Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of a Novel Gene Cluster Participating in Menaquinone (Vitamin K2) Biosynthesis

We recently described the isolation and sequence analysis of a DNA region containing the genes of Bacillus stearothermophilus heptaprenyl diphosphate synthase, which catalyzes the synthesis of the prenyl side chain of menaquinone-7 of this bacterium. Sequence analyses revealed the presence of three open reading frames (ORFs), designated as ORF-1, ORF-2, and ORF-3, and the structural genes of the heptaprenyl diphosphate synthase were proved to consist of ORF-1 (heps-1) and ORF-3 (heps-2) (Koike-Takeshita, A., Koyama, T., Obata, S., and Ogura, K. (1995)J. Biol. Chem. 270, 18396–18400). The predicted amino acid sequence of ORF-2 (234 amino acids) contains a methyltransferase consensus sequence and shows a 22% identity with UbiG ofEscherichia coli, which catalyzesS-adenosyl-l-methionine-dependent methylation of 2-octaprenyl-3-methyl-5-hydroxy-6-methoxy-1,4-benzoquinone. These pieces of information led us to identify the ORF-2 gene product. The cell-free homogenate of the transformant of E. coli with an expression vector of ORF-2 catalyzed the incorporation ofS-adenosyl-l-methionine into menaquinone-8, indicating that ORF-2 encodes 2-heptaprenyl-1,4-naphthoquinone methyltransferase, which participates in the terminal step of the menaquinone biosynthesis. Thus it is concluded that the ORF-1, ORF-2, and ORF-3 genes, designated heps-1, menG, andheps-2, respectively, form another cluster involved in menaquinone biosynthesis in addition to the cluster ofmenB, menC, menD, andmenE already identified in the Bacillus subtilis and E. coli chromosomes.
Improving Heart Failure Symptom Recognition: A Diary Analysis

Background:Heart failure (HF) is a costly and highly disabling syndrome affecting nearly 5 million individuals yearly. Lifestyle changes are crucial to the successful management of HF, and daily weight monitoring is an essential component of self-care. Daily weights provide an objective indicator of fluid volume status in patients with HF. However, the practice of performing daily weights is underappreciated and infrequently implemented by patients. This may contribute to an inability to recognize worsening HF and, ultimately, delay in seeking medical care. Objective:The aim of this study was to evaluate weight monitoring diaries for adherence to daily weight monitoring, reasons for nonadherence, prevalence of weight gain of 3 lb or more in 1 day, and medical advice-seeking behavior after weight gain in a sample of patients with documented HF. Methods:A cohort study design was used to analyze data from 20 HF patients who participated in a tailored, one-on-one educational intervention. The analysis is part of a parent pilot study designed to improve symptom recognition and response to symptoms of fluid overload. Diary data were collected for 3 months after the intervention. The diaries provided information regarding symptoms that participants experienced, daily weights, and a record of unplanned hospital visits or contacts with their physician. Results:Of 20 participants in the study, 16 returned diaries for analysis. Two participants withdrew participation before the conclusion of the study and 2 participants who claimed to have completed their diary never returned the diary despite repeated reminders and telephone calls. Sixteen participant diaries were therefore available for analysis. The mean adherence score for these 16 participants was 79.4%. Seventy-five percent had weight gains of 3 lb or more in 1 day and only 1 person contacted his/her physician for weight gain. Vacation time was the most common reason for weighing nonadherence. Conclusion:This study revealed high adherence to daily weights in patients receiving an education session focused on fluid weight management. However, behavior related to daily weights did not lead to more appropriate use of physician or provider consultation. Diaries offer promise for symptom management and an opportunity for patients to engage in self-care; however, clinicians need to encourage patients to use the diary data to seek prompt medical care.
Oral insulin – a review of current status

