Miracle-dz/UniFAR-FTUs huggingface dataset:
Staphylococcus aureus Genotyping Using Novel Real-Time PCR Formats

ABSTRACT One approach to microbial genotyping is to make use of sets of single-nucleotide polymorphisms (SNPs) in combination with binary markers. Here we report the modification and automation of a SNP-plus-binary-marker-based approach to the genotyping of Staphylococcus aureus and its application to 391 S. aureus isolates from southeast Queensland, Australia. The SNPs used were arcC210, tpi243, arcC162, gmk318, pta294, tpi36, tpi241, and pta383. These provide a Simpson's index of diversity (D) of 0.95 with respect to the S. aureus multilocus sequence typing database and define 61 genotypes and the major clonal complexes. The binary markers used were pvl, cna, sdrE, pT181, and pUB110. Two novel real-time PCR formats for interrogating these markers were compared. One of these makes use of “light upon extension” (LUX) primers and biplexed reactions, while the other is a streamlined modification of kinetic PCR using SYBR green. The latter format proved to be more robust. In addition, automated methods for DNA template preparation, reaction setup, and data analysis were developed. A single SNP-based method for ST-93 (Queensland clone) identification was also devised. The genotyping revealed the numerical importance of the “South West Pacific” and “Queensland” community-acquired methicillin-resistant S. aureus (MRSA) clones and the clonal complex 239 “Aus-1/Aus-2” hospital-associated MRSA. There was a strong association between the community-acquired clones and pvl.
Chemokines induce axon outgrowth downstream of Hepatocyte Growth Factor and TCF/β-catenin signaling

Axon morphogenesis is a complex process regulated by a variety of secreted molecules, including morphogens and growth factors, resulting in the establishment of the neuronal circuitry. Our previous work demonstrated that growth factors [Neurotrophins (NT) and Hepatocyte Growth Factor (HGF)] signal through β-catenin during axon morphogenesis. HGF signaling promotes axon outgrowth and branching by inducing β-catenin phosphorylation at Y142 and transcriptional regulation of T-Cell Factor (TCF) target genes. Here, we asked which genes are regulated by HGF signaling during axon morphogenesis. An array screening indicated that HGF signaling elevates the expression of chemokines of the CC and CXC families. In line with this, CCL7, CCL20, and CXCL2 significantly increase axon outgrowth in hippocampal neurons. Experiments using blocking antibodies and chemokine receptor antagonists demonstrate that chemokines act downstream of HGF signaling during axon morphogenesis. In addition, qPCR data demonstrates that CXCL2 and CCL5 expression is stimulated by HGF through Met/b-catenin/TCF pathway. These results identify CC family members and CXCL2 chemokines as novel regulators of axon morphogenesis downstream of HGF signaling.
A CH domain‐containing N terminus in NuMA?

Nuclear mitotic apparatus protein (NuMA) is an essential vertebrate component in organizing microtubule ends at spindle poles. The NuMA‐dynactin/dynein motor multiprotein complex not only explains the transport of NuMA along spindle fibers but also is linked to the process of microtubule focusing. The interaction sites of NuMA to dynein/dynactin have not been mapped. In the yet functionally uncharacterized N terminus of NuMA, we predict a calponin‐homology (CH) domain, a motif with binding activity for actin‐like molecules. We substantiate the primary sequence analysis‐based prediction with secondary structure and fold recognition analysis, and we propose the N‐terminal CH domain of NuMA as a likely interaction site for actin‐related protein 1 (Arp1) protein of the dynactin/dynein complex.
Hemodynamics of the Carotid‐Artery Circulation in the Elderly “Dizzy” Patient

One hundred and one consecutive patients complaining of dizziness were assessed by noninvasive carotid‐artery testing, including oculoplethysmography, supraorbital directional Doppler and direct carotid flow Doppler. Hemodynamically significant carotid disease was found in 8 of 34 patients with the nonspecific complaint of “lightheadedness,” in 4 of 21 patients with syncope, in 3 of 12 patients with vertebrobasilar insufficiency, and in 7 of 27 patients with associated focal cerebral signs or symptoms. None of 7 patients with vertigo alone were affected. In summary, 21 of the 101 patients with dizziness had hemodynamically significant obstruction to flow in the carotid‐artery circulation. These findings suggest that in a fairly large proportion of patients complaining of dizziness, the symptoms may be the result of decreased cerebral perfusion due to carotid‐artery occlusive disease. In these patients, noninvasive carotid‐artery testing appears to be useful in identifying those with significant obstruction to blood flow in the carotid‐artery circulation.
Efficacy of HLA‐matched platelet transfusions for patients with hypoproliferative thrombocytopenia: a systematic review

