Miracle-dz/UniFAR-FTUs huggingface dataset:
An overview of Ca2+ mobilization assays in GPCR drug discovery

ABSTRACT Introduction: Calcium ions (Ca2+) serve as a second messenger or universal signal transducer implicated in the regulation of a wide range of physiological processes. A change in the concentration of intracellular Ca2+ is an important step in intracellular signal transduction. G protein-coupled receptors (GPCRs), the largest and most versatile group of cell surface receptors, transduce extracellular signals into intracellular responses via their coupling to heterotrimeric G proteins. Since Ca2+ plays a crucial role in GPCR-induced signaling, measurement of intracellular Ca2+ has attracted more and more attention in GPCR-targeted drug discovery. Areas covered: This review focuses on the most popular functional assays measuring GPCRs-induced intracellular Ca2+ signaling. These include photoprotein-based, synthetic fluorescent indicator-based and genetically encoded calcium indicator (GECI)-based Ca2+ mobilization assays. A brief discussion of the design strategy of fluorescent probes in GPCR studies is also presented. Expert opinion: GPCR-mediated intracellular signaling is multidimensional. There is an urgent need for the development of multiple-readout screening assays capable of simultaneous detection of biased signaling and screening of both agonists and antagonists in the same assay. It is also necessary to develop GECIs offering low cost and consistent assays suitable for investigating GPCR activation in vivo.
Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline

Objective: The aim was to formulate practice guidelines for the diagnosis and treatment of polycystic ovary syndrome (PCOS). Participants: An Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer developed the guideline. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. Two systematic reviews were conducted to summarize supporting evidence. Conclusions: We suggest using the Rotterdam criteria for diagnosing PCOS (presence of two of the following criteria: androgen excess, ovulatory dysfunction, or polycystic ovaries). Establishing a diagnosis of PCOS is problematic in adolescents and menopausal women. Hyperandrogenism is central to the presentation in adolescents, whereas there is no consistent phenotype in postmenopausal women. Evaluation of women with PCOS should exclude alternate androgen-excess disorders and risk factors for endometrial cancer, mood disorders, obstructive sleep apnea, diabetes, and cardiovascular disease. Hormonal contraceptives are the first-line management for menstrual abnormalities and hirsutism/acne in PCOS. Clomiphene is currently the first-line therapy for infertility; metformin is beneficial for metabolic/glycemic abnormalities and for improving menstrual irregularities, but it has limited or no benefit in treating hirsutism, acne, or infertility. Hormonal contraceptives and metformin are the treatment options in adolescents with PCOS. The role of weight loss in improving PCOS status per se is uncertain, but lifestyle intervention is beneficial in overweight/obese patients for other health benefits. Thiazolidinediones have an unfavorable risk-benefit ratio overall, and statins require further study.
Economic Adjustment in the Aftermath of 2008 Financial Crisis: A Case Study on the Chinese Economy under the Stimulus Package

The Chinese economy has been increasingly integrated into the global market, and thus has been severely hit by the outbreak of the Global financial crisis. With the introduction of the stimulus package that was launched in 2008, the economy has been affected by the stimulus package and the changes in macroeconomic policy significantly. The aim of the research is to provide a thorough analysis and assessment of the effects of the package on the economy, and possible policy recommendations and insights to the future development pattern will be provided in the thesis.
Researching on Superposition of Multi-Harmonics Sources in Power Supply System Based on the Central Limit Theorem

When nonlinear loads are put into operation at random phase angle in power system, the superposition of harmonics should be considered. Based on the characteristics of multi-harmonic source, this paper raised the central limit theorem to compute the superposition of harmonics currents of multi-harmonics sources. At the same time, the characteristic of probability statistic on the same order harmonics will be provided. It is proved that this method provided in the paper is feasible comparable to the Monte-Carlo simulation
Leaving An Abusive Partner

