Miracle-dz/UniFAR-FTUs huggingface dataset:
Transactivation of E2F-Regulated Genes by Polyomavirus Large T Antigen: Evidence for a Two-Step Mechanism

ABSTRACT Polyomavirus large T antigen transactivates a variety of genes whose products are involved in S phase induction. These genes are regulated by the E2F family of transcription factors, which are under the control of the pocket protein retinoblastoma protein and its relatives p130 and p107. The viral protein causes a dissociation of E2F-pocket protein complexes that results in transactivation of the genes. This reaction requires the N-terminal binding site for pocket proteins and the J domain that binds chaperones. We found earlier that a mutation of the zinc finger located within the C-terminal domain, a region assumed to function mainly in the replication of viral DNA, also interferes with transactivation. Here we show that binding of the histone acetyltransferase coactivator complex CBP/p300-PCAF to the C terminus correlates with the ability of large T antigen to transactivate genes. This interaction results in promoter-specific acetylation of histones. Inactive mutant proteins with changes within the C-terminal domain were nevertheless able to dissociate the E2F pocket protein complexes, indicating that this dissociation is a necessary but insufficient step in the T antigen-induced transactivation of genes. It has to be accompanied by a second step involving the T antigen-mediated recruitment of a histone acetyltransferase complex.
Participatory management: Guayllabamba case study

The social dimension in water management and the interaction of stakeholders is a challenge when modeling hydrological systems. Case studies are essential to uncovering relations and unexpected results. In this research, a case study of the Guayllabamba basin in Ecuador is proposed. Mainly, the interactions, perspectives, and relations between key stakeholders are analyzed. NGOs, water management government institutions and water users’ associations are the main focus. The political changes in Ecuador, the creation of new institutions and the new water law have shaken up the relations between these stakeholders and have provided a great opportunity to see what factors have affected the interactions of these stakeholders and have exacerbated some issues. Moreover, the capital of the country, Quito, is located in the Guayllabamba basin which allows the governmental institutions to be more hands on, thus generating interesting exchanges among all stakeholders. An assessment of the current legal framework is carried out to understand how the relations (mainly with the governmental stakeholders) should work, then interviews and surveys were applied to get a grasp on how the different stakeholders perceive each other and the main issues in the basin. Finally, direct observation was crucial to see the different stakeholders interacting and draw conclusions as to whether the responses to the interviews and survey are coherent with the observations made by the researcher. The methods used were mainly qualitative and the research followed an emergent design, meaning that modifications to the research were done along with the gathering of the data.
THE GEOGRAPHY OF MITOCHONDRIAL DNA VARIATION, POPULATION STRUCTURE, HYBRIDIZATION, AND SPECIES LIMITS IN THE FOX SPARROW (PASSERELLA ILIACA)

Geographic variation in mitochondrial DNA (mtDNA) restriction sites was studied in the fox sparrow (Passerella iliaca). Seventy‐eight haplotypes were found. Haplotypes fall into four phylogeographic groups that correspond to groups defined by plumage characters. The geographic distribution of these four groups does not appear congruent with mtDNA patterns in other vertebrates. Within each group, there is little geographic variation in mtDNA restriction sites, although there is geographic variation in plumage coloration and body size. The evolution of mtDNA diversity in fox sparrows seems best explained by vicariant events rather than isolation by distance. The mtDNA evidence suggests that Passerella megarhyncha and Passerella schistacea, two nonsister taxa that occur in western North America, have independently undergone bottlenecks. Hybridization is limited between all pairs of taxa except P. megarhyncha and P. schistacea, where mtDNA evidence suggests a narrow contact zone along the interface of the Great Basin and Sierra Nevada/Cascades. Morphometric characters intergrade over a broader area, suggesting that different processes are responsible for the two gradients. The occurrence of limited backcrossing among taxa suggests that cytoplasmic‐nuclear incompatibility is lacking. The number of biological species would range from one to four, depending on the degree of hybridization tolerated. The mtDNA and plumage characters suggest four phylogenetic species: P. iliaca, P. megarhyncha, P. unalaschcensis, and P. schistacea.
SR-BI-directed HDL-cholesteryl ester hydrolysis Published, JLR Papers in Press, November 16, 2002. DOI 10.1194/jlr.M200186-JLR200

