Miracle-dz/UniFAR-FTUs huggingface dataset:
Dipyridamole Promotes Changes in Calbindin-D28k and Tyrosine Hydroxylase Expression in Neonatal Rats

Background: Perinatal hypoxia alters the concentration of many neurochemicals in the brain, including adenosine, and promotes central nervous system (CNS) disorders in human infants such as periventricular leukomalacia or encephalopathy. Objective: Using the postnatal rat as a model of perinatal human development, we examined the effects of sustained increases in brain adenosine on CNS regions thought to be involved with both planning and execution of motor activity. Methods: To simulate hypoxia-induced changes in adenosine, Sprague-Dawley rats were injected twice daily from postnatal day (P) 3 to P14, with the adenosine uptake inhibitor dipyridamole (DIP) or the A1 adenosine receptor agonist N6-cyclopentyladenosine (CPA). Vehicle-injected animals served as controls. Immunohistochemical and morphological analyses were then performed to examine the expression of calbindin D-28k (CB) and the thickness of the external granule cell layer (eGL) in the cerebellum. Additionally tyrosine hydroxylase (TH) expression in the caudate putamen and ventricular size were also examined. Results: In the cerebellum, both DIP and CPA reduced the number of CB-positive Purkinje cells as well as decreased the thickness of the eGL compared to vehicle. In the caudate putamen we found that DIP but not CPA decreased TH expression when compared to vehicle. Neither agent significantly altered ventricular size when compared to vehicle. Conclusions: These observations suggest that elevations in brain adenosine, which can occur following hypoxia, leads to both neurochemical and cellular changes in regions of the brain which control the planning and execution of motor activity. Thus, therapeutic strategies that target brain regions most sensitive to adenosine may prevent or control at least some of the CNS damage observed following perinatal hypoxia.
Carbon monoxide induces vasodilation and nitric oxide release but suppresses endothelial NOS

Thorup, Christian, Caroline L. Jones, Steven S. Gross, Leon C. Moore, and Michael S. Goligorsky. Carbon monoxide induces vasodilation and nitric oxide release but suppresses endothelial NOS. Am. J. Physiol. 277 (Renal Physiol. 46): F882–F889, 1999. —The vascular effects of carbon monoxide (CO) resemble those of nitric oxide (NO), but it is unknown whether the two messengers converge or exhibit reciprocal feedback regulation. These questions were examined in microdissected perfused renal resistance arteries (RRA) studied using NO-sensitive microelectrodes. Perfusion of RRA with buffers containing increasing concentrations of CO resulted in a biphasic release of NO. The NO response peaked at 100 nM CO and then declined to virtually zero at 10 μM. When a series of 50-s pulses of 100 nM CO were applied repeatedly (150-s interval), the amplitude of consecutive NO responses was diminished. NO release from RRA showed dependence on L-arginine but not D-arginine, and the responses to CO were inhibited by pretreatment with NG-nitroL-arginine methyl ester (L-NAME), an inhibitor of NO synthases (NOS). CO (100 nM) also suppressed NO release induced by 100 μM carbachol, a potent agonist for endothelial NOS (eNOS). RRA from rats in which endogenous CO production from inducible HO was elevated (cobalt chloride 12 h prior to study) also showed suppressed responses to carbachol. Furthermore, responses consistent with these findings were obtained in juxtamedullary afferent arterioles perfused in vitro, where the vasodilatory response to CO was biphasic and the response to acetylcholine was blunted. Collectively, these data suggest that the CO-induced NO release could be attributed to either stimulation of eNOS or to NO displacement from a cellular storage pool. To address this, direct in vitro measurements with an NO-selective electrode of NO production by recombinant eNOS revealed that CO dosedependently inhibits NO synthesis. Together, the above data demonstrate that, whereas high levels of CO inhibit NOS activity and NO generation, lower concentrations of CO induce release of NO from a large intracellular pool and, therefore, may mimic the vascular effects of NO.
Skin ageing