HLA‐matched platelets (PLTs) are widely used to transfuse patients but the effectiveness of HLA matching has not been well defined and the cost is approximately five times the cost of preparing the random‐donor PLTs. The objective of this systematic review was to determine whether HLA‐matched PLTs lead to a reduction in mortality; reduction in frequency or severity of hemorrhage; reduction in HLA alloimmunization, refractoriness, or PLT utilization; or improvement in PLT count increment in patients with hypoproliferative thrombocytopenia.
Short-Term Choriocapillaris Changes in Patients with Central Serous Chorioretinopathy after Half-Dose Photodynamic Therapy

Background: Although photodynamic therapy (PDT) has become the standard treatment for central serous chorioretinopathy (CSC), its mechanism of action remains unclear. It is assumed that PDT induces short-term choriocapillaris (CC) occlusion and long-term choroidal vascular remodeling. In this paper, we describe the short-term CC changes induced by Half-Dose PDT (HD-PDT) in chronic CSC using optical coherence tomography-angiography (OCTA). Methods: This is a prospective interventional case series. Chronic CSC eyes underwent Spectral-Domain OCT, Fundus Autofluorescence, FA, ICGA (Heidelberg Spectralis, Heidelberg, Germany) and OCTA (RTVue XR Avanti with AngioVue; Optovue Inc., Fremont, CA, USA) before HD-PDT, with follow-up after one hour, one week, and one month. Vascular changes after PDT were analyzed within the CC layer. The CC vessel density was defined as the percentage of an area occupied by flow pixels, using Image J software to obtain measurements by applying a grey level threshold. All pixels with a grey level above the threshold were considered as indicators of blood flow. Results: 20 eyes of 19 patients were included. At baseline the mean CC vessel density was 94.87 ± 2.32%. It significantly differed from the density at 1 week and 1 month (92.79 ± 3.16% and 95.55 ± 2.05%, p < 0.001, respectively), but not with values at 1 h (94.8 ± 2.28%, p = 0.516). Conclusions: CC vessel density was significantly reduced at 1 week as compared with baseline, suggesting a possible short-term effect of PDT on CC perfusion. After 1 month however, the CC vessel density was even higher than the baseline, probably due to a CC recovery. OCTA seems to be useful in the visualization of CC vessels and in confirming the mechanism of action of PDT treatment in eyes with chronic CSC.
Temporal proof methodologies for real-time systems

We extend the specification language of temporal logic, the corresponding verification framework, and the underlying computational model to deal with real-time properties of reactive systems. The abstract notion of timed transition systems generalizes traditional transition systems conservatively: qualitative fairness requirements are replaced (and superseded) by quantitative lower-bound and upper-bound timing constraints on transitions. This framework can model real-time systems that communicate either through shared variables or by message passing and real-time issues such as time-outs, process priorities (interrupts), and process scheduling. We exhibit two styles for the specification of real-time systems. While the first approach uses bounded versions of temporal operators, the second approach allows explicit references to time through a special clock variable. Corresponding to the two styles of specification, we present and compare two fundamentally different proof methodologies for the verification of timing requirements that are expressed in these styles. For the bounded-operatoT style, we provide a set of proof rules for establishing bounded-invariance and bounded-response properties of timed transition systems. This approach generalizes the standard temporal proof rules for verifying invariance and response properties conservatively. For the explicit-clock style, we exploit the observation that every time-bounded property is a safety property and use the standard temporal proof rules for establishing safety properties.
Threshold Learning for Optimal Decision Making

Decision making under uncertainty is commonly modelled as a process of competitive stochastic evidence accumulation to threshold (the drift-diffusion model). However, it is unknown how animals learn these decision thresholds. We examine threshold learning by constructing a reward function that averages over many trials to Wald's cost function that defines decision optimality. These rewards are highly stochastic and hence challenging to optimize, which we address in two ways: first, a simple two-factor reward-modulated learning rule derived from Williams' REINFORCE method for neural networks; and second, Bayesian optimization of the reward function with a Gaussian process. Bayesian optimization converges in fewer trials than REINFORCE but is slower computationally with greater variance. The REINFORCE method is also a better model of acquisition behaviour in animals and a similar learning rule has been proposed for modelling basal ganglia function.
Sphingosine 1-phosphate elicits proinflammatory responses in ARPE-19 cells.