We have examined the metabolic fate of HDL cholesteryl ester (CE) delivered to cells expressing scavenger receptor class B type I (SR-BI). Comparison of SR-BI with a related class B scavenger receptor, CD36, showed a greater uptake and a more rapid and extensive hydrolysis of HDL-CE when delivered by SR-BI. In addition, hydrolysis of HDL-CE delivered by both receptors was via a neutral CE hydrolase. These data indicate that SR-BI, but not CD36, can efficiently direct HDL-CE to a neutral CE hydrolytic pathway. In contrast, LDL-CE was delivered and hydrolyzed equally well by SR-BI and CD36. Hydrolysis of LDL-CE delivered by SR-BI was via a neutral CE hydrolase but that delivered by CD36 occurred via an acidic CE hydrolase, indicating that SR-BI and CD36 deliver LDL-CE to different metabolic pathways. Comparison of inhibitor sensitivities in Y1-BS1 adrenal, Fu5AH hepatoma, and transfected cells suggests that hydrolysis of HDL-CE delivered by SR-BI occurs via cell type-specific neutral CE hydrolases. Furthermore, HDL-CE hydrolytic activity was recovered in a membrane fraction of Y1-BS1 cells. These findings suggest that SR-BI efficiently delivers HDL-CE to a metabolically active membrane compartment where CE is hydrolyzed by a neutral CE hydrolase.
Feasibility study to deploy air bags at night using visual sensor

Airbags are primarily designed to supplement the protection provided by seat belts. Their non-deployment results into severe injuries. Preliminary measures are to be adopted to reduce the possibility of non-deployment. Regardless low traffic volume, most fatal accidents happen at night due to low visibility and ineffectiveness of drivers. In this paper, a redundant mechanism is purposed to deploy airbags at night. Distance of proceeding vehicle is measured using visual sensor. If the speed of vehicle is such that collision is inevitable for measured distance, airbag is purposed to deploy beforehand.
Aluminum Resistance in Maize Cannot Be Solely Explained by Root Organic Acid Exudation. A Comparative Physiological Study1[w]

Root apical aluminum (Al) exclusion via Al-activated root citrate exudation is widely accepted as the main Al-resistance mechanism operating in maize (Zea mays) roots. Nonetheless, the correlation between Al resistance and this Al-exclusion mechanism has not been tested beyond a very small number of Al-resistant and Al-sensitive maize lines. In this study, we conducted a comparative study of the physiology of Al resistance using six different maize genotypes that capture the range of maize Al resistance and differ significantly in their genetic background (three Brazilian and three North American genotypes). In these maize lines, we were able to establish a clear correlation between root tip Al exclusion (based on root Al content) and Al resistance. Both Al-resistant genotypes and three of the four Al-sensitive lines exhibited a significant Al-activated citrate exudation, with no evidence for Al activation of root malate or phosphate release. There was a lack of correlation between differential Al resistance and root citrate exudation for the six maize genotypes; in fact, one of the Al-sensitive lines, Mo17, had the largest Al-activated citrate exudation of all of the maize lines. Our results indicate that although root organic acid release may play a role in maize Al resistance, it is clearly not the only or the main resistance mechanism operating in these maize roots. A number of other potential Al-resistance mechanisms were investigated, including release of other Al-chelating ligands, Al-induced alkalinization of rhizosphere pH, changes in internal levels of Al-chelating compounds in the root, and Al translocation to the shoot. However, we were unsuccessful in identifying additional Al-resistance mechanisms in maize. It is likely that a purely physiological approach may not be sufficient to identify these novel Al-resistance mechanisms in maize and this will require an interdisciplinary approach integrating genetic, molecular, and physiological investigations.
Gene therapy for osteosarcoma: steps towards clinical studies

Gene therapy, an applied form of biotechnology, relies on the delivery of foreign DNA into cells. More than 50% of all reported clinical trials for gene therapy are for cancer, though only a scant number for osteosarcoma. Osteosarcoma is a neoplasm afflicting young adults, who in their prime years of life suffer debilitation if not death. The disease is not entirely curable, even with surgery combined with aggressive chemotherapy. Thus, other forms of therapies are being evaluated, including gene therapy. There exist two major forms of gene transfer: viral and non‐viral. This review only covers proof‐of‐principle work carried out in cancer beyond the cell culture stage, in animals. Drawing from the experiences of gene therapy against other cancers, studies for which have already reached the clinical phase, the review discusses potential pitfalls and solutions to enhance gene therapy for osteosarcoma.
Subclinical arterial and cardiac damage in white-coat and masked hypertension

