Miracle-dz/UniFAR-FTUs huggingface dataset:
In pursuit of small molecule chemistry for calcium‐permeable non‐selective TRPC channels – mirage or pot of gold?

The primary purpose of this review is to address the progress towards small molecule modulators of human Transient Receptor Potential Canonical proteins (TRPC1, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7). These proteins generate channels for calcium and sodium ion entry. They are relevant to many mammalian cell types including acinar gland cells, adipocytes, astrocytes, cardiac myocytes, cochlea hair cells, endothelial cells, epithelial cells, fibroblasts, hepatocytes, keratinocytes, leukocytes, mast cells, mesangial cells, neurones, osteoblasts, osteoclasts, platelets, podocytes, smooth muscle cells, skeletal muscle and tumour cells. There are broad‐ranging positive roles of the channels in cell adhesion, migration, proliferation, survival and turning, vascular permeability, hypertrophy, wound‐healing, hypo‐adiponectinaemia, angiogenesis, neointimal hyperplasia, oedema, thrombosis, muscle endurance, lung hyper‐responsiveness, glomerular filtration, gastrointestinal motility, pancreatitis, seizure, innate fear, motor coordination, saliva secretion, mast cell degranulation, cancer cell drug resistance, survival after myocardial infarction, efferocytosis, hypo‐matrix metalloproteinase, vasoconstriction and vasodilatation. Known small molecule stimulators of the channels include hyperforin, genistein and rosiglitazone, but there is more progress with inhibitors, some of which have promising potency and selectivity. The inhibitors include 2‐aminoethoxydiphenyl borate, 2‐aminoquinolines, 2‐aminothiazoles, fatty acids, isothiourea derivatives, naphthalene sulfonamides, N‐phenylanthranilic acids, phenylethylimidazoles, piperazine/piperidine analogues, polyphenols, pyrazoles and steroids. A few of these agents are starting to be useful as tools for determining the physiological and pathophysiological functions of TRPC channels. We suggest that the pursuit of small molecule modulators for TRPC channels is important but that it requires substantial additional effort and investment before we can reap the rewards of highly potent and selective pharmacological modulators.
Entrepreneurship in Haiti: Toward an Identification of The ‘Blind Spots’

In countries that have experienced abusive power relationships, ongoing poverty, prejudice, violence and natural disaster, changes hardly happen and if they do, they are very slow. Haiti is not an exception. The problem of entrepreneurship in Haiti goes beyond human management and business management skills. It is first of all a human issue: The primary needs of the locals need to be met; a sense of community needs to be developed and the locals need to be able to dream; and finally, the right context needs to be put in place and the ‘yes, we can spirit’ encouraged. It is the improvement of the well-being of Haitians that is going to lead to the development of a strong entreprrenurial system. It is a one way relationship. In poor countries like Haiti it is important to address the human condition first. Unlocking change through: transformational leadership; enterprise reform; technology innovation; corporate transparency; stakeholders engagement; social responsibility; integrated value and finally, through future-fitness could be a potential option for Haiti.
Expected Utility Theory and Experimental Utility Measurement, 1950–1985. From Confidence to Skepticism

The paper reconstructs the history of the experimental attempts to measure the cardinal utility of money between 1950 and 1985 within the framework provided by expected utility theory (EUT). It is shown that this history displays a definite trajectory: from the confidence in EUT and the EUT-based measurement of utility of the 1950s to the scepticism that, from the mid-1970s, haunted the validity of EUT as well as the significance of the utility measures obtained through it. By exploring the diverse aspects and causes of this trajectory, the paper covers new ground in the history of both decision theory and utility measurement.
T2 magnetic resonance assay for the rapid diagnosis of candidemia in whole blood: a clinical trial.