Oral insulin is one of the most exciting areas of development in the treatment of diabetes because of its potential benefit in patient convenience, rapid insulinization of liver, adequate insulin delivery avoiding peripheral hyperinsulinaemia while potentially avoiding adverse effects of weight gain and hypoglycaemia. Growing evidence that earlier initiation of intensive insulin therapy produces sustained tight glycaemic control resulting in substantial delay in complications makes an effective oral insulin product even more vital for the management of patients with diabetes. Despite knowledge of this unmet medical need, oral delivery of insulin has been unsuccessful because of several barriers. For several decades, researchers have tried to develop oral insulin using various technologies without much clinical or commercial success. This review summarizes the development status of oral insulins which are publicly reported to be undergoing clinical studies. Currently, two oral insulin products are in an advanced stage of clinical development and first data from long‐term therapy are expected to be available in the second half of 2010.
Preoperative, Postoperative and One-Year Follow-Up of N-Terminal Pro-B-Type Natriuretic Peptide Levels in Volume Overload of Aortic Regurgitation: Comparison with Pressure Overload of Aortic Stenosis

Objectives: Limited data are available regarding the impact of pressure or volume overload on the clinical or echocardiographic parameters and the levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with chronic severe aortic valve diseases. We aimed to investigate and compare the relationships between these parameters in such patients. Methods: One hundred twenty-four consecutive patients who underwent aortic valve replacement for chronic severe aortic valve diseases were enrolled. Plasma NT- proBNP was measured and echocardiographic parameters were recorded before surgery, before discharge and 12 months after surgery. Results: NT-proBNP levels were significantly higher in patients with aortic regurgitation (AR) (n = 63) than in those with aortic stenosis (n = 61) (1,836.0 ± 376.1 vs. 508.4 ± 74.5 pg/ml, p = 0.001). There was a significant relationship between NT-proBNP levels and left ventricular mass index (LVMI) in AR (r = 0.436, p = 0.002) and a weaker, but significant, relationship between NT-proBNP levels and LVMI in aortic stenosis patients (r = 0.290, p = 0.046). In the AR group, preoperative NT-proBNP levels positively correlated with LVMI regression during the 12 months after surgery (r = 0.488, p = 0.001). Conclusion: NT-proBNP levels may reflect LVMI changes that are caused by volume overload rather than pressure overload in chronic aortic valve diseases. Higher preoperative NT-proBNP levels may predict left ventricular reverse remodeling early after surgery for chronic severe AR.
Prevalence of high-risk human papilloma virus types and cervical smear abnormalities in female sex workers in Chandigarh, India

Purpose: Cervical cancer is the most common cancer among women in developing nations. Nearly 90% of the cases have been linked to the presence of high-risk human papillomavirus (hrHPV) types 16 and 18. The risk of cervical cancer may be high in female sex workers (FSWs) due to multiple sexual partners. This study aimed to determine the prevalence of cytological abnormalities and hrHPV types 16 and 18 in FSWs in Chandigarh, North India using the liquid-based cytology (LBC) approach. Materials and Methods: The cervical brush samples were collected from 120 FSW and 98 age-matched healthy controls (HCs). These were subjected to pap smear using conventional method, LBC and the detection of hrHPV types 16 and 18 was carried out using polymerase chain reaction. Results: The LBC samples showed better cytological details and also reduced the number of unsatisfactory smears from 11% in Pap to 1.5% in the LBC. A significantly higher number of inflammatory smears were reported in FSWs (51.7% vs. 34.7%, P = 0.01). The hrHPV types 16/18 were detected in 33/120 (27.5%) FSW versus 23/98 (23.5%) HCs. The risk of acquiring hrHPV was higher in FSWs, who had age at first sex ≤25 years, higher income and the habit of smoking. Conclusion: The high prevalence of hrHPV among FSWs and HCs suggests the need for the implementation of effective National Screening Programme for early detection of hrHPV types to decrease the burden of cervical cancer, especially in high-risk population.
Phosphorylation of the Nuclear Transport Machinery Down-regulates Nuclear Protein Import in Vitro *

