Miracle-dz/UniFAR-FTUs huggingface dataset:
A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice

Powering down yields a healthier heart In hypertrophic cardiomyopathy (HCM), the heart muscle enlarges and becomes progressively less efficient at pumping blood. HCM can be caused by mutations in components of the sarcomere (the heart's contractile unit), most notably myosin. Hypercontractility is among the earliest heart disturbances seen in mice carrying these myosin mutations, implying that the mutations inflict their damage by increasing myosin's power production. Green et al. identified a small molecule that binds to myosin and inhibits its activity (see the Perspective by Warshaw). When orally administered to young mice, the molecule prevented the development of several hallmark features of HCM without adversely affecting skeletal muscle. Science, this issue p. 617; see also p. 556 A small molecule that reduces cardiac muscle contraction prevents a certain type of heart disease in mice. [Also see Perspective by Warshaw] Hypertrophic cardiomyopathy (HCM) is an inherited disease of heart muscle that can be caused by mutations in sarcomere proteins. Clinical diagnosis depends on an abnormal thickening of the heart, but the earliest signs of disease are hyperdynamic contraction and impaired relaxation. Whereas some in vitro studies of power generation by mutant and wild-type sarcomere proteins are consistent with mutant sarcomeres exhibiting enhanced contractile power, others are not. We identified a small molecule, MYK-461, that reduces contractility by decreasing the adenosine triphosphatase activity of the cardiac myosin heavy chain. Here we demonstrate that early, chronic administration of MYK-461 suppresses the development of ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis and attenuates hypertrophic and profibrotic gene expression in mice harboring heterozygous human mutations in the myosin heavy chain. These data indicate that hyperdynamic contraction is essential for HCM pathobiology and that inhibitors of sarcomere contraction may be a valuable therapeutic approach for HCM.
Bioactive dietary polyphenols inhibit heme iron absorption in a dose-dependent manner in human intestinal Caco-2 cells.

UNLABELLED Although heme iron is an important form of dietary iron, its intestinal absorption mechanism remains elusive. Our previous study revealed that (-)-epigallocatechin-3-gallate (EGCG) and grape seed extract (GSE) markedly inhibited intestinal heme iron absorption by reducing the basolateral iron export in Caco-2 cells. The aim of this study was to examine whether small amounts of EGCG, GSE, and green tea extract (GT) could inhibit heme iron absorption, and to test whether the inhibitory action of polyphenols could be offset by ascorbic acid. A heme-⁵⁵Fe absorption study was conducted by adding various concentrations of EGCG, GSE, and GT to Caco-2 cells in the absence and presence of ascorbic acid. Polyphenolic compounds significantly inhibited heme-⁵⁵Fe absorption in a dose-dependent manner. The addition of ascorbic acid did not modulate the inhibitory effect of dietary polyphenols on heme iron absorption when the cells were treated with polyphenols at a concentration of 46 mg/L. However, ascorbic acid was able to offset or reverse the inhibitory effects of polyphenolic compounds when lower concentrations of polyphenols were added (≤ 4.6 mg/L). Ascorbic acid modulated the heme iron absorption without changing the apical heme uptake, the expression of the proteins involved in heme metabolism and basolateral iron transport, and heme oxygenase activity, indicating that ascorbic acid may enhance heme iron absorption by modulating the intracellular distribution of ⁵⁵Fe. These results imply that the regular consumption of dietary ascorbic acid can easily counteract the inhibitory effects of low concentrations of dietary polyphenols on heme iron absorption but cannot counteract the inhibitory actions of high concentrations of polyphenols. PRACTICAL APPLICATION Bioactive dietary polyphenols inhibit heme iron absorption in a dose-dependent manner. The small amounts of polyphenolic compounds present in foods are capable of reducing heme iron transport across the intestinal enterocyte. However, the inhibitory effects of dietary polyphenolic compounds on heme iron absorption can be offset by ascorbic acid and can possibly be avoided by decreasing the consumption of polyphenols while simultaneously taking ascorbic acid.
Effect of Intermittent Positive Pressure Ventilation on Cardiac Systolic Time Intervals