BACKGROUND Microbiologic cultures, the current gold standard diagnostic method for invasive Candida infections, have low specificity and take up to 2-5 days to grow. We present the results of the first extensive multicenter clinical trial of a new nanodiagnostic approach, T2 magnetic resonance (T2MR), for diagnosis of candidemia. METHODS Blood specimens were collected from 1801 hospitalized patients who had a blood culture ordered for routine standard of care; 250 of them were manually supplemented with concentrations from <1 to 100 colony-forming units (CFUs)/mL for 5 different Candida species. RESULTS T2MR demonstrated an overall specificity per assay of 99.4% (95% confidence interval [CI], 99.1%-99.6%) with a mean time to negative result of 4.2 ± 0.9 hours. Subanalysis yielded a specificity of 98.9% (95% CI, 98.3%-99.4%) for Candida albicans/Candida tropicalis, 99.3% (95% CI, 98.7%-99.6%) for Candida parapsilosis, and 99.9% (95% CI, 99.7%-100.0%) for Candida krusei/Candida glabrata. The overall sensitivity was found to be 91.1% (95% CI, 86.9%-94.2%) with a mean time of 4.4 ± 1.0 hours for detection and species identification. The subgroup analysis showed a sensitivity of 92.3% (95% CI, 85.4%-96.6%) for C. albicans/C. tropicalis, 94.2% (95% CI, 84.1%-98.8%) for C. parapsilosis, and 88.1% (95% CI, 80.2%-93.7%) for C. krusei/C. glabrata. The limit of detection was 1 CFU/mL for C. tropicalis and C. krusei, 2 CFU/mL for C. albicans and C. glabrata, and 3 CFU/mL for C. parapsilosis. The negative predictive value was estimated to range from 99.5% to 99.0% in a study population with 5% and 10% prevalence of candidemia, respectively. CONCLUSIONS T2MR is the first fully automated technology that directly analyzes whole blood specimens to identify species without the need for prior isolation of Candida species, and represents a breakthrough shift into a new era of molecular diagnostics. CLINICAL TRIALS REGISTRATION NCT01752166.
Intracellular localization of HSP73 and HSP90 in rat kidneys with acute lysosomal thesaurismosis

We previously reported that HSP73 and HSP90, major chaperone proteins, accumulated within lysosomes of proximal tubular epithelial cells in rat kidneys with acute gentamicin nephropathy. In this study, we observed serial localization of HSP73 and HSP90 in rat kidneys with acute lysosomal thesaurismosis. Sprague‐Dawley rats received poly‐ D‐glutamic acid (PDGA) (250 mg/kg per day) for 3 days, and developed acute lysosomal thesaurismosis of proximal tubular epithelial cells. The intracellular localization of HSP73 and HSP90 was examined by electron microscopy. We also compared the results with those of a non‐chaperone protein, a renal isoform of argininosuccinate synthetase, which is an abundant enzyme in proximal tubular epithelial cells. After the PDGA exposure, HSP73 and HSP90 accumulated within enlarged lysosomes of proximal tubular epithelial cells. These accumulations started to appear from day 4 after the first PDGA administration, enlarged in size until day 14, and continued until day 19. Argininosuccinate synthetase also accumulated within the lysosomes, but the magnitude of this lysosomal accumulation was less than those of HSP73 and HSP90. Our findings demonstrated that HSP73 and HSP90 chaperone proteins specifically accumulated within lysosomes of proximal tubular epithelial cells during the course of PDGA‐induced acute lysosomal thesaurismosis.
Burnout: Results of an empirical study of New Zealand nurses

Abstract Burnout is conceptualised as a syndrome consisting of three components-emotional exhaustion, reduced personal accomplishment and depersonalisation of clients or patients that occurs in individuals who work in the human service professions, particularly nursing. It has been observed that nurses are at a high risk of burnout and burnout has been described as the ‘professional cancer’ of nursing. This is the first New Zealand study to use the Maslach Burnout Inventory (MBI) and the Phase Model of Burnout to determine the extent and severity of burnout in a population of 1134 nurses. Results revealed an overall ‘low to average’ level of burnout, suggesting that New Zealand nurses, apart from those in the 41—45 age group, are doing better than expected insofar as they are managing to avoid or not progress to the advanced phases of burnout. Possible explanations and directions for future research are presented.
Interaction between Cell Cycle Regulator, E2F-1, and NF-κB Mediates Repression of HIV-1 Gene Transcription*