We have examined whether signal-mediated nucleocytoplasmic transport can be regulated by phosphorylation of the nuclear transport machinery. Using digitonin-permeabilized cell assays to measure nuclear import and export, we found that the phosphatase inhibitors okadaic acid and microcystin inhibit transport mediated by the import receptors importin β and transportin, but not by the export receptor CRM1. Several lines of evidence, including the finding that transport inhibition is partially reversed by the broad specificity protein kinase inhibitor staurosporine, indicate that transport inhibition is due to elevated phosphorylation of a component of the nuclear transport machinery. The kinases and phosphatases involved in this regulation are present in the permeabilized cells. A phosphorylation-sensitive component of the nuclear transport machinery also is present in permeabilized cells and is most likely a component of the nuclear pore complex. Substrate binding by the importin α·β complex and the association of the complex with the nucleoporins Nup358/RanBP2 and Nup153 are not affected by phosphatase inhibitors, suggesting that transport inhibition by protein phosphorylation does not involve these steps. These results suggest that cells have mechanisms to negatively regulate entire nuclear transport pathways, thus providing a means to globally control cellular activity through effects on nucleocytoplasmic trafficking.
Oxidative stress in the blood of farm workers following intensive pesticide exposure

The aim of this study was to evaluate oxidative stress in workers who formulate organophosphate, synthetic pyrethroid and carbamate pesticides. In this survey, blood erythrocytes from a group of 94 pesticide-formulating workers (at least 5-years experience in pest-control in apple and cherry production) and 45 control subjects were examined for oxidative stress parameters. The control group was composed of 45 healthy people living in the same region with no exposure to pesticides. Lipid peroxidation level, catalase, superoxide dismutase and glutathione peroxidase activities in erythrocytes were analysed as biomarkers of oxidative stress. In addition, the acetylcholinesterase activity was measured as a biomarker of toxicity. Results indicated that chronic exposure to organophosphate, synthetic pyrethroid and carbamate pesticides were associated with increased activities of catalase, SOD and lipid peroxidation in erythrocytes (p < 0.05). Acetylcholinesterase activity did not show any significant differences between the two groups (p > 0.05). It is concluded that human chronic exposure to pesticides may result in stimulated antioxidant enzymes.
Measures of underlying inflation for the euro area

Headline inflation can be noisy, blurring the signal on the medium-term inflationary pressure relevant for monetary policy. To help distinguish signal from noise in the data, central banks monitor measures of underlying inflation. As there are many ways of measuring underlying inflation, it is important to understand the properties of the various indicators and what factors may account for any divergence between them. This article describes in detail the measures of underlying inflation typically used at the ECB and evaluates them against a set of empirical criteria. Our results suggest that no one measure of underlying inflation is superior in all situations as the performance of the indicators varies over time. In practice, each indicator comes with merits and shortcomings, which calls for monitoring the full range of measures of underlying inflation. JEL Classification: C52, C82, E31
YM598, an Orally Active ETA Receptor Antagonist, Ameliorates the Progression of Cardiopulmonary Changes and Both-side Heart Failure in Rats with Cor Pulmonale and Myocardial Infarction

The effects of the novel, selective endothelin-A (ETA) receptor antagonist YM598 on both-side heart failure were investigated. Right-side heart failure secondary to pulmonary hypertension was produced by a single subcutaneous injection of 60 mg/kg monocrotaline, and post-ischemic congestive left-side heart failure (CHF) produced by surgical left coronary artery ligation. In right-side heart failure rats, oral YM598 (0.1 and 1 mg/kg for 4 weeks), but not bosentan (30 mg/kg), significantly inhibited the progression of pulmonary hypertension and the development of right ventricular hypertrophy. YM598 also improved hypoxemia and morphological pulmonary lesions in these rats. In CHF rats, moreover, long-term oral administration of YM598 (1 mg/kg/day for approximately 30 weeks) significantly ameliorated their poor survival rate (P < 0.05). In the measurement of cardio-hemodynamic parameters, YM598 improved the contractile/diastolic capacity of the left ventricle and the preload in the right ventricle to the levels seen in sham-operated rats. YM598 also markedly inhibited both ventricular hypertrophy and pulmonary congestion, as well as lowering high plasma brain natriuretic peptide levels in CHF rats. These findings suggest that YM598 may have a clinical benefit with regards to ameliorating the cardiopulmonary changes of right-side heart failure, and the cardiac dysfunction and mortality/morbidity of CHF.
Applicability of a System for Fully Automated Nucleic Acid Extraction From Formalin-fixed Paraffin-embedded Sections for Routine KRAS Mutation Testing