PURPOSE To investigate the effects of sphingosine 1-phosphate (S1P) on the production of inflammatory mediators and the signaling pathways involved in S1P-mediated production of cytokines by ARPE-19 cells. METHODS Expression of S1P receptors was examined using RT-PCR and real-time PCR. ARPE-19 cells were stimulated with S1P or TNF-α, and by coculturing with S1P in the presence or absence of pertussis toxin (PTX) or a series of kinase inhibitors. The induction of inflammatory cytokine production was determined by ELISA. Western blot analysis was used to detect the activation of signaling mediators and S1P(3) receptor. RESULTS ARPE-19 cells express all the known receptors for S1P. Moreover, exogenously applied S1P induces ARPE-19 cell secretion of interleukin-8 (IL-8) in a dose- and time-dependent manner, but not IL-6 and monocyte chemotactic protein-1 (MCP-1). S1P-mediated IL-8 secretion is regulated by PTX, extracellular regulated protein kinases 1/2 (ERK1/2), and p38 mitogen-activated protein kinase (MAPK). Interestingly, treatment of ARPE-19 cells with TNF-α increases S1P(3) expression and correlates with the enhancement of S1P-induced IL-8 and IL-6 production. CONCLUSIONS This study demonstrates that S1P significantly promoted ARPE-19 cells to secrete inflammatory mediators. extracellular regulated protein kinases 1/2 (ERK1/2), p38 MAPK, and G(i)-dependent pathways are important signaling components in S1P-mediated IL-8 secretion by ARPE-19 cells. Moreover, these results provide evidence that S1P stimulation of RPE cells may play a role in regulating leukocyte function during ocular inflammation.
Flow cytometric analysis of the DNA synthetic cycle of Candida species

The total DNA per cell and DNA synthetic cycle phases were determined by flow cytometry in five Candida isolates including three species: Candida albicans 208R1, Candida tropicalis ATCC 750, and Candida parapsilosis 970, 3138, and ATCC 22019. The cells were prepared for flow cytometry by fixation in Carnoy fixative followed by staining with mithramycin. Marked but stable and reproducible inter- and intraspecific differences in total DNA per cell of stationary-phase cultures were found which did not correlate directly to diphenylamine estimates of the same parameter. This discrepancy was resolved by mathematically converting flow cytometry data into diphenylamine data. The reason for the discrepancy was found in studies of the DNA synthetic cycle of these yeasts: a large but isolate-specific variable proportion of the population is arrested in the S and G2-M phases after the culture passes from exponential to stationary phase. Histograms of exponential-growth-phase Candida isolates demonstrate that the majority of the population is in the G2-M phase of the DNA synthetic cycle. The DNA content of the C. tropicalis and C. parapsilosis isolates studied is as high as or higher than that of C. albicans. Extranuclear fluorescent particles were observed in the C. tropicalis isolate. No equivalent particles could be detected in the other four Candida isolates. The nature of the particles is unknown.
This Is a Publication of The American Association for Artificial Intelligence

n This article introduces a generic framework for constraint-directed search. The research literature in constraint-directed scheduling is placed within the framework both to provide insight into, and examples of, the framework and to allow a new perspective on the scheduling literature. We show how a number of algorithms from the constraint-directed–scheduling research can be conceptualized within the framework. This conceptualization allows us to identify and compare variations of components of our framework and provides new perspective on open research issues. We discuss the prospects for an overall comparison of scheduling strategies and show that ﬁrm conclusions vis-a-vis such a comparison are not supported by the literature. Our principal conclusion is the need for an empirical model of both the characteristics of scheduling problems and the solution techniques themselves. Our framework is offered as a tool for the development of such an understanding of con-straint-directed scheduling and, more generally, constraint-directed search.
MDE of manufacturing automation software — Integrating SysML and standard development tools

