Miracle-dz/UniFAR-FTUs huggingface dataset:
ATP-Binding Cassette Transporter VcaM from Vibrio cholerae is Dependent on the Outer Membrane Factor Family for Its Function

Vibrio cholerae ATP-binding cassette transporter VcaM (V. cholerae ABC multidrug resistance pump) has previously been shown to confer resistance to a variety of medically important drugs. In this study, we set to analyse its properties both in vitro in detergent-solubilised state and in vivo to differentiate its dependency on auxiliary proteins for its function. We report the first detailed kinetic parameters of purified VcaM and the rate of phosphate (Pi) production. To determine the possible functional dependencies of VcaM on the tripartite efflux pumps we then utilized different E. coli strains lacking the principal secondary transporter AcrB (Acriflavine resistance protein), as well as cells lacking the outer membrane factor (OMF) TolC (Tolerance to colicins). Consistent with the ATPase function of VcaM we found it to be susceptible to sodium orthovanadate (NaOV), however, we also found a clear dependency of VcaM function on TolC. Inhibitors targeting secondary active transporters had no effects on either VcaM-conferred resistance or Hoechst 33342 accumulation, suggesting that VcaM might be capable of engaging with the TolC-channel without periplasmic mediation by additional transporters. Our findings are indicative of VcaM being capable of a one-step substrate translocation from cytosol to extracellular space utilising the TolC-channel, making it the only multidrug ABC-transporter outside of the MacB-family with demonstrable TolC-dependency.
The abiotic and biotic drivers of rapid diversification in Andean bellflowers (Campanulaceae)

Summary The tropical Andes of South America, the world's richest biodiversity hotspot, are home to many rapid radiations. While geological, climatic, and ecological processes collectively explain such radiations, their relative contributions are seldom examined within a single clade. We explore the contribution of these factors by applying a series of diversification models that incorporate mountain building, climate change, and trait evolution to the first dated phylogeny of Andean bellflowers (Campanulaceae: Lobelioideae). Our framework is novel for its direct incorporation of geological data on Andean uplift into a macroevolutionary model. We show that speciation and extinction are differentially influenced by abiotic factors: speciation rates rose concurrently with Andean elevation, while extinction rates decreased during global cooling. Pollination syndrome and fruit type, both biotic traits known to facilitate mutualisms, played an additional role in driving diversification. These abiotic and biotic factors resulted in one of the fastest radiations reported to date: the centropogonids, whose 550 species arose in the last 5 million yr. Our study represents a significant advance in our understanding of plant evolution in Andean cloud forests. It further highlights the power of combining phylogenetic and Earth science models to explore the interplay of geology, climate, and ecology in generating the world's biodiversity.
The effect of metabolic syndrome on male reproductive health: A cross-sectional study in a group of fertile men and male partners of infertile couples

This study aimed to determine the effect of metabolic syndrome (MS) on the reproductive function in fertile (FM) and male partners of infertile couples (MPIC). We performed a cross-sectional study formatting two study groups: partners of pregnant women (n = 238; mean age 32.0) as FM and male partners of infertile couples (n = 2642; mean age 32.6) as MPIC. A standard semen analysis was performed and clinical, laboratory and lifestyle data were analysed. The adapted NCEP-ATPIII criteria were used to define MS. 12.2% of FM and 17.8% of MPIC had MS. In both groups, men with MS were older, they were centrally obese and had higher triglycerides, systolic and diastolic blood pressure and decreased HDL cholesterol values as compared to men without MS. However, glucose concentrations as well as fasting insulin levels were significantly higher only in the MPIC-MS+ group. MS was not associated with semen parameters. Testosterone levels were negatively correlated to MS in both groups. This negative association persisted within the BMI categories between MPIC-MS- and MPIC-MS+ groups. LH was negatively correlated to MS but only in MPIC. FSH and oestradiol were not correlated to MS. Smoking and alcohol consumption were higher among men with MS. This study shows that except for testosterone, MS has no independent effect on major fertility parameters in different subgroups of men.
Do Lizards Avoid Habitats in Which Performance Is Submaximal? The Relationship between Sprinting Capabilities and Structural Habitat Use in Caribbean Anoles