Four facets of leaving an abusive relationship are reviewed: (a) factors related to initially leaving an abusive partner; (b) the process of leaving an abusive relationship; (c) the psychological well-being of survivors after leaving; and (d) the predictors of this well-being. The conceptual and methodological limitations of studies in each of these areas are presented. Consistently found predictors of leaving include both material and psychological factors. Because battered women typically undergo several shifts in their thinking about the abuse before leaving permanently, research on leaving as a process is highlighted. A stress-process framework is used to explain the seemingly paradoxical finding that some women just out of the abusive relationship may have greater psychological difficulties than those who are still in it. For those experiencing the most stress, psychological health can worsen over time. Researchers and practitioners need to pay more attention to the plight of women who have left abusive partners.
Transition asymptotics of Toeplitz determinants and emergence of Fisher–Hartwig representations

We compute the transition asymptotics (double-scaling limits) of Toeplitz determinants generated by symbols f t possessing Fisher–Hartwig singularities. The symbols f t that we consider depend on a parameter t such that f t has one Fisher–Hartwig singularity when t > 0 and two Fisher–Hartwig singularities when t = 0. Unlike in the other studies of the transition asymptotics of Toeplitz determinants, our setting involves the emergence of Fisher–Hartwig representations as . We use the Riemann–Hilbert problem for orthogonal polynomials and its connection to Painlevé transcendents to obtain the asymptotics. We apply our results to study a special correlator known as the emptiness formation probability (EFP) for the one-dimensional anisotropic XY spin-1/2 chain in a transverse magnetic field, and describe its transition between different regions in the phase diagram across critical lines.
Bicycling breaks the ice for freezers of gait

Patients with freezing of gait (FOG) have episodic problems with generating adequate steps. This phenomenon is both common and debilitating in patients with Parkinson's disease (PD) or atypical parkinsonism. We recently presented a video case of a patient with longstanding PD and severe FOG, who showed a remarkably preserved ability to ride a bicycle. Here, we comment on the scientific and clinical implications of this single case observation, and show the video of a similar case. We first consider several pathophysiological explanations for this striking discrepancy between walking and cycling in PD. We then discuss the merits and shortcomings of cycling as a potential new avenue for rehabilitation and exercise training in patients grounded by FOG. Finally, we provide some directions for future research stimulated by this fascinating observation. © 2011 Movement Disorder Society
Human enteric Caliciviridae: a new prevalent small round-structured virus group defined by RNA-dependent RNA polymerase and capsid diversity.

Sequence comparison of the RNA-dependent RNA polymerases of small round-structured viruses (SRSVs) from 10 recent U.K. outbreaks of gastroenteritis revealed significant genetic variation. Computer analyses indicated that these viruses can be divided into two discrete groups. SRSV group I contains the previously characterized antigenic type 1 Norwalk and type 3 Southampton viruses. The amino acid sequences of the RNA polymerase, capsid and ORF3 of these two viruses are relatively similar (about 92%, 69% and 72% amino acid identity, respectively). A representative member of group II SRSVs, Bristol virus, was subjected to a detailed genetic analysis. Bristol virus is a recent antigenic type 2 isolate from a U.K. hospital outbreak of gastroenteritis. Using a single clinical sample the 3'-terminal 3881 nucleotide cDNA sequence [excluding the poly(A) tail] of this virus was determined. Analysis of the sequence revealed significant differences from those of group I viruses with the RNA polymerase region, capsid and ORF3 showing only about 62%, 43% and 30% amino acid identity respectively with the equivalent proteins of the Norwalk and Southampton viruses. These data suggest that the morphologically identical SRSVs belong to at least two genetically distinct groups.
[Vacuum assisted closure (V.A.C.) therapy is an essential tool for treatment of complex defect injuries of the upper extremity].