In the paper, a SysML-based approach that supports the model-driven engineering (MDE) of manufacturing automation software is presented. The approach adapts the Systems Modeling Language (SysML) and defines a specialized language profile, the SysML-AT, to support automated code generation for IEC 61131-3 runtime environments. For adapted SysML Parametric Diagrams (PD), a prototypical tool support was realized inside a commonly used automation software development environment. Inside the prototypical tool, the linking between the realized PD model editor and online data from the IEC 61131-3 runtime environment enables direct debugging within a SysML-AT model. The concept was evaluated by case studies and by usability experiments, which proved the usability of the SysML-based MDE approach for future users.
Combination With Low-dose Dextromethorphan Improves the Effect of Amlodipine Monotherapy in Clinical Hypertension

AbstractThe combination of low rather than high dose of dextromethorphan (DXM) with amlodipine (AM) could improve blood pressure (BP) reduction in hypertensive animals. The study aimed to evaluate the feasibility of different doses of DXM combined with standard AM treatment in clinical hypertension.This was a prospective, 14-week, dose-escalation, multicenter study. After 2-week run-in period with AM 5 mg/day, hypertensive patients who got the BP goal of 140/90 mmHg kept receiving AM monotherapy for another 12 weeks. The nonresponders, while kept on AM 5 mg/day, received additional DXM treatment for 3 sequential dose-titrated periods with initially 2.5 mg/day, followed by 7.5 mg/day, and finally 30 mg/day. Each period was for 4 weeks. The patients at BP goal after each treatment period were defined as the responders and kept on the same combination till the end of the study. The responder rate of each treatment period was recorded. The changes of BP and serum antioxidant/endothelial markers between week 14 and week 2 were evaluated.Of the 103 patients initially enrolled, 89 entered the treatment period. In the 78 patients completing the study, 31 (40%) at BP goal after 2-week AM run-in kept on AM monotherapy (DXM0). The addition of 2.5 (DXM2.5) and 7.5 mg/day (DXM7.5) of DXM enabled BP goal achievement in 22 (47%) nonresponders to AM monotherapy including 16 (29%) with DXM2.5 and 6 (18%) with DXM7.5. Only 4 patients (16%) reached BP goal with the combination of DXM 30 mg/day (DXM30). Overall, 73% of the 78 patients reached BP goal at the end of the 14-week study. Mean systolic BP was reduced by 7.9% ± 7.0% with DXM2.5 (P < 0.001) and by 5.4% ± 2.4% with DXM7.5 (P = 0.003) respectively at week 14 from that at week 2, which was unchanged in either DXM0 or DXM30 group. Besides, the effects of combination treatment were particularly significant in the patients with impaired endothelial function suggested by reduced serum NOx level at baseline.Accordingly, the combination with low dose of DXM was feasible to improve BP control in patients who failed to achieve the BP goal by standard AM monotherapy. The benefit effects might be significant especially in patients with impaired endothelial function.
The effect of vitamin D supplementation on bone formation around titanium implants in diabetic rats

Background: Diabetes has become the next most widespread disease after cancer. Recent studies have found that diabetes and moderate to severe vitamin D deficiency are associated with reduced bone mineral content; therefore administration of vitamin D may correct these conditions. The purpose of this research is to compare the effect of vitamin D administration on bone to implant contact in diabetic rats with control group. Materials and Methods: In this randomized placebo-controlled trial, 48 Wistar rats were rendered diabetic (130≤ blood sugar ≤200 mg/dl) by IV injection of 35 mg/kg Alloxan. Implants were inserted in tibial bone; Then rats were divided into study and control groups and received oral vitamin D3 (160 IU) or placebo respectively for one week. Bone to implant contact value was measured under light microscope at 3 and 6 weeks. Results: Analysis of data indicated that vitamin D had no significant effect on bone to implant contact (BIC). At 3 weeks, the control group (n = 5) reported BIC level at 44 ± 19 and study group (n = 7) at 57 ± 20. At 6 weeks, the control group (n = 5) reported BIC level at 70 ± 29, and study group (n = 10) at 65 ± 22. Twenty one samples were missed because of death or incorrect lab processes. Conclusion: It seems that vitamin D supplement has no significant effect on BIC in 130 mg/dL ≤ blood sugar ≤200 mg/dL (P = 0.703) andwas also not time dependent (P = 0.074).
Hedgehog pathway inhibitors: a patent review (2009 – present)