Recent years have seen an increased emphasis on measuring ecologically relevant performance capabilities to understand associations between morphology and habitat use. Such studies presume that performance is invariant, but in eight Caribbean Anolis lizard species, we found that maximal sprinting ability depends on surface diameter. Moreover, these species differ in the degree to which sprint speed declines with decreasing surface diameter, defined as “sprint sensitivity” (high sprint \documentclass{aastex} \usepackage{amsbsy} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{bm} \usepackage{mathrsfs} \usepackage{pifont} \usepackage{stmaryrd} \usepackage{textcomp} \usepackage{portland,xspace} \usepackage{amsmath,amsxtra} \usepackage[OT2,OT1]{fontenc} \newcommand\cyr{ \renewcommand\rmdefault{wncyr} \renewcommand\sfdefault{wncyss} \renewcommand\encodingdefault{OT2} \normalfont \selectfont} \DeclareTextFontCommand{\textcyr}{\cyr} \pagestyle{empty} \DeclareMathSizes{10}{9}{7}{6} \begin{document} \landscape $$\mathrm{sensitivity}\,=\mathrm{substantial}\,$$ \end{document} declines in speed between broad and narrow dowels). The habitat constraint hypothesis postulates that Anolis lizards will avoid structural habitats in which their maximal sprinting capabilities are impaired. The habitat breadth hypothesis postulates that species whose performance is less affected by substrate will use a greater variety of habitats than species whose performance varies to a greater extent on surfaces of different diameters. Field observations quantified the proportion of time that lizards spent on different perch diameters. Both hypotheses were confirmed: species with high values of sprint sensitivity avoided using perches on which their maximal sprinting abilities are impaired, whereas species with low sprint sensitivity used such “submaximal” surfaces more frequently. Species with low sprint sensitivity used a broader range of structural habitats than species with high sprint sensitivity.
Cabozantinib Is Active against Human Gastrointestinal Stromal Tumor Xenografts Carrying Different KIT Mutations

In the majority of gastrointestinal stromal tumors (GIST), oncogenic signaling is driven by KIT mutations. Advanced GIST is treated with tyrosine kinase inhibitors (TKI) such as imatinib. Acquired resistance to TKI is mainly caused by secondary KIT mutations, but can also be attributed to a switch of KIT dependency to another receptor tyrosine kinase (RTK). We tested the efficacy of cabozantinib, a novel TKI targeting KIT, MET, AXL, and vascular endothelial growth factor receptors (VEGFR), in patient-derived xenograft (PDX) models of GIST, carrying different KIT mutations. NMRI nu/nu mice (n = 52) were bilaterally transplanted with human GIST: UZLX-GIST4 (KIT exon 11 mutation, imatinib sensitive), UZLX-GIST2 (KIT exon 9, imatinib dose-dependent resistance), or UZLX-GIST9 (KIT exon 11 and 17 mutations, imatinib resistant). Mice were grouped as control (untreated), imatinib (50 mg/kg/bid), and cabozantinib (30 mg/kg/qd) and treated orally for 15 days. Cabozantinib resulted in significant tumor regression in UZLX-GIST4 and -GIST2 and delayed tumor growth in -GIST9. In all three models, cabozantinib inhibited the proliferative activity, which was completely absent in UZLX-GIST4 and significantly reduced in -GIST2 and -GIST9. Increased apoptotic activity was observed only in UZLX-GIST4. Cabozantinib inhibited the KIT signaling pathway in UZLX-GIST4 and -GIST2. In addition, compared with both control and imatinib, cabozantinib significantly reduced microvessel density in all models. In conclusion, cabozantinib showed antitumor activity in GIST PDX models through inhibition of tumor growth, proliferation, and angiogenesis, in both imatinib-sensitive and imatinib-resistant models. Mol Cancer Ther; 15(12); 2845–52. ©2016 AACR.
Risk Stratification and Shared Decision Making for Colorectal Cancer Screening