The measurement of systolic time intervals (STI) has been widely used as a non‐invasive method of assessing the inotropic state of the heart, and normal values are available for healthy individuals breathing spontaneously. The present study was performed in order to evaluate how intermittent positive pressure ventilation (IPPV) affects STI. Ten subjects were investigated before and during halothane anaesthesia for routine surgery. Oesophageal pressure, respiratory minute volume and frequency, arterial blood‐gas tensions, cardiac output and heart rate were also measured simultaneously.
New genotype of hepatitis C virus in South Africa

Partial nucleotide sequences in the core region of the hepatitis C viral genome were determined by reverse transcription followed by polymerase chain reaction, in a patient with chronic hepatitis from South Africa. These nucleotide sequences showed a low degree of homology with known types of HCV: the degree of homology between the nucleotide sequences of these clones with HC‐J1, J4, J6, J7, Tr, and Eb‐1 were 86.1‐87.3%, 87.3‐87.9%, 83.0‐83.9%, 81.1‐82.0%, 81.0‐82.2%, and 82.8‐83.4%, respectively, and that the deduced amino acid sequence homologies between these clones and HC‐J1, J4, H6, J7, Tr, and Eb‐1 were 90.7‐91.6%, 89.7‐91.6%, 91.6‐93.5%, 90.7‐91.6%, 81.5‐82.4%, and 89.2‐90.2%, respectively. The nucleotide sequence homologies of these clones with HC‐J1, J4, J6, J7, Tr, and Eb‐1 were very low, compared to those between the same genotype. Further comparison using molecular evolutionary methods suggested that this sequence should be classified in a new genotype. © 1994 Wiley‐Liss, inc.
Effects of sampling instrument and processing technique on DNA yield and detection rate for feline herpesvirus-1 via polymerase chain reaction assay.

OBJECTIVE To assess effects of disease severity, sampling instrument, and processing technique on extracted DNA yield and detection rate for feline herpesvirus-1 (FHV-1) via PCR assay. SAMPLE POPULATION Crandell-Rees feline kidney (CRFK) cells grown in vitro and conjunctival samples from 40 eyes of 20 cats. PROCEDURES Samples of CRFK cells (collected by use of a swab or cytology brush, with or without suspension in PBS solution) underwent DNA extraction; DNA yield was quantified spectrophotometrically. In affected cats, signs of herpetic disease were subjectively assessed. Conjunctival swab and brush samples were collected bilaterally for measurement of DNA concentration; a defined mass (DM) of DNA and defined volume (DV) of sample were assessed for FHV-1 via PCR assays. RESULTS For CRFK cells, DNA yields from unsuspended swabs and brushes were greater than for suspended swabs and brushes; suspended swab samples yielded less DNA than suspended brush samples. For conjunctival samples, DNA yields from swabs were greater than for brushes. Clinical score was not correlated with double-stranded DNA yield collected via either sampling instrument; however, cats with FHV-1-positive assay results had higher clinical scores than cats with FHV-1-negative results. Detection of FHV-1 in swab and brush samples was similar. Double-stranded DNA yield and FHV-1 detection were inversely related via DM-PCR assay. The DV-PCR assay had a significantly higher FHV-1 detection rate than the DM-PCR assay. CONCLUSIONS AND CLINICAL RELEVANCE The DV-PCR assay of DNA extracted from an unsuspended swab sample was the preferred method for assessment of conjunctival shedding of FHV-1 in cats.
Application of TaqMan Low-Density Arrays for Simultaneous Detection of Multiple Respiratory Pathogens

ABSTRACT The large and growing number of viral and bacterial pathogens responsible for respiratory infections poses a challenge for laboratories seeking to provide rapid and comprehensive pathogen identification. We evaluated a novel application of the TaqMan low-density array (TLDA) cards for real-time PCR detection of 21 respiratory-pathogen targets. The performance of the TLDA was compared to that of individual real-time PCR (IRTP) assays with the same primers and probes using (i) nucleic acids extracted from the 21 pathogen strains and 66 closely related viruses and bacteria and (ii) 292 clinical respiratory specimens. With spiked samples, TLDA cards were about 10-fold less sensitive than IRTP assays. By using 292 clinical specimens to generate 2,238 paired individual assays, the TLDA card exhibited 89% sensitivity (95% confidence interval [CI], 86 to 92%; range per target, 47 to 100%) and 98% specificity (95% CI, 97 to 99%; range per target, 85 to 100%) overall compared to IRTP assays as the gold standard with a threshold cycle (CT ) cutoff of 43. The TLDA card approach offers promise for rapid and simultaneous identification of multiple respiratory pathogens for outbreak investigations and disease surveillance.
5-Lipoxygenase and atherosclerosis