The NF-κB/Rel family of transcription factors is one of the main targets of cytokines and other agents that induce HIV-1 gene expression. Some of these extracellular stimuli arrest cells in the G1 phase of the mitotic division cycle and modulate the activity of the tumor suppressor protein Rb and its partner E2F-1. Earlier studies indicated that E2F-1, a transcription factor that stimulates expression of S-phase-specific genes, is able to repress transcription directed by the human immunodeficiency virus (HIV-1) type-1 promoter in a variety of cells, including those of glial and lymphocytic origin. Here, we demonstrate that E2F-1 may regulate the activity of the HIV-1 long terminal repeat through its ability to bind sequences in the NF-κB enhancer region and to interact with the NF-κB subunit, p50. Gel retardation and methylation interference assays show that E2F-1 is able to bind specifically to a site embedded within the two NF-κB elements. Gel retardation/immunoblot analysis using purified E2F-1 and p50 homodimers reveals the presence of complexes containing both proteins. Affinity chromatography and co-immunoprecipitation assays provide evidence for direct interaction of E2F-1 and p50 in the absence of their DNA target sequences. In vitro transcription assay demonstrates that E2F-1 represses NF-κB mediated transcription in a cell-free system. Functional studies in Jurkat T lymphocytic cells point to the importance of both the E2F and NF-κB binding sites in E2F-1 mediated repression of HIV-1 promoter, in vivo. The results of this study suggest that NF-κB activity may be regulated by its interaction with the cell cycle regulatory protein, E2F-1.
DRUG USAGE AND ADVERSE DRUG REACTIONS IN PAEDIATRIC PATIENTS

Abstract. The development of epidemiological methods for the study of adverse drug reactions is reviewed in connection with the presentation of data obtained by intensive monitoring of 1000 admissions to a medical paediatric unit. Compared with adults and American children, the patients received fewer drugs and experienced fewer reactions while in hospital. The drug usage pattern was different from that of American paediatric practice and general practice in the United Kingdom. Fifty‐one (6%) patients experienced 119 adverse drug reactions. These occurred more frequently in children suffering from serious disorders and in the majority of cases the basic therapy was continued regardless of the severity of the drug side–effects. Treatment was required for the effects of 66 (55 %) adverse reactions. It appears that drug monitoring in paediatric practice may be of greater value if surveillance programmes are designed to provide a “therapeutic audit” and extended to include children receiving drugs in the community.
Main banks’ influence on financial reporting quality in Japan

ABSTRACT This study investigated main banks’ influence on the quality of accounting firms’ audits and corporate firms’ earnings, focusing on companies on Japan’s Nikkei 500 index. We posed three questions in this research study about main banks’ influence on corporate clients’ earnings management. First, does a weakened main bank relationship influence corporate clients’ financial reporting quality? Second, does Japan’s firewall deregulation influence firms’ earnings quality? Finally, does the relationship between accounting firms and main banks affect client firms’ earnings quality? Our main findings were that main banks are not related to client firms’ earnings management; however, main banks mitigate client firms’ earnings management after firewall deregulation. On the other hand, firewall deregulation does motivate firms to manipulate their earnings management. Finally, using Pong and Kita’s (2006) study as a framework, we found that main banks and client firms using the same accounting firms had no influence on earnings management. Based on these evidences presented, our findings suggest that the quality of corporate clients’ financial reporting changes before and after firewall deregulation.
Resistance to antimony and treatment failure in human Leishmania (Viannia) infection.

BACKGROUND Failure of antimonial therapy has been increasingly reported in anthroponotic visceral leishmaniasis and in cutaneous disease. The role of drug resistance in treatment failure has been difficult to ascertain because therapeutic response is multifactorial, and the efficacy of antimonial drugs depends on an effective immune response. In this study, we sought to determine whether standard treatment selects for resistant organisms and whether drug resistance contributes to treatment failure. METHODS We evaluated the susceptibility to antimony of 19 strains isolated before treatment with meglumine antimoniate and 21 strains isolated at treatment failure from 20 patients. The 50% effective dose (ED50) of antimony in the form of additive-free meglumine antimoniate was determined for intracellular amastigotes in human promonocytic U-937 cells. RESULTS Before treatment, 16% of strains (3/19) showed primary resistance (ED50 of >128 microg Sb/mL), whereas 84% (16/19) were susceptible (ED50 of <20 microg Sb/mL). However, 88% of susceptible strains (14/16) had ED90 values of >128 microg Sb/mL. At treatment failure, 40% of strains (8/20) were resistant. Secondary resistance was documented in 4 patients. CONCLUSIONS Primary and secondary resistance to antimony can contribute to treatment failure in American cutaneous leishmaniasis. Selection for resistance to antimony occurs during standard treatment with antimonial drugs, and primary resistance to antimony supports the plausibility of anthroponotic transmission.
Rearrangement of neuronal responses in the trigeminal system of the rat following peripheral nerve section.