Background. Eliciting patient preferences within the context of shared decision making has been advocated for colorectal cancer (CRC) screening, yet providers often fail to comply with patient preferences that differ from their own. Purpose. To determine whether risk stratification for advanced colorectal neoplasia (ACN) influences provider willingness to comply with patient preferences when selecting a desired CRC screening option. Design. Randomized controlled trial. Setting/Participants. Asymptomatic, average-risk patients due for CRC screening in an urban safety net health care setting. Intervention. Patients were randomized 1:1 to a decision aid alone (n = 168) or decision aid plus risk assessment (n = 173) arm between September 2012 and September 2014. Outcomes. The primary outcome was concordance between patient preference and test ordered; secondary outcomes included patient satisfaction with the decision-making process, screening intentions, test completion rates, and provider satisfaction. Results. Although providers perceived risk stratification to be useful in selecting an appropriate screening test for their average-risk patients, no significant differences in concordance were observed between the decision aid alone and decision aid plus risk assessment groups (88.1% v. 85.0%, P = 0.40) or high- and low-risk groups (84.5% v. 87.1%, P = 0.51). Concordance was highest for colonoscopy and relatively low for tests other than colonoscopy, regardless of study arm or risk group. Failure to comply with patient preferences was negatively associated with satisfaction with the decision-making process, screening intentions, and test completion rates. Limitations. Single-institution setting; lack of provider education about the utility of risk stratification into their decision making. Conclusions. Providers perceived risk stratification to be useful in their decision making but often failed to comply with patient preferences for tests other than colonoscopy, even among those deemed to be at low risk of ACN.
Male apoE*3‐Leiden.CETP mice on high‐fat high‐cholesterol diet exhibit a biphasic dyslipidemic response, mimicking the changes in plasma lipids observed through life in men

Physiological adaptations resulting in the development of the metabolic syndrome in man occur over a time span of several decades. This combined with the prohibitive financial cost and ethical concerns to measure key metabolic parameters repeatedly in subjects for the major part of their life span makes that comprehensive longitudinal human data sets are virtually nonexistent. While experimental mice are often used, little is known whether this species is in fact an adequate model to better understand the mechanisms that drive the metabolic syndrome in man. We took up the challenge to study the response of male apoE*3‐Leiden.CETP mice (with a humanized lipid profile) to a high‐fat high‐cholesterol diet for 6 months. Study parameters include body weight, food intake, plasma and liver lipids, hepatic transcriptome, VLDL – triglyceride production and importantly the use of stable isotopes to measure hepatic de novo lipogenesis, gluconeogenesis, and biliary/fecal sterol secretion to assess metabolic fluxes. The key observations include (1) high inter‐individual variation; (2) a largely unaffected hepatic transcriptome at 2, 3, and 6 months; (3) a biphasic response curve of the main metabolic features over time; and (4) maximum insulin resistance preceding dyslipidemia. The biphasic response in plasma triglyceride and total cholesterol appears to mimic that of men in cross‐sectional studies. Combined, these observations suggest that studies such as these can help to delineate the causes of metabolic derangements in patients suffering from metabolic syndrome.
Disentangling Factors of Variation by Mixing Them

We propose an approach to learn image representations that consist of disentangled factors of variation without exploiting any manual labeling or data domain knowledge. A factor of variation corresponds to an image attribute that can be discerned consistently across a set of images, such as the pose or color of objects. Our disentangled representation consists of a concatenation of feature chunks, each chunk representing a factor of variation. It supports applications such as transferring attributes from one image to another, by simply mixing and unmixing feature chunks, and classification or retrieval based on one or several attributes, by considering a user-specified subset of feature chunks. We learn our representation without any labeling or knowledge of the data domain, using an autoencoder architecture with two novel training objectives: first, we propose an invariance objective to encourage that encoding of each attribute, and decoding of each chunk, are invariant to changes in other attributes and chunks, respectively; second, we include a classification objective, which ensures that each chunk corresponds to a consistently discernible attribute in the represented image, hence avoiding degenerate feature mappings where some chunks are completely ignored. We demonstrate the effectiveness of our approach on the MNIST, Sprites, and CelebA datasets.
Evaluating the impact of single nucleotide variants on transcription factor binding