Abstract The study aimed to compare arterial and echocardiographic parameters in subjects with newly diagnosed masked (MH) or white-coat hypertension (WCH) to subjects with sustained normotension or sustained hypertension, defined according to the 2014 European Society of Hypertension practice guidelines for ambulatory blood pressure (BP) monitoring. We recruited 303 participants (mean age 46.9 years) in a family-based population study. SpaceLabs monitors and oscillometric sphygmomanometers were used to evaluate ambulatory and office BP, respectively. Central pulse pressure (PP) and aortic pulse-wave velocity (PWV) were measured with pulse-wave analysis (SphygmoCor software). Carotid intima–media thickness (IMT) and cardiac evaluation were assessed by ultrasonography. Analysing participants without antihypertensive treatment (115 sustained normotensives, 41 sustained hypertensives, 20 with WCH, 25 with MH), we detected significantly higher peripheral and central PP, PWV, IMT and left ventricular mass index in hypertensive subgroups than in those with sustained normotension. The differences between categories remained significant for peripheral PP and PWV after adjustment for confounding factors, including 24 h systolic and diastolic BP. Participants with WCH and MH, defined according to strict criteria, had more pronounced arterial and heart involvement than normotensive participants. The study demonstrates a high prevalence of these conditions in the general population that deserves special attention from physicians.
Dual Mechanism of Integrin αIIbβ3 Closure in Procoagulant Platelets*

Background: Inactivation of integrin αIIbβ3 reverses platelet aggregate formation upon coagulation. Results and conclusion: Platelets from patient (Scott) and mouse (Capn1−/− and Ppif−/−) blood reveal a dual mechanism of αIIbβ3 inactivation: by calpain-2 cleavage of integrin-associated proteins and by cyclophilin D/TMEM16F-dependent phospholipid scrambling. Significance: These data provide novel insight into the switch mechanisms from aggregating to procoagulant platelets. Aggregation of platelets via activated integrin αIIbβ3 is a prerequisite for thrombus formation. Phosphatidylserine-exposing platelets with a key role in the coagulation process disconnect from a thrombus by integrin inactivation via an unknown mechanism. Here we show that αIIbβ3 inactivation in procoagulant platelets relies on a sustained high intracellular Ca2+, stimulating intracellular cleavage of the β3 chain, talin, and Src kinase. Inhibition of calpain activity abolished protein cleavage, but only partly suppressed αIIbβ3 inactivation. Integrin αIIbβ3 inactivation was unchanged in platelets from Capn1−/− mice, suggesting a role of the calpain-2 isoform. Scott syndrome platelets, lacking the transmembrane protein TMEM16F and having low phosphatidylserine exposure, displayed reduced αIIbβ3 inactivation with the remaining activity fully dependent on calpain. In platelets from Ppif−/− mice, lacking mitochondrial permeability transition pore (mPTP) formation, agonist-induced phosphatidylserine exposure and αIIbβ3 inactivation were reduced. Treatment of human platelets with cyclosporin A gave a similar phenotype. Together, these data point to a dual mechanism of αIIbβ3 inactivation via calpain(-2) cleavage of integrin-associated proteins and via TMEM16F-dependent phospholipid scrambling with an assistant role of mPTP formation.
Immunocytochemical Phenotyping of Disseminated Tumor Cells in Bone Marrow by uPA Receptor and CK18: Investigation of Sensitivity and Specificity of an Immunogold/Alkaline Phosphatase Double Staining Protocol