Due to the approval of various new targeted therapies for the treatment of cancer, molecular pathology laboratories with a diagnostic focus have to meet new challenges: simultaneous handling of a large number of samples, small amounts of input material, and fragmentation of nucleic acids because of formalin fixation. As a consequence, fully automated systems for a fast and standardized extraction of high-quality DNA from formalin-fixed paraffin-embedded (FFPE) tissues are urgently needed. In this study, we tested the performance of a fully automated, high-throughput method for the extraction of nucleic acids from FFPE tissues. We investigated the extraction performance in sections of 5 different tissue types often analyzed in routine pathology laboratories (cervix, colon, liver, lymph node, and lung; n=340). Furthermore, we compared the quality, labor input, and applicability of the method for diagnostic purposes with those of a laboratory-validated manual method in a clinical setting by screening a set of 45 colorectal adenocarcinoma for the KRAS mutation. Automated extraction of both DNA and RNA was successful in 339 of 340 FFPE samples representing 5 different tissue types. In comparison with a conventional manual extraction protocol, the method showed an overall agreement of 97.7% (95% confidence interval, 88.2%-99.9%) for the subsequent mutational analysis of the KRAS gene in colorectal cancer samples. The fully automated system is a promising tool for a simple, robust, and rapid extraction of DNA and RNA from formalin-fixed tissue. It ensures a standardization of sample processing and can be applied to clinical FFPE samples in routine pathology.
Stilbenedisulfonate binding kinetics to band 3 (AE 1): relationship between transport and stilbenedisulfonate binding sites and role of subunit interactions in transport.

Stilbenedisulfonates are competitive inhibitors of band 3 (AE1) anion exchange. It has been assumed that competitive binding implies that the stilbenedisulfonates bind to the transport site. In this paper, I summarize briefly an extensive series of stopped-flow fluorescence kinetic studies which indicate that stilbenedisulfonates do not compete with substrate anions directly, but rather that they behave as allosteric competitive inhibitors of monovalent anion binding to band 3. Monovalent anions lower stilbenedisulfonate affinity by accelerating the rate of their release from band 3, without changing the value of the initial second-order "on" kinetic constant. In addition, partial covalent labeling of the band 3 population with stilbenedisulfonates revealed subunit interaction effects: (a) in steady-state and pre-steady-state transport kinetic studies, (b) in studies on the kinetics of reversible stilbenedisulfonate binding to the unlabeled portion of the band 3 population, and (c) in microcalorimetric studies of the thermal unfolding of the membrane domain of band 3. Studies on the kinetics of reversible stilbenedisulfonate binding to erythrocyte membranes from an individual with Southeast Asian ovalocytosis also revealed subunit interaction effects. The demonstration of allosteric competition between stilbenedisulfonates and substrate anions and the observation of numerous examples of subunit interaction effects suggest that allosteric effects may play a significant role in band 3 function.
Is there Momentum in Factor Premia? Evidence from International Equity Markets

This study examines the momentum effect in the returns of factor premia representing a broad set of stock market strategies. Using cross-sectional and time-series tests, we investigate the performance persistence of market, value, size, momentum, low-risk, and quality premia within a sample of 24 international equity markets for the years 1990–2016. We provide strong evidence that the top performing factors continue to outperform the worst performing factors both in individual equity markets and in the cross-country framework. The momentum in factor premia is largely explained by the classic stock-level momentum effect.
Glaciers and Ice Sheets As Analog Environments of Potentially Habitable Icy Worlds