Abstract Diseases and phenotypes caused by disrupted transcription factor (TF) binding are being identified, but progress is hampered by our limited capacity to predict such functional alterations. Improving predictions may be dependent on expanding the set of bona fide TF binding alterations. Allele-specific binding (ASB) events, where TFs preferentially bind to one of the two alleles at heterozygous sites, reveal the impact of sequence variations in altered TF binding. Here, we present the largest ASB compilation to our knowledge, 10 765 ASB events retrieved from 45 ENCODE ChIP-Seq data sets. Our analysis showed that ASB events were frequently associated with motif alterations of the ChIP'ed TF and potential partner TFs, allelic difference of DNase I hypersensitivity and allelic difference of histone modifications. For TF dimers bound symmetrically to DNA, ASB data revealed that central positions of the TF binding motifs were disproportionately important for binding. Lastly, the impact of variation on TF binding was predicted by a classification model incorporating all the investigated features of ASB events. Classification models using only DNase I hypersensitivity and sequence data exhibited predictive accuracy approaching the models with substantially more features. Taken together, the combination of ASB data and the classification model represents an important step toward elucidating regulatory variants across the human genome.
Fluid shear-induced mechanical signaling in MC3T3-E1 osteoblasts requires cytoskeleton-integrin interactions.

Mechanical stimulation of bone induces new bone formation in vivo and increases the metabolic activity and gene expression of osteoblasts in culture. We investigated the role of the actin cytoskeleton and actin-membrane interactions in the transmission of mechanical signals leading to altered gene expression in cultured MC3T3-E1 osteoblasts. Application of fluid shear to osteoblasts caused reorganization of actin filaments into contractile stress fibers and involved recruitment of β1-integrins and α-actinin to focal adhesions. Fluid shear also increased expression of two proteins linked to mechanotransduction in vivo, cyclooxygenase-2 (COX-2) and the early response gene product c-fos. Inhibition of actin stress fiber development by treatment of cells with cytochalasin D, by expression of a dominant negative form of the small GTPase Rho, or by microinjection into cells of a proteolytic fragment of α-actinin that inhibits α-actinin-mediated anchoring of actin filaments to integrins at the plasma membrane each blocked fluid-shear-induced gene expression in osteoblasts. We conclude that fluid shear-induced mechanical signaling in osteoblasts leads to increased expression of COX-2 and c-Fos through a mechanism that involves reorganization of the actin cytoskeleton. Thus Rho-mediated stress fiber formation and the α-actinin-dependent anchorage of stress fibers to integrins in focal adhesions may promote fluid shear-induced metabolic changes in bone cells.
ESPVR of in situ rat left ventricle shows contractility-dependent curvilinearity.

We developed a miniaturized conductance catheter for in situ rat left ventricular (LV) volumetry. After the validation study of the conductance volumetry in 11 rats, we characterized the end-systolic pressure-volume relationship (ESPVR) in 24 sinoaortic-denervated, vagotomized and urethan-anesthetized rats. Stroke volume (SV) measured with the conductance catheter correlated closely with that measured by electromagnetic flowmetry ( r > 0.95). No significant difference was found between the in situ LV end-diastolic volumes measured by conductance volumetry and postmortem morphometry; a linear regression analysis indicated that the correlation coefficient was 0.934, that the slope was not significantly different from 1, and that the intercept was not significantly different from 0. During cardiac sympathotonic conditions, the ESPVR was curvilinear. The estimated slope of ESPVR (end-systolic elastance, E es) by quadratic curve fitting at end-systolic pressure of 100 mmHg was 2,647 ± 846 mmHg/ml. Bilateral cervical and stellate ganglionectomy depressed contractility and made the ESPVR linear; a quadratic equation did not improve the fit. E es was 946 ± 55 mmHg/ml with the volume-axis ( V 0) intercept of 0.076 ± 0.007 ml. Administration of propranolol (1 mg/kg) further reduced E es (573 ± 61 mmHg/ml, P < 0.001) and increased V 0 slightly (0.091 ± 0.011 ml). We conclude that the conductance catheter method is useful for the assessment of the ESPVR of the in situ rat left ventricle and that the ESPVR displays contractility-dependent curvilinearity.
iTRAQ Mitoproteome Analysis Reveals Mechanisms of Programmed Cell Death in Arabidopsis thaliana Induced by Ochratoxin A