Similar to the entire organism, skin is subject to an unpreventable intrinsic ageing process. Additionally, skin ageing is also influenced by exogenous factors. Ultraviolet radiation in particular results in premature skin ageing, also referred to as extrinsic skin ageing or photoageing, which is the main cause of the changes associated with the ageing process in sun‐exposed areas. Despite their morphological and pathophysiological differences, intrinsic and extrinsic ageing share several molecular similarities. The formation of reactive oxygen species and the induction of matrix metalloproteinases reflect the central aspects of skin ageing. Accumulation of fragmented collagen fibrils prevents neocollagenesis and accounts for the further degradation of the extracellular matrix by means of positive feedback regulation. The importance of extrinsic factors in skin ageing and the detection of its mechanisms have furthered the development of various therapeutic and preventive strategies.
Computational Biology of Gene Regulation Lecturer : Dr Alex Stark Scriber :

The main topic of this lecture is about how gene expression is regul at d. The regulation of gene expression is of utmost importance for both unicellular organisms that need to adapt to environmental changes and nutritional stresses, and for meta zoa, in which individual cells respond to extracellular signals such as hormones and growth factors by switching their activities from one state to another or changin g their proliferation or differentiation status [8]. Notably, different genes have differe nt expression patterns and the regulation of gene expression is normally accomplished at two maj r stages: (1) the transcription level via transcription factors/motifs (such as E2F4 transcription fac tor for cell-cycle regulation); (2) the translation level (also known as post-transcriptional regulation) via microRNAs (such as some microRNA inhibits the E 2F1 protein, which regulates cell proliferation [9]). microRNA appears to bind to me ssenger RNA (mRNA) before it can be translated to proteins that switch genes on and off.
Recent advances in proteomic profiling of pancreatic ductal adenocarcinoma and the road ahead

ABSTRACT Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide. However, there remain many unmet clinical needs, from diagnosis to treatment strategies. The inherent complexity of the molecular characteristics of PDAC has made it difficult to meet these challenges, rendering proteomic profiling of PDAC a critical area of research. Area covered: In this review, we present recent advances in mass spectrometry (MS) and its current application in proteomic studies on PDAC. In addition, we discuss future directions for research that can efficiently incorporate current MS-based technologies that address key issues of PDAC proteomics. Expert commentary: Compared with other cancer studies, little progress has been made in PDAC proteomics, perhaps attributed to the difficulty in performing in-depth and large-scale clinical studies on PDAC. However, recent advances in mass spectrometry can advance PDAC proteomics past the fundamental research stage.
Moving beyond genome-wide association studies.

The sequencing of the human genome1 and the subsequent completion of the human haplotype mapping (HapMap) project2 have led to unparalleled research into the structure and biology of the genome. These milestones held the promise of revolutionizing our understanding of the genetic basis for human disease, with the hope that population research would quickly lead to improved screening and diagnosis, along with targeted medical treatment. The advent of new genotyping technology and collaborative scientific efforts allowed for extensive scans across the genome to uncover genetic associations with various complex diseases and traits using genome-wide association (GWA) studies. At the end of 2010, the catalogue of published GWA studies compiled by the National Human Genome Research Institute (www.genome.gov/gwastudies) listed more than 700 published GWA studies and associations with nearly 4000 single-nucleotide polymorphisms (SNPs), providing new insights into the genetic architecture underlying disease.3 For the most part, however, the identified variants explain a relatively small proportion of the overall genetic variance of a given trait or disease,4 and the promise of a revolution in disease risk prediction and personalized genomic medicine has not yet been realized. Instead, what has occurred has been a revolution in biology rather than clinical medicine. Genetic studies have revealed a much greater complexity underlying the genomic basis for disease than scientists originally hypothesized. To maximize our understanding of these new biological mechanisms that may lead to advancements in the science of medicine, there is a need to follow up on GWA studies using multiple experimental methods and techniques with collaboration between different scientific disciplines. Many significant associations discovered by GWA studies have not been within previously known candidate genes, thus identifying critical gaps in our knowledge and providing new clues to the pathophysiologic mechanisms underlying cardiovascular disease (CVD). However, when it comes to …
Criminal behavior analysis based on Complex Networks theory