Phenotyping of cytokeratin (CK) 18-positive cells in bone marrow is gaining increasing importance for future prognostic screening of carcinoma patients. Urokinase-type plasminogen activator receptor (uPA-R) is one example of a potential aggressive marker for those cells. However, a valid and reliable double staining method is needed. Using monoclonal antibodies against uPA-R and CK18, we modified an immunogold/alkaline phosphatase double staining protocol. UPA-R/CK18-positive tumor cell controls exhibited black uPA-R staining in 15–80% of cases and red CK18 staining in almost 100% of tumor cells. Isotype- and cross-matched controls were completely negative. Bone marrow from healthy donors was always CK18-negative. Reproducibility of CK18-positive cell detection was estimated in a series of specimens from 61 gastric cancer patients comparatively stained with the single alkaline phosphatase-anti-alkaline phosphatase (APAAP) and our double staining method (106 bone marrow cells/patient). In four cases, double staining could not reproduce CK18-positive cells. In 34 cases it revealed fewer or equal numbers, and in 23 cases more CK18-positive cells than the APAAP method. Overall quantitative analysis of detected cell numbers (838 in APAAP, range 1–280 in 106; double staining 808, range 0–253) demonstrated relative reproducibility of APAAP results by double staining of 97%. Correlation of results between both methods was significant (p<0.001, linear regression). Sensitivity of double staining tested in logarithmic tumor cell dilutions was one CK18-positive cell in 300,000. Specific uPA-R staining was seen on CK18-positive cells in bone marrow from 29 of 61 patients, and also on single surrounding bone marrow cells. To test the specificity of this staining, bone marrow cytospins from 10 patients without tumor disease were stained for uPA-R with the APAAP method. uPA-R expression was confirmed in all 10 cases, with a mean of 6.5% uPA-R-positive cells in 1000 bone marrow cells (SEM 1.2%). These results suggest that our double staining protocol is a sensitive, reproducible, and specific method for routine uPA-R phenotyping of disseminated CK18-positive cells in bone marrow of carcinoma patients.
Targeting the methionine cycle for melanoma therapy with 3‐O‐(3,4,5‐trimethoxybenzoyl)‐(−)‐epicatechin

The higher expression of methionine cycle genes in melanoma cells than in normal melanocytes may be related with increased protein synthesis and transmethylation reactions and the subsequent need for high levels of methionine. 3‐O‐(3,4,5‐trimethoxybenzoyl)‐(−)‐epicatechin (TMECG), a trimethoxy derivative of epicatechin‐3‐gallate (ECG), effectively suppressed proliferation of melanoma cells in cultures by inducing apoptosis. TMECG modulates the expression of genes involved in methionine metabolism, cellular methylation and glutathione synthesis in melanoma cells. TMECG treatment of melanoma cells resulted in the downregulation of antiapoptotic Bcl‐2, the upregulation of proapoptotic Bax and the activation of caspase‐3; however, it did not induce the expression of the apoptosis protease‐activating factor‐1 (Apaf‐1). Having elucidated the effects of TMECG on the melanoma methionine cycle, we designed therapeuthical strategies to increase its effectiveness. Combinations of TMECG with S‐adenosylmethionine or compounds that modulate the intracellular concentration of adenosine strongly increase the antiproliferative effects of TMECG. The ability of TMECG to target multiple aspects related with melanoma survival, with a high degree of potency, points to its clinical value in melanoma therapy. © 2008 Wiley‐Liss, Inc.
Therapeutic Potential of Human Chorionic Gonadotropin Against Painful Bladder Syndrome/Interstitial Cystitis

Painful bladder syndrome/interstitial cystitis is a debilitating chronic bladder disease that primarily affects women. The disease is due to a damage of urothelial cell lining. As a result, potassium particles and other toxic substances in urine can leak into bladder mucosa, causing the symptoms of lower abdominal/pelvic discomfort, pain, increased urination frequency, urgency, nocturia, and so on, all of which can substantially reduce the quality of daily life. There are multiple symptom reliving therapies. Among them, only pentosan polysulfate sodium, sold under the brand name of Elmiron, has been approved for oral use by US Food and Drug Administration. It provides the relief after several months of use. Based on the scientific leads presented in this article, we propose that human chorionic gonadotropin has a therapeutic potential that is worth investigating for the treatment of this disease.
Getting what you deserve : navigating work and welfare after a cancer diagnosis

Across Europe there are increasing numbers of older working age people experiencing long term health conditions, including cancer. Symptomatic of an ageing population and consequent ageing workforces, it represents a significant and ongoing challenge to labour markets at both a local and national level. Older workers with long term health conditions such as cancer often recourse to state welfare during their illness, with many navigating a return to their specific workplace, or the labour market more widely. It is this navigation, between work and welfare in the context of long term ill health, that is the focus of this paper.
Myocardial Insulin Resistance During Acute Endotoxin Shock in Dogs