Purpose of review 5-Lipoxygenase (5LO) was recently identified as a gene that makes an important contribution to atherosclerosis in mice and humans, but the underlying mechanism(s) remains unknown. Recent findings Studies of the 5LO pathway in other disease areas suggest that 5LO could contribute to atherosclerosis at different levels, such as lesion initiation, growth and cellular proliferation within the lesion, and/or destabilization of plaques that can lead to their rupture. Summary Recent advances in our understanding of how 5LO is involved in the atherosclerotic process will have important implications for diagnostic and therapeutic strategies in the future.
Pharmacokinetics and Pharmacodynamics of Lansoprazole in Children with Gastroesophageal Reflux Disease

Objectives: To evaluate the pharmacokinetics and pharmacodynamics of lansoprazole in children between 1 and 11 years of age with gastroesophageal reflux disease (GERD). Methods: In a multicenter, open‐label trial of pediatric patients with symptomatic GERD, children were assigned, based on their weight, to receive lansoprazole 15 mg (patients weighing ≤30 kg) or lansoprazole 30 mg (patients weighing > 30 kg) once daily. The effects of lansoprazole on 24‐hour median intragastric pH, the percentages of time intragastric pH was above 3 and 4, and pharmacokinetic parameters were assessed at the day‐5 visit and compared to baseline. Results: Sixty‐six children were enrolled in the study. Mean lansoprazole Cmax values of 790.9 ng/mL and 898.5 ng/mL and Tmax values of 1.5 hours and 1.7 hours were observed in the ≤30 kg and the > 30 kg body weight treatment groups, respectively. AUC0‐24 values of 1707 ng‐h/mL and 1883 ng‐h/mL and T1/2 values of 0.68 hours and 0.71 hours were observed in the ≤ 30 kg and > 30 kg lansoprazole body weight treatment groups, respectively. There was no statistical significant difference in AUC0‐24 between the two groups (P = 0.2571). After 5 days of treatment lansoprazole produced significant increases in patients' 24‐hour mean intragastric pH and the percentages of time intragastric pH was above 3 and 4 compared to baseline. Conclusion: The observed pharmacokinetic properties of lansoprazole in children between 1 and 11 years of age with GERD were similar to those previously observed in healthy adult subjects. Lansoprazole significantly increased the mean 24‐hour intragastric pH and the percentages of time intragastric pH was above 3 and 4 when children were dosed with either 15 or 30 mg according to body weight.
Frequent expression of FAS/APO‐1 in Hodgkin's disease and anaplastic large cell lymphomas FAS/APO‐1 in Hodgkin's disease and anaplastic large cell lymphomas

FAS/APO‐1 (CD95) is a membrane glycoprotein belonging to the tumour necrosis factor/nerve growth factor receptor family, and which can trigger apoptosis in some lymphoid cell lines. Immunohistochemistry combined with Northern blotting allowed determination of the pattern of FAS/APO‐1 expression in a series of Ki‐1 [CD30] positive lymphoid malignancies, including 27 Hodgkin's disease and eight anaplastic large cell lymphomas. CD30 negative tumours used as controls included 27 B‐cell non‐Hodgkin's lymphomas, 14 T‐cell non‐Hodgkin's lymphomas, four reactive lymphadenitis, and non‐lymphoid tissues. Immunohistochemistry, performed on frozen sections, revealed a strong FAS/APO‐1 expression in 25 out of 27 (92%) Hodgkin's disease cases, predominantly in Reed Sternberg cells; 50 to 100% of the neoplastic cells in eight out of (100%) anaplastic large cell lymphoma cases were positive. In contrast, positive FAS/APO‐1 immunostaining was observed only in 22 out of 41 (53%) CD30 negative non‐Hodgkin's lymphomas. Northern blot analysis detected variable amounts of the FAS/APO‐1 transcript in the immunohistochemistry‐positive samples. These results suggest possible hyper‐expression of FAS/APO‐1 (CD95) in Hodgkin's disease and anaplastic large cell lymphomas.
Prevalence of hepatitis C virus genotypes in risk groups in the Republic of Macedonia: A 5 years survey