A criminal location relationship network model based on Complex Networks theory is set up in this paper. By the research of this criminal location relationships network, a real weighted network, a number of methods and knowledge which are ignored by experts and scholars in their research are found here. Firstly, the criminal location relationship network model is built by using a considerable number of real data. Then, the criminal location relationship network is projected to other weighted networks: the criminal-location-case relationship network and the criminal-location-number relationship network. Finally, the two weighted networks above are simulated and analyzed.
Activation of IL-6R/JAK1/STAT3 Signaling Induces De Novo Resistance to Irreversible EGFR Inhibitors in Non–Small Cell Lung Cancer with T790M Resistance Mutation

The secondary T790M mutation in epidermal growth factor receptor (EGFR) is the major mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (TKI) in non–small cell lung cancer (NSCLC). Although irreversible EGFR TKIs, such as afatinib or dacomitinib, have been introduced to overcome the acquired resistance, they showed a limited efficacy in NSCLC with T790M. Herein, we identified the novel de novo resistance mechanism to irreversible EGFR TKIs in H1975 and PC9-GR cells, which are NSCLC cells with EGFR T790M. Afatinib activated interleukin-6 receptor (IL-6R)/JAK1/STAT3 signaling via autocrine IL-6 secretion in both cells. Inhibition of IL-6R/JAK1/STAT3 signaling pathway increased the sensitivity to afatinib. Cancer cells showed stronger STAT3 activation and enhanced resistance to afatinib in the presence of MRC5 lung fibroblasts. Blockade of IL-6R/JAK1 significantly increased the sensitivity to afatinib through inhibition of afatinib-induced STAT3 activation augmented by the interaction with fibroblasts, suggesting a critical role of paracrine IL-6R/JAK1/STAT3 loop between fibroblasts and cancer cells in the development of drug resistance. The enhancement of afatinib sensitivity by inhibition of IL-6R/JAK1/STAT3 signaling was confirmed in in vivo PC9-GR xenograft model. Similar to afatinib, de novo resistance to dacomitinib in H1975 and PC9-GR cells was also mediated by dacomitinib-induced JAK1/STAT3 activation. Taken together, these findings suggest that IL-6R/JAK1/STAT3 signaling can be a potential therapeutic target to enhance the efficacy of irreversible EGFR TKIs in patients with EGFR T790M. Mol Cancer Ther; 11(10); 2254–64. ©2012 AACR.
A NEW ASK DEMODULATOR FOR A PERIPHERAL NERVE STIMULATING SYSTEM

A new ASK demodulator is presented that is used in implantable peripheral nerve stimulating systems powered through an inductive link. In these systems the received signal, which is a carrier modulated with the incoming data, is used both for generating the system’s power supply and transferring the data stream that is needed for the control of the system. The new demodulator uses two of the signals that are already available in the power generation block to demodulate the data. The circuit is designed for a typical 0. 5μm Standard N-Well CMOS process and occupies 65μmx180μm silicon area. Keyword: ASK Demodulator, Implantable Peripheral Nerve Stimulating Systems, Telemetry-Powered Systems, CMOS Analog Circuits.
IMD Anaysis-Based TC-CI/OFDM System for PAPR Reduction and BER Improvement

OFDM (orthogonal frequency division multiplexing) is very effective for the high speed communication system. However, this OFDM communication becomes poor because many overlapped time-domain signals produces the high PAPR (peak to average power ratio) and this causes the nonlinear distortion in the HPA (high power amplifier). In this paper, we propose a new TC-CI/OFDM (tone controlled carrier interferometry) to solve the high PAPR problem and apply the IMD (inter-modulation distortion) reduction techniques into this TC-CI/OFDM system in order to improve BER performance. PAPR can be reduced by adding the control tones in each OFDM symbol in the CI/OFDM system. So, TC-CI/OFDM system is more robust to the nonlinearity and IMD. The influences of the third-order term of the nonlinear input/output polynomial expression and the nonlinear HPA are studied by the theoretical and simulation analyses. It can be shown that TC-CI/OFDM system based on the IMD reduction is better than the same system based on PAPR reduction
NURTURING LEARNER AUTONOMY: A CASE OF CONTINUOUS COMPREHENSIVE EVALUATION Benudhar Chinara Multifarious behavioural objectives, plurality of learning experiences, activity-based learning process, competency- oriented different modes of assessment, and multiple ways of expressing and interpreting lea