INTRODUCTION Complex injuries of the upper extremity remain a therapeutic challenge. The prognosis of the damaged extremity is often limited by soft tissue defects. Vacuum Assisted Closure (V.A.C.) therapy facilitates temporary coverage of soft tissue defects prior to surgical reconstruction. METHODS In a retrospective study all patients with complex defect injuries of the upper extremity that were treated by V.A. C. prior to reconstruction between August 2003 and September 2005 were analyzed. RESULTS 7 patients (6 male, 1 female, 14-70 years) were included in the study. The patients suffered from subtotal upper arm (n = 1) and forearm (n = 1) amputation, complex multilevel amputation injury of the forearm (n = 1), slash wound of the forearm with skin defect and discontinuity of all volar structures (n = 1), complex open forearm fractures with skin and soft tissue defects (n = 2), and almost complete necrosis of the flexor compartment following distal radius and proximal ulnar fracture and compartment syndrome (n = 1). Stabile defect coverage was achieved in all patients following V.A. C. therapy by myocutaneous free flaps (n = 2), split thickness skin grafts (STSG) (n = 2), sequential secondary suture (n = 1), and STSG + secondary suture (n = 2). Wound conditions improved significantly under V.A. C. therapy. 5 patients reported pain relief following induction of V.A. C. therapy. Due to reduction of tissue oedema secondary suture was facilitated in 3 patients. DISCUSSION V.A. C. therapy represents an essential tool for treatment of complex injuries of the upper extremity with extended soft tissue defects. Decreased frequency of dressing changes as well as reduced tissue oedema considerably improved patient's comfort. Posttraumatic compartment syndrome or skin necrosis, which are often associated with macro amputations of the upper extremity, are efficiently treated with V.A. C. , and secondary sutures may be performed despite initial skin defects.
Comparison of an Established Simple Office-Based Immunological FOBT With Fecal Tumor Pyruvate Kinase Type M2 (M2-PK) for Colorectal Cancer Screening: Prospective Multicenter Study

OBJECTIVES:The immunological fecal occult blood test (IFOBT) has established itself as a more precise marker for colorectal cancer (CRC) screening than traditional guaiac-based FOBT. The simpler, cheaper, and more convenient newer office-based IFOBTs have been validated for diagnosing CRC. Dimeric isoenzyme of pyruvate kinase, M2-PK, expressed by tumor cells, has as well been proposed as a screening tool for CRC. This is the first study comparing fecal M2-PK as a screening biomarker for CRC against previously evaluated office-based IFOBT and colonoscopy.METHODS:Six hundred forty consecutive subjects (symptomatic, as well as for CRC screening) referred for colonoscopy for various indications across five centers in Germany provided the stool samples for performing M2-PK and an immunochemical FOB strip test. The IFOBT used was a rapid immunochromatographic assay for detection of fecal hemoglobin. For M2-PK, a commercially available sandwich enzyme-linked immunosorbent assay (ELISA) was used. The M2-PK test needs 6 h, while the office-based test can be read in just 10 min and is five times cheaper.RESULTS:Office-based IFOBT had sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and positive and negative likelihood ratios (LR) of 64.5, 96.3, 72.0, 94.9, 17.5, and 0.4 for diagnosing colorectal neoplasia (CRN), while the above performance characteristics for M2-PK at a cutoff value of 4U/mL were 72.4, 73.8, 29.0, 94.8, 2.8, and 0.8 respectively.CONCLUSIONS:This office-based IFOBT was found to have significantly higher specificity, PPV, and positive LR as compared with M2-PK. IFOBT proved to be a convenient, noncumbersome, quick, and cheap tool in patients with above-average risk for detection of CRN.
The Anti-inflammatory Effects of Inhaled Corticosteroids versus Anti-leukotrienes on the Lymphocyte P-Glycoprotein (PGP) Expression in Asthmatic Children

Background. Inhaled corticosteroids (ICS) are used in asthma therapy for their anti-inflammatory effects. P-glycoprotein (PGP) is a transmembrane efflux pump for many drugs, including corticosteroids. Expression of PGP is associated with therapy resistant disease. Objective. The purpose of this study was to compare expression levels of PGP in blood lymphocytes of pediatric asthma patients either on ICS or on the leukotriene inhibitor montelukast medication. Patients and Methods. The evaluation of lymphocyte PGP expression was performed on a sample of 99 children (66 boys and 33 girls) aged 2–18 (median 12) years with intermittent or persisting mild asthma, (as defined by GINY 2002). The asthmatic children were divided into 3 groups: (1) treated by ICS budesonide 200–400 μg per day (n = 27) more than 1 year; (2) treated by oral montelukast 4 or 5 mg at an age-based dose (n = 16); and (3) treated by inhaled corticosteroids and montelukast (n = 45). Reference PGP values were obtained from a group of 64 healthy children (23 boys and 29 girls) aged 2–15 years (median, 10 years). The expression of lymphocyte PGP was determined on fixed and permeabilized blood mononuclear cells using indirect immunofluorescence staining technique by flow cytometry modified according to Boer et al., 1997. Results. Based on the weighted medians for PGP expression in peripheral blood lymphocytes, we found a significant difference (p < 10−3) between the group of asthma patients (n = 99), (619 ± 5.3) and healthy controls (n = 64) (446.9 ± 4.4). Second, there was a lower level of PGP expression in the group treated by ICS (548.6 ± 9) than the group treated by montelukast and montelukast with budesonide (643.2 ± 6.3) (p < 10−6). Conclusions. The anti-inflammatory activity of ICS is more effective in decreasing the production of pro-inflammatory mediators and results in reduced multidrug resistence (MDR-1) gene activity and expression of lymphocyte PGP in asthmatic children.
Comparison of Innovative Molecular Approaches and Standard Spore Assays for Assessment of Surface Cleanliness