The prevalence of hepatitis C virus (HCV) genotypes depends on geographical location. HCV genotyping is important for epidemiological investigations and treatment management. The aim of this study was to determine the HCV genotype prevalence in the most prominent risk groups in the Republic of Macedonia in the last 5 years and to evaluate its association with patient's age, gender, and mode of transmission. A total of 1,167 HCV positive patients, divided into three risk groups (intravenous drug use, chronic hemodialysis, and other risk factor), were genotyped using an in‐house ASO hybridization method with genotype‐specific oligonucleotide probes. The genotypes 1, 2, and 3 were present with 52.2%, 0.6%, and 47.0%, respectively. Genotype 1 was most prevalent in hemodialysis (89.0%) and other risk factor group (53.8%). It was found associated independently with hemodialysis, age >40 and female gender. Genotype 3 predominated in intravenous drug users (64.0%) and was associated significantly also with age ≤40 and male gender. Multivariable logistic regression analysis pointed out hemodialysis (P < 0.0001, Exp (B) = 12.0) as a positive predictor factor for genotype 1 and age ≤40 (P = 0.021, Exp (B) = 1.8) and intravenous drug use (P < 0.0001, Exp (B) = 8.4) as a positive predictor factors for genotype 3. In conclusion, the main transmission route of HCV infection in the Republic of Macedonia is intravenous drug use, followed by hemodialysis. HCV genotypes 1 and 3 dominate in these two most prominent risk groups in the Republic of Macedonia. J. Med. Virol. 85:2072–2078, 2013. © 2013 Wiley Periodicals, Inc.
The extent of IT-enable organizational flexibility: an exploration study among Australian organizations

The intensity of market competition, the ever increasing demand for shortening time to market and the pressure of first mover advantage are forcing businesses to develop non-imitable sources of value creation. Information technology (IT) plays a key role as a necessary, but not sufficient, source of value. For IT to generate business value, IT has to adapt itself to a firm's continuously changing competitive environment. The strategic value of IT can be defined as an enabler of organizational flexibility. Hence, IT-enabled organizational flexibility is of strategic importance to organizations and has been found to affect competitive advantage. This study uses an enhanced concept of IT-enabled flexibility to investigate IT-enabled organizational flexibility among Australian organizations. The findings show that, even though Australian companies exhibit IT enabled organizational flexibility, company and IT department size are influencing the flexibility of IT. The paper provides an indication of the extent to which Australian organizations are poised to exploit the value generating potential of IT. Practitioners can use the result to benchmark where they stand in regards to the flexibility of their IT.
A phase II trial of intravenous etoposide (VP-16-213) in epithelial ovarian cancer resistant to cisplatin or carboplatin: clinical and serological evidence of activity

Etoposide (VP16) was administered intravenously at a dose of 150 mg/m2 daily for 2 days every 2 weeks to 24 patients with progressing epithelial ovarian carcinoma which was resistant to platinum analogues. Using standard response criteria there were five clinical partial responses (21%, 95% confidence limits 5–37%) and three disease stabilizations. However, the aim of our study was to determine if etoposide was non-cross-resistant with platinum analogues and therefore we also developed additional response criteria based on serial CA 125 levels. This was to enable us to differentiate within the heterogeneous group of responses that form the stable disease category. Nine of 23 patients (39%, 95% confidence limits 19–59%) demonstrated a fall (all rising prior to etoposide) and of these, three had a serologic partial remission (65% or greater fall). The serologic and clinical responses were strongly correlated. Falling CA 125 levels occurred in the eight patients with either clinical partial responses or disease stabilizations.
Multidrug-resistant phenotype influences the differentiation of a human colon carcinoma cell line.