Ochratoxin A (OTA) is one of the most common and dangerous mycotoxins in the world. Previous work indicated that OTA could elicit spontaneous HR-like lesions formation Arabidopsis thaliana, reactive oxygen species (ROS) play an important role in OTA toxicity, and their major endogenous source is mitochondria. However, there has been no evidence as to whether OTA induces directly PCD in plants until now. In this study, the presence of OTA in Arabidopsis thaliana leaves triggered accelerated respiration, increased production of mitochondrial ROS, the opening of ROS-dependent mitochondrial permeability transition pores and a decrease in mitochondrial membrane potential as well as the release of cytochrome c into the cytosol. There were 42 and 43 significantly differentially expressed proteins identified in response to exposure to OTA for 8 and 24 h, respectively, according to iTRAQ analysis. These proteins were mainly involved in perturbation of the mitochondrial electron transport chain, interfering with ATP synthesis and inducing PCD. Digital gene expression data at transcriptional level was consistent with the cell death induced by OTA being PCD. These results indicated that mitochondrial dysfunction was a prerequisite for OTA-induced PCD and the initiation and execution of PCD via a mitochondrial-mediated pathway.
Preparation of Hydroxyapatite Coating by Using Citric Acid Sodium Citrate Buffer System in the Biomimetic Procedure

Abstract The present study has been aimed to investigate the preparation and analysis of calcium phosphate (CaP) based hydroxyapatite (HA, Ca10(PO4)6(OH)2) coatings formed on Ti6Al4V alloys in a new buffer environment. The coating process has been performed by means of biomimetic method. In the study, a synthetic body fluid (SBF), which is fully compatible with human blood plasma, has been prepared for the first time in the literature by using the citric acid – sodium citrate buffer system. Using this buffer system will not cause any toxic reactions in the human body. CaP coating of the Ti6Al4V surface has been performed in this new SBF. The surface roughness and thickness specifications of the coatings have been determined, their microstructures have been analyzed by using a scanning electron microscope (SEM), the elemental analysis (EDX) of the coating surfaces and the XRD analysis have been done. The results are presented and discussed.
Biomarkers of Human Cardiopulmonary Response After Short-Term Exposures to Medical Laser-Generated Particulate Matter From Simulated Procedures: A Pilot Study

Objective: We conducted an exposure chamber study in humans using a simulated clinical procedure lasing porcine tissue to demonstrate evidence of effects of exposure to laser-generated particulate matter (LGPM). Methods: We measured pre- and post-exposure changes in exhaled nitric oxide (eNO), spirometry, heart rate variability (HRV), and blood markers of inflammation in five volunteers. Results: Change in pre- and post-exposure measurements of eNO and spirometry was unremarkable. Neutrophil and lymphocyte counts increased and fibrinogen levels decreased in four of the five subjects. Measures of HRV showed decreases in the standard deviation of normal between beat intervals and sequential 5-minute intervals. Conclusion: These data represent the first evidence of human physiologic response to LGPM exposure. Further exploration of coagulation effects and HRV is warranted.
Identification of Neuroendocrine Stress Response-Related Circulating MicroRNAs as Biomarkers for Type 2 Diabetes Mellitus and Insulin Resistance

Background Chronic stress plays an important role in the development of type 2 diabetes mellitus (T2DM) and insulin resistance (IR). MicroRNAs (miRNAs) play key roles in mediating stress responses by regulating the expression of target genes. This study systematically screened and identified the neuroendocrine stress response-related circulating miRNAs which are associated with T2DM and IR. Methods Based on the differential plasma expression profiles between individuals with and without T2DM, stress-related miRNAs were selected from those differently expressed miRNAs whose targets are involved in known neuroendocrine pathway of stress response. Candidate miRNAs were further validated by quantitative real-time polymerase chain reaction in a large sample, including 112 T2DM patients, 72 individuals with impaired fasting glucose (IFG), and 94 healthy controls. The association between miRNA expression and potential risk of T2DM and IFG was assessed by multivariate logistic regression models. The miRNA predictors of IR were identified by stepwise multiple regression analysis. The diagnostic performance for T2DM was evaluated by area under the curve (AUC) of receiver operating characteristic (ROC). Results let-7b, let-7i, miR-142, miR-144, miR-155, and miR-29a were selected as candidate miRNAs for validation. Increased expression of let-7b, miR-144, and miR-29a and decreased expression of miR-142 were significant independent predictors of T2DM, IFG, and IR (P < 0.0125). These miRNAs significantly correlated with stress hormone levels (P < 0.0125). A three-miRNA panel, including let-7b, miR-142, and miR-144 had a high accuracy for diagnosing T2DM (AUC = 0.871, 95% CI: 0.822–0.919). Conclusion let-7b, miR-142, miR-144, and miR-29a in plasma may be important markers of neuroendocrine stress response and may play a role in the pathogenesis of T2DM and IR.