The infraorbital nerve was cut in either neonatal (on day 0) or adult (day 60) rats and the peripheral regeneration prevented. After 60 days either anatomical or electrophysiological techniques were used to study the peripheral nerve, trigeminal nucleus and somatosensory cortex. In neonatally sectioned animals the number of myelinated fibres surviving, at 60 days, in the peripheral nerve proximal to the lesion was 11% compared with 100% survival after adult nerve section. This reduction in surviving nerve fibres in neonatally lesioned animals was associated with a significant reduction in cross‐sectional area of all trigeminal nuclei (principalis, oralis, interpolaris and caudalis) of 18‐29%. No significant change in area was present in animals sectioned as adults. Neonatally lesioned animals also showed a reduction of approximately 20% in the number of cells visible in cross‐sections of all trigeminal nuclei. Animals sectioned as neonates showed marked plasticity at all nuclei in the trigeminal complex as well as in the cortex. Deafferented cells responded to new peripheral receptive fields so that the somatotopic organization of these cells was modified. Such cells are referred to throughout as 'reactivated' cells. However, in animals sectioned as adults no evidence of plasticity could be detected in the trigeminal nuclei. Only very limited reactivation was apparent in the cortex, so that the majority of deafferented cells remained unresponsive at both sites. A detailed comparison was made of twenty‐three reactivated cells and twenty‐five normal cells from nucleus principalis of animals with nerve section on day 0. The reactivated cells commonly showed larger, more complex receptive fields, longer latencies and lower following frequencies, although stimulus thresholds were similar. Thus reactivated cells showed more convergence and poorer synaptic security than normal cells. However, stimulation of the contralateral thalamus produced similar responses from both groups of cells, suggesting that not all inputs to reactivated cells were modified. The time course of the reactivation of cells in nucleus caudalis from animals lesioned on day 0 was followed over 30 days. No acute effect, for up to 24 h, was detected. However, somatotopic reorganization had started by day 7, proceeded rapidly between days 7 and 14, and was completed by day 21.
Imaging Atherosclerosis and Vulnerable Plaque

Identifying patients at high risk for an acute cardiovascular event such as myocardial infarction or stroke and assessing the total atherosclerotic burden are clinically important. Currently available imaging modalities can delineate vascular wall anatomy and, with novel probes, target biologic processes important in plaque evolution and plaque stability. Expansion of the vessel wall involving remodeling of the extracellular matrix can be imaged, as can angiogenesis of the vasa vasorum, plaque inflammation, and fibrin deposits on early nonocclusive vascular thrombosis. Several imaging platforms are available for targeted vascular imaging to acquire information on both anatomy and pathobiology in the same imaging session using either hybrid technology (nuclear combined with CT) or MRI combined with novel probes targeting processes identified by molecular biology to be of importance. This article will discuss the current state of the art of these modalities and challenges to clinical translation.
Comparative analysis of the effects of a sphingosine kinase inhibitor to temozolomide and radiation treatment on glioblastoma cell lines

ABSTRACT Glioblastoma multiforme (GBM) exhibits high resistance to the standard treatment of temozolomide (TMZ) combined with radiotherapy, due to its remarkable cell heterogeneity. Accordingly, there is a need to target alternative molecules enhancing specific GBM autocrine or paracrine mechanisms and amplifying the effect of standard treatment. Sphingosine 1-phosphate (S1P) is such a lipid target molecule with an important role in cell invasion and proliferation. Sphingosine kinase inhibitors (SKI) prevent S1P formation and induce increased production of reactive oxygen species (ROS), which may potentiate radiation cytotoxicity. We analyzed the effect of SKI singular versus combined treatments with TMZ and radiation on 2 human GBM cell lines characterized by a lack of MGMT expression and low or high expression of the anti-oxidant enzyme, glutathione peroxidase 1 (GPx1). Effects were drug concentration-, cell line-dependent and partly ROS-mediated. Clonogenic survival assay demonstrates that SKI was more effective than TMZ in increasing the sensitivity of U87 cells, which express low GPx1 amount, to a 2 Gy X-ray dose. Addition of both SKI and TMZ drastically decreased U87 cells survival compared with the combination temozolomide/radiation. SKI less effectively than TMZ sensitized LN229 cells to the 2 Gy X-ray dose. Its combination to TMZ in absence of irradiation was as efficient as TMZ combination with X-ray. We provide first evidence for SKI as an alternative or complementary treatment to TMZ, and for efficient combinations of low doses of drugs and X-ray. These may help as novel bi-modal and tri-modal therapies to contend with GBM heterogeneity.
Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: a randomized trial.