The human colon carcinoma cell line HT29-D4, which constitutively expresses a very low level of the MDR1 gene product, was made multidrug resistant by transfection with a human MDR1 cDNA from the pHaMDR1/A expression vector and selection by colchicine. Resistant clones were 3- to 15-fold resistant to colchicine and were cross-resistant to doxorubicin (3- to 4-fold). MDR1 gene expression was associated with the expression of functional P-glycoprotein (gp-170); the function was reversed by verapamil and cyclosporin A. HT29-D4 cells are able to differentiate in vitro by replacement of glucose by galactose in the culture medium and also to release the carcinoembryonic antigen (CEA). Under these culture conditions, MDR1 mRNA and gp-170 were always expressed and the protein remained functional. Upon galactose treatment, resistant clones were less differentiated since they showed a heterogeneous monolayer organization accompanied by heterogeneous staining of cell-surface CEA and a high decrease (60-90%) of CEA release.
Variation in drought response of sal (Shorea robusta) seedlings.

Plant development and distribution in areas with seasonal rainfall are often related to the ability of plants to postpone desiccation or tolerate low water potentials during drought. Regeneration of Shorea robusta Gaertn. (sal), a commercially valuable, widely distributed tree of the Indian tropical belt, is unsuccessful at the base of the Himalaya. Seedling shoots die back repeatedly during the long drought that follows the monsoon rain. During the course of one year, we monitored changes in plant and soil water potentials (Psi), leaf conductance (gw), osmotic and elastic adjustment, and xylem conductance of sal seedlings of different sizes from three landforms: an alluvial plain at 540 m elevation, a slope at 510 m, and a montane site at 1370 m. Predawn plant Psi and gw were lowest in the smallest seedlings (< 20 cm tall). Across sites and seasons, seedlings > 100 cm tall had higher morning gw than seedlings in the other size classes. In all size classes, plant Psi was lowest during early summer, when leafing begins. Among sites, Psi and gw were lowest in seedlings at the montane site. Osmotic potential was lowest during leaf development and highest during the rainy season, and tissue elasticity was highest during winter. As leaf area increased during leaf development, xylem conductance per unit of xylem cross-sectional area also increased. We conclude that low Psi is unlikely to be a major cause of seedling mortality. Small seedlings, with low Psi, had low leaf conductance. Adjustments of osmotic and elastic properties appear to aid responses of seedlings to drought.
Diversification and the Value of Internal Capital Markets: The Case of Tracking Stock

Numerous studies document that diversified firms sell at a discount relative to comparable portfolios of stand-alone firms. One explanation is that these firms suboptimally invest by subsidizing poor performing business segments with resources from profitable business segments. On average, firms may indeed have internal capital markets that diminish firm value; however, it is also possible that internal capital markets add to firm value by relieving liquidity constraints. We examine the link between firm value and the value of internal capital markets using a relatively new form of corporate restructuring called tracking stock. We present a model that illustrates that the announcement effect of a tracking stock equity restructuring conveys information about the market's assessment of the value of a firm's internal capital market. We develop a direct measure of the profitability of the internal capital market, and we find a strong positive relation between it and tracking stock announcement effects, a finding consistent with our model.
Differential expression of SHP-1 in chronic myeloid leukemia

DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication. Just Accepted by Leukemia & Lymphoma
Réflexions sur Internet et les tendances de la criminalité

Cet essai envisage l’influence eventuelle d’Internet sur la criminalite traditionnelle, c’est-a-dire sur le volume total des vols et des violences dans nos societes. Apres avoir evalue les recherches sur l’effet criminogene des medias tels que les bandes dessinees, la television et les jeux video, nous examinons les effets potentiels d’Internet sur les tendances de la criminalite. En concordance avec la theorie de Cohen et Felson (1979), selon laquelle les changements dans nos activites routinieres sont lies aux fluctuations de la criminalite, nous nous demandons comment Internet a pu changer nos habitudes de vies et ainsi jouer sur le volume des crimes. Notre reflexion nous amene a penser qu’Internet fait baisser la criminalite pour trois raisons principales. Premierement, l’usage d’Internet confine son utilisateur a la maison ou au travail, des lieux de relative securite. Deuxiemement, l’usage d’Internet laisse des traces pratiquement indelebiles, ce qui est de nature a dissuader des delinquants potentiels de passer a l’acte. Et troisiemement, Internet fourmille d’informations qui ont un potentiel de protection contre le crime.