Icy worlds in the solar system and beyond have attracted a remarkable attention as possible habitats for life. The current consideration about whether life exists beyond Earth is based on our knowledge of life in terrestrial cold environments. On Earth, glaciers and ice sheets have been considered uninhabited for a long time as they seemed too hostile to harbor life. However, these environments are unique biomes dominated by microbial communities which maintain active biochemical routes. Thanks to techniques such as microscopy and more recently DNA sequencing methods, a great biodiversity of prokaryote and eukaryote microorganisms have been discovered. These microorganisms are adapted to a harsh environment, in which the most extreme features are the lack of liquid water, extremely cold temperatures, high solar radiation and nutrient shortage. Here we compare the environmental characteristics of icy worlds, and the environmental characteristics of terrestrial glaciers and ice sheets in order to address some interesting questions: (i) which are the characteristics of habitability known for the frozen worlds, and which could be compatible with life, (ii) what are the environmental characteristics of terrestrial glaciers and ice sheets that can be life-limiting, (iii) What are the microbial communities of prokaryotic and eukaryotic microorganisms that can live in them, and (iv) taking into account these observations, could any of these planets or satellites meet the conditions of habitability? In this review, the icy worlds are considered from the point of view of astrobiological exploration. With the aim of determining whether icy worlds could be potentially habitable, they have been compared with the environmental features of glaciers and ice sheets on Earth. We also reviewed some field and laboratory investigations about microorganisms that live in analog environments of icy worlds, where they are not only viable but also metabolically active.
DAY-NIGHT VARIATION IN THE IN VITRO CONTRACTILITY OF AORTA AND MESENTERIC AND RENAL ARTERIES IN TRANSGENIC HYPERTENSIVE RATS*

TGR(mREN2)27 (TGR) rats develop severe hypertension and an inverted circadian blood pressure profile with peak blood pressure in the daytime rest phase. The present study investigated the in vitro responsiveness of different arteries of TGR rats during day and night. Twelve-week-old TGR rats and normotensive Sprague-Dawley (SPRD) controls, synchronized to 12h light, 12h dark (LD 12:12) (light 07:00 19:00), were killed at 09:00 (during rest) and 21:00 (during activity), and endothelium-dependent relaxation by acetylcholine and vascular contraction by angiotensin II were studied by measuring isometric force in ring segments of abdominal aorta and mesenteric and renal arteries. In SPRD rats, consistent day-night variation was found, with greater responses to angiotensin II during the daytime rest span. In TGR rats, biological time-dependent differences were found in the renal vasculature, but not in the aorta and mesenteric artery. Relaxation of SPRD rat aorta and mesenteric artery by acetylcholine was greater at 09:00, whereas in TGR rats, day-night variation was absent (mesenteric artery) or inverted (aorta). In conclusion, based on the study of two time points, daynight variation in vascular contractility of aorta and mesenteric artery is blunted in TGR rats, whereas renal artery segments showed an unchanged daynight pattern compared to SPRD controls. (Chronobiology International, 18(4), 665 681, 2001)
The Conserved Hypothetical Protein Rv0574c Is Required for Cell Wall Integrity, Stress Tolerance, and Virulence of Mycobacterium tuberculosis

ABSTRACT The virulence of Mycobacterium tuberculosis is intimately related to its distinctive cell wall. The biological significance of poly-α-l-glutamine (PLG), a component in the cell wall of virulent mycobacteria, has not been explored adequately. The focus of this study is to investigate the role of a locus, Rv0574c, coding for a polyglutamate synthase-like protein, in the synthesis of poly-α-l-glutamine in the context of mycobacterial virulence. Evaluation of Rv0574c gene expression in M. tuberculosis demonstrated its growth-phase-linked induction with concomitant accumulation of poly-α-l-glutamine in the cell wall. Rv0574c was activated under conditions prevalent in the tubercular granuloma, e.g., hypoxia, nitric oxide, and CO2. For functional characterization, we produced a deletion mutant of the Rv0574c gene by allelic exchange. The mutant produced smaller amounts of poly-α-l-glutamine in the cell wall than did the wild-type bacterium. Additionally, the increased sensitivity of the mutant to antitubercular drugs, SDS, lysozyme, and mechanical stress was accompanied by a drastic reduction in the ability to form biofilm. Growth of the ΔRv0574c strain was normal under in vitro conditions but was retarded in THP-1 macrophages and in the lungs and spleen of BALB/c mice. This was in agreement with histopathology of the lungs showing slow growth and less severe pathology than that of the wild-type strain. In summary, this study demonstrates that the protein encoded by the Rv0574c locus, by virtue of modulating PLG content in the cell wall, helps in maintaining cellular integrity in a hostile host environment. Also, its involvement in protecting the pathogen from host-generated lethal factors contributes to the infectious biology of M. tuberculosis.