Introduction: The hedgehog (Hh) pathway is a developmental signaling pathway that plays a key role in directing cellular growth and tissue patterning during embryonic development. Dysregulation of Hh signaling has been linked to the development of a variety of human tumors, and numerous drug development programs in both academia and industry are actively exploring inhibitors of the pathway as anti-cancer agents. Areas covered: This review surveys the recent patent literature (2009 – 2012) for Hh pathway inhibitors as treatments for a variety of human malignancies. Expert opinion: To date, all of the pathway inhibitors that have entered clinical trials and the majority of compounds identified via high-throughput screens target smoothened (Smo), a transmembrane protein that is essential for pathway signaling. While these compounds have shown initial promise in preclinical and clinical trials, several mechanisms of resistance to Smo inhibitors have been identified. Even with this knowledge, the majority of small-molecule pathway inhibitors disclosed in the recent patent literature directly target Smo. The continued identification of Hh pathway inhibitors that function either upstream or downstream is warranted not only to combat these emerging resistance mechanisms, but also to help elucidate the various cellular mechanisms that control both normal and oncogenic pathway signaling.
Using a Delphi Technique to Seek Consensus Regarding Definitions, Descriptions and Classification of Terms Related to Implicit and Explicit Forms of Motor Learning

Background Motor learning is central to domains such as sports and rehabilitation; however, often terminologies are insufficiently uniform to allow effective sharing of experience or translation of knowledge. A study using a Delphi technique was conducted to ascertain level of agreement between experts from different motor learning domains (i.e., therapists, coaches, researchers) with respect to definitions and descriptions of a fundamental conceptual distinction within motor learning, namely implicit and explicit motor learning. Methods A Delphi technique was embedded in multiple rounds of a survey designed to collect and aggregate informed opinions of 49 international respondents with expertise related to motor learning. The survey was administered via an online survey program and accompanied by feedback after each round. Consensus was considered to be reached if ≥70% of the experts agreed on a topic. Results Consensus was reached with respect to definitions of implicit and explicit motor learning, and seven common primary intervention strategies were identified in the context of implicit and explicit motor learning. Consensus was not reached with respect to whether the strategies promote implicit or explicit forms of learning. Discussion The definitions and descriptions agreed upon may aid translation and transfer of knowledge between domains in the field of motor learning. Empirical and clinical research is required to confirm the accuracy of the definitions and to explore the feasibility of the strategies that were identified in research, everyday practice and education.
A nonlocal multiscale discrete‐continuum model for predicting mechanical behavior of granular materials

A three‐dimensional nonlocal multiscale discrete‐continuum model has been developed for modeling mechanical behavior of granular materials. In the proposed multiscale scheme, we establish an information‐passing coupling between the discrete element method, which explicitly replicates granular motion of individual particles, and a finite element continuum model, which captures nonlocal overall responses of the granular assemblies. The resulting multiscale discrete‐continuum coupling method retains the simplicity and efficiency of a continuum‐based finite element model, while circumventing mesh pathology in the post‐bifurcation regime by means of staggered nonlocal operator. We demonstrate that the multiscale coupling scheme is able to capture the plastic dilatancy and pressure‐sensitive frictional responses commonly observed inside dilatant shear bands, without employing a phenomenological plasticity model at a macroscopic level. In addition, internal variables, such as plastic dilatancy and plastic flow direction, are now inferred directly from granular physics, without introducing unnecessary empirical relations and phenomenology. The simple shear and the biaxial compression tests are used to analyze the onset and evolution of shear bands in granular materials and sensitivity to mesh density. The robustness and the accuracy of the proposed multiscale model are verified in comparisons with single‐scale benchmark discrete element method simulations. Copyright © 2015 John Wiley & Sons, Ltd.