Multifarious behavioural objectives, plurality of learning experiences, activity-based learning process, competencyoriented different modes of assessment, and multiple ways of expressing and interpreting learner’s attainment characterising Continuous and Comprehensive Evaluation should inherently be integrated with and guided by some basic principles of freedom, flexibility, plurality, continuity and consistency. Practising this process from the beginning and other higher levels of schooling may nurture autonomy in student-learners and subsequently yield the same with diversified areas and range at higher education level for truly empowering him/her how to learn, how to learn with joys and how to grow with challenges.
The Self-focused Practice Questionnaire (SfPQ): Preliminary Psychometric Properties of a Measure of Therapist Self-focused Practice

Background: Therapist self-practice, in its various forms, is common across therapeutic modalities, but a measure of its impact on participants does not yet exist. Aims: This paper describes the development and reliability testing of the ‘Self-focused Practice Questionnaire’ (SfPQ), a measure of self-perceived impact of one's self-focused practice. Method: Exploratory factor analysis (EFA), internal consistency and reliability were assessed in a convenience sample of 112 trainee therapists. Results: Five factors, rating impacts on therapist Personal-self (Awareness of Developmental experiences, Experience of Personal Change and Felt-sense/Self-awareness), and Therapist-self (Internalization of the Model, and Development of Empathy) were identified, with good internal consistency and acceptable to good test–retest reliability. Conclusions: Though more work is needed, these preliminary results support the SfPQ's reliability and validity. The SfPQ is an important measure, which may enhance routine rating of self-focused practice in training institutions.
Stroke Recovery Profile and the Modified Rankin Assessment

Background and Purpose: The purpose of this study was to examine the relationship between the Modified Rankin Scale (MRS) and poststroke recovery in neurological deficits, activities of daily living (ADL), higher level of physical and social functioning and the patients’ preference for health state. Methods: Four hundred and fifty-nine participants in the Kansas City Stroke Study were prospectively assessed for measures of MRS, NIH Stroke Scale (NIHSS), Barthel ADL, SF-36 physical functioning, SF-36 social functioning, and Time Trade-Off (TTO). ANOVA and Bonferroni multiple comparisons were used to examine any differences in 3-month scores of NIHSS, Barthel ADL, SF-36 physical functioning, SF-36 social functioning and TTO between levels of the MRS. In addition, SF-36 physical functioning, SF-36 social functioning and TTO were characterized in patients who demonstrated improvement in global MRS outcome and also achieved a Barthel Index (BI) ≧95 at 3 months after stroke. Results: Two hundred and eighty patients (62%) shifted at least one grade in MRS from baseline to 3 months after stroke. Only 67 or 194 patients were considered to have a favorable outcome using MRS 0/1 or MRS 0/1/2, respectively, as criteria. Mean 3-month NIHSS and Barthel ADL scores were not significantly different between Rankin 0/1 and 2, but they were significantly different among Rankin 3, 4 and 5 (all p < 0.05). Mean 3-month scores of physical functioning and SF-36 social functioning were significantly different among Rankin 0/1, 2, 3 and 4 (all pairwise p < 0.05). Proportions of patients who achieved NIHSS ≤1 or BI ≧95 decreased as MRS grades worsened. In patients who showed improvement in MRS global outcome and also achieved BI ≧95, mean scores on TTO were similar. Conclusions: Definition of favorable outcomes should include transition in the Modified Rankin score rather than MRS dichotomized as 0/1 or 0/1/2 because patients with transition in MRS scores have improvement in ADL, increased higher level of functioning and higher utility for health state.
A new Computer Friendly Notation for Musical Composition in Just Intonation allowing Easy Transposition by Multiplication of Notations

Musical notation systems provide ways of recording which notes musicians should play at which times. One essential parameter described is the frequency. For twelve note tuning systems the frequency can be described using letters A to G with sharp or flat symbols. For Just Intonation tuning systems these symbols are insufficient. This paper provides a system for describing any frequency which is a rational number multiplied by a suitable base frequency. Explicit notation is given for low prime numbers, and an algorithm for higher primes described. Also the differences between exact note names and note names up to octave equivalence are discussed.
Sleep apnea--a major public health problem.