ABSTRACT A bacterial spore assay and a molecular DNA microarray method were compared for their ability to assess relative cleanliness in the context of bacterial abundance and diversity on spacecraft surfaces. Colony counts derived from the NASA standard spore assay were extremely low for spacecraft surfaces. However, the PhyloChip generation 3 (G3) DNA microarray resolved the genetic signatures of a highly diverse suite of microorganisms in the very same sample set. Samples completely devoid of cultivable spores were shown to harbor the DNA of more than 100 distinct microbial phylotypes. Furthermore, samples with higher numbers of cultivable spores did not necessarily give rise to a greater microbial diversity upon analysis with the DNA microarray. The findings of this study clearly demonstrated that there is not a statistically significant correlation between the cultivable spore counts obtained from a sample and the degree of bacterial diversity present. Based on these results, it can be stated that validated state-of-the-art molecular techniques, such as DNA microarrays, can be utilized in parallel with classical culture-based methods to further describe the cleanliness of spacecraft surfaces.
Efficacy of succimer chelation for reducing brain lead in a primate model of human lead exposure.

The extent to which succimer (meso-2,3-dimercaptosuccinic acid [DMSA], Chemet) reduces brain lead (Pb) levels may be a primary consideration in evaluating its efficacy for reducing neurotoxicity. Clinical research in this area has been hampered by the need to use blood Pb levels as the index of treatment efficacy, despite the fact that brain Pb level is the exposure parameter of greater relevance to cognitive outcomes. Here, a nonhuman primate model of human Pb exposure was used to determine: (1) The efficacy of oral succimer for reducing brain Pb derived from chronic or recent exposures, and (2) The extent to which blood Pb levels reflect brain Pb prior to and following chelation. Adult rhesus monkeys were chronically exposed to Pb orally for 5 weeks to reach and maintain a target blood Pb level of 35-40 microg/dL. Chelation of Pb from recent exposures was assessed using a stable (204)Pb isotope tracer administered over 4 days prior to treatment. Immediately prior to chelation, a prefrontal cortex (PFC) biopsy was collected to determine pretreatment brain Pb levels. Subsequently, monkeys were assigned to vehicle (n = 5) or succimer (n = 6, 30 mg/kg/day x 5 days followed by 20 mg/kg/day x 14 days) groups. Blood and brain PFC, frontal lobe (FL), hippocampus (H), and striatum (S) were analyzed for total Pb and (204)Pb tracer concentrations by magnetic sector inductively coupled plasma-mass spectrometry. There were no measurable differences in brain Pb concentrations between the succimer and vehicle groups, indicating that succimer treatment was not efficacious in reducing brain Pb levels. In contrast, the cessation of Pb exposure significantly reduced brain (PFC) Pb ( approximately 34%) when compared to pretreatment levels (succimer and vehicle groups). Pb concentrations also varied among brain regions (PFC > FL approximately H > S). Finally, pretreatment PFC Pb concentrations were significantly correlated with the integrated blood Pb level (AUC) over the Pb exposure period, but not with the single pretreatment blood Pb collected concurrently with the PFC biopsy. Following treatment, blood Pb levels correlated only with Pb in the PFC, and not the other brain regions measured (FL, H, S). These data indicate that, under the conditions of this study, succimer treatment did not reduce brain Pb levels beyond the cessation of Pb exposure alone. Moreover, a single blood Pb measurement may be a poor predictor of brain Pb levels, reflecting limitations in the use of blood Pb level as an indicator of treatment efficacy.
Spatial differences in fatigue‐associated electromyographic behaviour of the human first dorsal interosseus muscle.