BACKGROUND Although chemotherapy and ovarian function suppression are both effective adjuvant therapies for patients with early-stage breast cancer, little is known of the efficacy of their sequential combination. In an International Breast Cancer Study Group (IBCSG) randomized clinical trial (Trial VIII) for pre- and perimenopausal women with lymph node-negative breast cancer, we compared sequential chemotherapy followed by the gonadotropin-releasing hormone agonist goserelin with each modality alone. METHODS From March 1990 through October 1999, 1063 patients stratified by estrogen receptor (ER) status and radiotherapy plan were randomly assigned to receive goserelin for 24 months (n = 346), six courses of "classical" CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy (n = 360), or six courses of classical CMF followed by 18 months of goserelin (CMF --> goserelin; n = 357). A fourth arm (no adjuvant treatment) with 46 patients was discontinued in 1992. Tumors were classified as ER-negative (30%), ER-positive (68%), or ER status unknown (3%). Twenty percent of patients were aged 39 years or younger. The median follow-up was 7 years. The primary outcome was disease-free survival (DFS). RESULTS Patients with ER-negative tumors achieved better disease-free survival if they received CMF (5-year DFS for CMF = 84%, 95% confidence interval [CI] = 77% to 91%; 5-year DFS for CMF --> goserelin = 88%, 95% CI = 82% to 94%) than if they received goserelin alone (5-year DFS = 73%, 95% CI = 64% to 81%). By contrast, for patients with ER-positive disease, chemotherapy alone and goserelin alone provided similar outcomes (5-year DFS for both treatment groups = 81%, 95% CI = 76% to 87%), whereas sequential therapy (5-year DFS = 86%, 95% CI = 82% to 91%) provided a statistically nonsignificant improvement compared with either modality alone, primarily because of the results among younger women. CONCLUSIONS Premenopausal women with ER-negative (i.e., endocrine nonresponsive), lymph node-negative breast cancer should receive adjuvant chemotherapy. For patients with ER-positive (i.e., endocrine responsive) disease, the combination of chemotherapy with ovarian function suppression or other endocrine agents, and the use of endocrine therapy alone should be studied.
New localism or fuzzy centralism: policymakers’ perceptions of public education and involvement in education

ABSTRACT This research examines local authority involvement in education as a function of local policymakers’ perceptions of education as a public service – namely, whether public education is for the benefit of society as a whole, or for individual students and parents. Perceptions of education and involvement in education were assessed through 107 questionnaires returned by mayors and heads of local education departments in Israel. The results show that (1) local policymakers tend to perceive public education as a general public service, and (2) the relationship between this perception and involvement in education varies with the locality’s centre-periphery status. In peripheral localities, perceiving education as a general public service and an understanding of ‘society’ as the local community leads to greater involvement in education. In central localities, involvement rose with a more individualised perception. Implications of the findings are discussed in line with viewing education in the spirit of new localism.
Repeater insertion to reduce delay and power in RC tree structures

In large chips, the propagation delay of the data and clock signals is limited due to long resistive interconnect. The proper insertion of repeaters alleviates the quadratic increase in propagation delay with the interconnect length while decreasing the power dissipation by reducing the short-circuit current. These repeaters are inserted within different types of common resistive interconnect structures, such as a line or a tree. The application of repeaters to RC tree structures is discussed. A tree topology is a common interconnect structure frequently found in VLSI circuits. A short-channel transistor model is used as a foundation for the development of delay and power expressions to develop a design methodology for inserting repeaters into an RC tree network. Power dissipation expressions for these repeater structures are presented which consider both dynamic and short-circuit power. These design expressions are validated against simulated experiments with a maximum 11% and 16% deviation from SPICE for delay and power, respectively.