Myocardial insulin responsiveness was determined in open-chest pentobarbital sodium-anesthetized dogs before and after endotoxin administration. Animals were instrumented to measure mean arterial blood pressure (MABP), heart rate (HR), and coronary blood flow. Myocardial glucose uptake and myocardial oxygen uptake (MVO2) were determined during a basal control period and after a hyperinsulinemic-euglycemic clamp procedure over a wide range of insulin concentrations. The clamp was accomplished by intravenously infusing insulin (0–4000 mU/min) and 20% glucose in sufficient amounts to maintain arterialglucose concentrations within 5 mg/dl of the control value. In a separate series of experiments, myocardial insulin responsiveness was determined by use of a single dose of insulin (4000 mU/min). This was done to determine whether antecedent insulin infusions during the sequential clamp procedure would affect the responsiveness of the heart. In control experiments, myocardial glucose uptake increased without any changes in HR, MVO2, or MABP. Maximum myocardial glucose uptake occurred at an insulin infusion rate between 400 and 4000 mU/min. A single concentration of insulin resulted in similar increases in myocardial glucose uptake as with the sequential clamp protocol. Acute endotoxin shock was induced by bolus injection of 1 mg/kg Salmonella typhimurium endotoxin (Difco Labs, Detroit, MI). One hour after administration of endotoxin, basal myocardial glucose uptake was decreased compared with the control animals. After 1 h of endotoxin shock, the heart was refractory to all concentrations of insulin, suggesting the site for altered insulin response was being mediated by a postreceptor mechanism.
Economic growth of the country and national intellectual capital (evidence from the post-socialist countries of the central and eastern Europe)

The purpose of the article is to study the innovation levers of developing the intellectual background for economic growth in two groups of post-socialist Central and Eastern European countries (middle-income and lower-middle-income countries). To achieve that, the quantitative effect of the national intellectual capital components (human capital, market capital, structural capital and capital of renewal and development) on the dynamics of the countries’ economic growth was determined.For both groups, multiple regressions have been constructed that reflect the quantitative relationship between the economic growth rates (in the regressions – the indicator of real gross domestic product per capita) and the components of national intellectual capital in 2010–2018. It has been established that the key innovative indicator of the economic growth of middle-income countries is the national capital of renewal and development, which in general corresponds to the pan-European model of innovation and investment development. Education is the main factor that provides the basis for the economic growth of lower-middle-income countries. Recommendations on improvement of national innovation policy are offered.
Work-related asthma in Montreal, Quebec: population attributable risk in a community-based study.

BACKGROUND Occupational exposures are an important cause of adult-onset asthma but the population attributable risk percentage (PAR%) has been less frequently studied. OBJECTIVES To examine the distribution and determinants of adult asthma in six centres across Canada using data gathered in a community-based study. METHODS Data were gathered in a community survey of 2959 adults using the European Community Respiratory Health Survey Protocol. A subsample of 498 subjects completed detailed health and occupational questionnaires, methacholine challenge tests and allergy skin tests. Asthma was defined in three ways: current wheeze, asthma symptoms and/or medication, and airway hyperresponsiveness. Occupational exposures were classified as sensitizers or irritants. Associations between asthma and occupational exposures were examined using logistic regression analysis. Model selection was based on the findings for current wheeze, and the same model was applied to the other definitions of asthma. RESULTS Fifty-six per cent of subjects reported ever having had occupational exposure to sensitizers, and 9.8% to irritants. Current wheeze was associated with exposure to irritants (PAR% 4.54%), and airway hyperresponsiveness was associated with exposure to sensitizers (PAR% 30.7%). Neither a history of childhood asthma, atopy, nor confining the analysis to adult-onset asthma affected these associations. Analysis of effect modification suggested two types of work-related asthma: one due to exposure to occupational sensitizers, and the other due to exposure to irritants. CONCLUSIONS Detailed assessment of past and current exposures is essential in the investigation of work-related asthma. Childhood asthma reactivated or aggravated by work exposures is not easy to distinguish from asthma induced by work, a misclassification that could lead to an underestimation of work-induced asthma. This should be taken into account in jurisdictions in which persons with work-aggravated asthma are not eligible for workers' compensation.