The National Commission on Sleep Disorders Research was established by Congress in 1988 “to conduct a comprehensive study of sleep disorders and to develop a long-range plan for the use and organization of national resources to deal effectively with sleep disorders research and medicine”1. The report of the commission, which was recently published,1 indicates that each year the lives of millions of Americans are disturbed, disrupted, or destroyed by the consequences of sleep disorders. Among specific sleep disorders, the most serious in terms of morbidity and mortality is obstructive sleep apnea2. This disorder is characterized by recurrent episodes .
USE OF MOLECULAR MARKERS FOR EVALUATION OF GENETIC DIVERSITY AND IN ANIMAL PRODUCTION

INTRODuCTION Genetic markers provide information about allelic variation at a given locus. The increasing availability of molecular markers in farm animals allows the detailed analyses and evaluation of genetic diversity and furthermore the detection of genes influencing economically important traits. The majority of molecular markers used nowadays with high-throughput systems are microsatellite markers (simple tandem repeat, STR). Variable number of tandem repeats (VNTRs), random amplified polymorphic DNA (RAPD) markers, single strand conformation polymorphisms (SSCPs), restriction fragment length polymorphisms (RFLPs) and amplified fragment length polymorphisms (AFLPs) markers are not commonly applied in farm animals. Additionally within diversity and phylogeny studies specific mtDNA and Y chromosome markers are used for the identification of maternal and paternal lineages. Beyond diversity studies molecular markers are also used for mapping quantitative trait loci (QTL) and within marker assisted selection (MAS). Until recently microsatellites were the markers used for mapping quantitative trait loci for production and functional traits in farm animals (Hiendleder et al., 2003; Kuhn et al., 2003) and tightly linked markers are used for marker assisted selection in practise. They are also the prerequisite for the identification of positional and functional candidate genes responsible for quantitative traits. The detailed use of molecular markers for the evaluation of genetic diversity and identification of economically important traits in animal production is presented on the basis of different examples.
Evaluation and Clinical Analyses of Downstream Targets of the Akt Inhibitor GDC-0068

Purpose: The oncogenic PI3K/Akt/mTOR pathway is an attractive therapeutic target in cancer. However, it is unknown whether the pathway blockade required for tumor growth inhibition is clinically achievable. Therefore, we conducted pharmacodynamic studies with GDC-0068, an ATP competitive, selective Akt1/2/3 inhibitor, in preclinical models and in patients treated with this compound. Experimental Design: We used a reverse phase protein array (RPPA) platform to identify a biomarker set indicative of Akt inhibition in cell lines and human-tumor xenografts, and correlated the degree of pathway inhibition with antitumor activity. Akt pathway activity was measured using this biomarker set in pre- and post-dose tumor biopsies from patients treated with GDC-0068 in the dose escalation clinical trial. Results: The set of biomarkers of Akt inhibition is composed of 10 phosphoproteins, including Akt and PRAS40, and is modulated in a dose-dependent fashion, both in vitro and in vivo. In human-tumor xenografts, this dose dependency significantly correlated with tumor growth inhibition. Tumor biopsies from patients treated with GDC-0068 at clinically achievable doses attained a degree of biomarker inhibition that correlated with tumor growth inhibition in preclinical models. In these clinical samples, compensatory feedback activation of ERK and HER3 was observed, consistent with preclinical observations. Conclusion: This study identified a set of biomarkers of Akt inhibition that can be used in the clinical setting to assess target engagement. Here, it was used to show that robust Akt inhibition in tumors from patients treated with GDC-0068 is achievable, supporting the clinical development of this compound in defined patient populations. Clin Cancer Res; 19(24); 6976–86. ©2013 AACR.