1. Fatigue‐associated electromyographic (EMG) reactions of intrinsic hand muscles were studied during maintained isometric voluntary contractions of normal subjects. Most measurements concerned actions of the first dorsal interosseus (FDI). In a smaller number of subjects, complementary measurements were obtained for adductor pollicis (AP). 2. Measurements were made of isometric force (thumb adduction, index finger abduction and flexion) and of surface EMG amplitudes (AP and FDI) after rectification and smoothing (rsEMG). 3. In the analysis of fatigue, the subjects were required to maintain a steady isometric force (index finger abduction or thumb adduction) of half their maximum voluntary contraction (1/2MVC test) for as long as possible. Average endurance times were 88 +/‐ 19 s (mean +/‐ S.D.) for FDI and 119 +/‐ 29 s for AP (Student's t test, P < 0.02). 4. Pronounced differences in fatigue‐associated EMG behaviour were observed between AP and FDI. In AP the reaction was as expected: a rise of EMG during maintained force (mean rsEMG at end of fatigue test/mean rsEMG at start of test (rsEMG‐FI): 181 +/‐ 64%). In FDI this reaction was seen in half of the recorded cases, the remainder displaying bidirectional changes or a more or less marked decrease of EMG during the endurance task (mean for all cases together: rsEMG‐FI, 103 +/‐ 15%; difference between AP vs. FDI significant, P < 0.01). 5. The unexpected EMG variability of the FDI reactions was further analysed with multiple bipolar recordings of surface EMG. For all the four thoroughly studied subjects, recordings were obtained which showed simultaneously occurring EMG changes in opposite directions (decrease and increase) at different sites of FDI while force was kept constant at 50% of the maximum voluntary contraction (MVC). 6. Further observations on FDI showed that EMGs simultaneously obtained from different recording sites could show dramatic differences in their responses depending on ‘synergistic context’ (e.g. in relation to changes in index finger extension force during maintained abduction at 50% MVC). Evidence for ‘task switching’ (shift in rsEMG distribution, shift in hand muscle synergy) was frequently observed during the performance of the 1/2MVC test. 7. The results indicate that FDI is not handled in a topographically homogeneous manner during the execution of an isometric constant force endurance test. Furthermore, the results suggest that this seemingly simple motor performance can be executed in several alternative manners associated with the activation of different muscle synergies and with different distributions of activity within the FDI.
US power plant sites at risk of future sea-level rise

Unmitigated greenhouse gas emissions may increase global mean sea-level by about 1 meter during this century. Such elevation of the mean sea-level enhances the risk of flooding of coastal areas. We compute the power capacity that is currently out-of-reach of a 100-year coastal flooding but will be exposed to such a flood by the end of the century for different US states, if no adaptation measures are taken. The additional exposed capacity varies strongly among states. For Delaware it is 80% of the mean generated power load. For New York this number is 63% and for Florida 43%. The capacity that needs additional protection compared to today increases by more than 250% for Texas, 90% for Florida and 70% for New York. Current development in power plant building points towards a reduced future exposure to sea-level rise: proposed and planned power plants are less exposed than those which are currently operating. However, power plants that have been retired or canceled were less exposed than those operating at present. If sea-level rise is properly accounted for in future planning, an adaptation to sea-level rise may be costly but possible.
The Potential of Emerging Technology for Social Change

The purpose of this panel is to explore the potential for emerging technology to engender social change. Technology is transformative, and has already seen innovative application in business and industry, and of course in relation to society and social networking. We will discuss the current state of 'emerging technology', and several perspectives of considerations with emerging technologies and society. We will describe some current applications of emerging technology in a range of fields, in order to identify the potential for emerging technology to support social change. Our goal is to open discussions about opportunities for emerging technology, and practical applications or approaches to how these opportunities can be exploited.