For Advanced Biomedical Implants

Human bone can easily regenerate in normal conditions, so in case of fractures some support devices are used to take the load from the new forming bone. However, in case of diseases, ageing and large traumas, the bone has to be helped to regenerate. Usually, large bone defects are filled with natural material from a donor site from the same patient (‘‘autografting”). Unfortunately the transplantable bone is limited and the procedure requires the extension of the operating site (Lahav et al., 2006). The concept of an artificial device able to help human parts to regenerate or to replace entirely one of the body functions, stimulated numerous research teams around the globe to test materials and combinations of materials aiming towards the “holly grail” of biocompatibility: the biomimetism. There are evidences that prove early tests on bone repair using metal parts, dating from antiquity (Bliquez, 1996). Up to present time, metals have been the elements of choice for manufacturing implants or prostheses in various shapes and dimensions. Tests and clinic reports have all agreed in time, that the best metal for such devices is Ti (Emsley, 2001). It is bio tolerated by the human body and it has a low density and mechanical properties that do not negatively affect the bone (Oshida, 2006). Orthopedics as a medicine branch does not consider bio tolerated devices as satisfactory. The general aim of an orthopedic device is to stimulate the bone to regenerate, in other words it has to be bioactive. Ceramic materials made of calcium phosphates (CaP) in various formulas, pure or doped have been extensively studied in literature for their resemblance to the mineral part of the bone (Leon & Jansen, 2010). Because ceramics brittle when submitted to high tensions, devices made completely out of these materials are not convenient. The common consensus is to use for the bulk implant metals as main components, covered by a very thin and adherent ceramic layer, thus making the surface bioactive (Park, 2008). This chapter is dedicated to bioactive glasses (BG), “intelligent materials” superior in bioactivity to CaP, made of various metal oxide combinations. They change their composition in vivo after prolonged contact with body fluids, transforming in an equivalent of the mineral bone (Hench & Wilson, 1993).
CADMIUM AND ZINC BIOAVAILABILITY TO SELENASTRUM CAPRICORNUTUM (CHLOROPHYCEAE): ACCIDENTAL METAL UPTAKE AND TOXICITY IN THE PRESENCE OF CITRATE

Toxicities of cadmium (Cd) and zinc (Zn) to the green alga Selenastrum capricornutum Printz were determined over 72 h in defined synthetic media buffered by citrate (FRAQCIT ; [citrate] = 100 μM or 5 μM) or nitrilotriacetate (FRAQNTA ; [NTA] = 5 μM). Algal sensitivity to free Cd2+ or free Zn2+ in FRAQCIT was much higher than in FRAQNTA. In parallel experiments, short‐term intracellular uptake of radiolabeled 109Cd was measured as a function of time (0–30 min) in FRAQCIT and FRAQNTA; for a given free Cd2+ concentration (8, 250, or 610 nM), intracellular accumulation of Cd was consistently higher in FRAQCIT than in FRAQNTA. Under the same conditions, the alga accumulated 14C‐labeled citrate almost linearly over a 2‐h period. Loss of 109Cd from algal cells that had been prelabeled with the radionuclide occurred slowly, and the loss rate was insensitive to the presence or absence of citrate, indicating that the overall permeability of the algal membrane to Cd was unaffected by citrate. The enhanced bioavailability of Cd in the presence of citrate could be explained by membrane transport of a charged Cd–citrate complex, presumably by accidental transport.
A large-scale study of the ultrawideband microwave dielectric properties of normal breast tissue obtained from reduction surgeries

The efficacy of emerging microwave breast cancer detection and treatment techniques will depend, in part, on the dielectric properties of normal breast tissue. However, knowledge of these properties at microwave frequencies has been limited due to gaps and discrepancies in previously reported small-scale studies. To address these issues, we experimentally characterized the wideband microwave-frequency dielectric properties of a large number of normal breast tissue samples obtained from breast reduction surgeries at the University of Wisconsin and University of Calgary hospitals. The dielectric spectroscopy measurements were conducted from 0.5 to 20 GHz using a precision open-ended coaxial probe. The tissue composition within the probe's sensing region was quantified in terms of percentages of adipose, fibroconnective and glandular tissues. We fit a one-pole Cole–Cole model to the complex permittivity data set obtained for each sample and determined median Cole–Cole parameters for three groups of normal breast tissues, categorized by adipose tissue content (0–30%, 31–84% and 85–100%). Our analysis of the dielectric properties data for 354 tissue samples reveals that there is a large variation in the dielectric properties of normal breast tissue due to substantial tissue heterogeneity. We observed no statistically significant difference between the within-patient and between-patient variability in the dielectric properties.
Lack of Evidence from Studies of Soluble Protein Fragments that Knops Blood Group Polymorphisms in Complement Receptor-Type 1 Are Driven by Malaria

Complement receptor-type 1 (CR1, CD35) is the immune-adherence receptor, a complement regulator, and an erythroid receptor for Plasmodium falciparum during merozoite invasion and subsequent rosette formation involving parasitized and non-infected erythrocytes. The non-uniform geographical distribution of Knops blood group CR1 alleles Sl1/2 and McCa/b may result from selective pressures exerted by differential exposure to infectious hazards. Here, four variant short recombinant versions of CR1 were produced and analyzed, focusing on complement control protein modules (CCPs) 15–25 of its ectodomain. These eleven modules encompass a region (CCPs 15–17) key to rosetting, opsonin recognition and complement regulation, as well as the Knops blood group polymorphisms in CCPs 24–25. All four CR1 15–25 variants were monomeric and had similar axial ratios. Modules 21 and 22, despite their double-length inter-modular linker, did not lie side-by-side so as to stabilize a bent-back architecture that would facilitate cooperation between key functional modules and Knops blood group antigens. Indeed, the four CR1 15–25 variants had virtually indistinguishable affinities for immobilized complement fragments C3b (K D = 0.8–1.1 µM) and C4b (K D = 5.0–5.3 µM). They were all equally good co-factors for factor I-catalysed cleavage of C3b and C4b, and they bound equally within a narrow affinity range, to immobilized C1q. No differences between the variants were observed in assays for inhibition of erythrocyte invasion by P. falciparum or for rosette disruption. Neither differences in complement-regulatory functionality, nor interactions with P. falciparum proteins tested here, appear to have driven the non-uniform geographic distribution of these alleles.
A fast massively parallel two-phase flow solver for microfluidic chip simulation

This work presents a parallel finite element solver of incompressible two-phase flow targeting large-scale simulations of three-dimensional dynamics in high-throughput microfluidic separation devices. The method relies on a conservative level set formulation for representing the fluid-fluid interface and uses adaptive mesh refinement on forests of octrees. An implicit time stepping with efficient block solvers for the incompressible Navier–Stokes equations discretized with Taylor–Hood and augmented Taylor–Hood finite elements is presented. A matrix-free implementation is used that reduces the solution time for the Navier–Stokes system by a factor of approximately three compared to the best matrix-based algorithms. Scalability of the chosen algorithms up to 32,768 cores and a billion degrees of freedom is shown.