Miracle-dz/UniFAR-FTUs huggingface dataset:
Structural Basis of Transcription Initiation by Bacterial RNA Polymerase Holoenzyme*

Background: Cellular RNA polymerases start transcription by de novo RNA priming. Results: Structures and biochemical studies of initially transcribing complexes elucidate the de novo transcription initiation and early stage of RNA transcription. Conclusion: 5′-end of RNA in the transcribing complex starts σ ejection from core enzyme. Significance: Insights from this study can be applicable to all cellular RNA polymerases. The bacterial RNA polymerase (RNAP) holoenzyme containing σ factor initiates transcription at specific promoter sites by de novo RNA priming, the first step of RNA synthesis where RNAP accepts two initiating ribonucleoside triphosphates (iNTPs) and performs the first phosphodiester bond formation. We present the structure of de novo transcription initiation complex that reveals unique contacts of the iNTPs bound at the transcription start site with the template DNA and also with RNAP and demonstrate the importance of these contacts for transcription initiation. To get further insight into the mechanism of RNA priming, we determined the structure of initially transcribing complex of RNAP holoenzyme with 6-mer RNA, obtained by in crystallo transcription approach. The structure highlights RNAP-RNA contacts that stabilize the short RNA transcript in the active site and demonstrates that the RNA 5′-end displaces σ region 3.2 from its position near the active site, which likely plays a key role in σ ejection during the initiation-to-elongation transition. Given the structural conservation of the RNAP active site, the mechanism of de novo RNA priming appears to be conserved in all cellular RNAPs.
Expression pattern of breast‐cancer‐associated protein pS2/BCEI in colorectal tumors

Recently, several carcinomas of the gastrointestinal tract were tested for pS2/BCEI activity, a gene isolated from breast‐cancer cells and coding for a small secreted peptide. In the latter tumors, its activity is under estrogen control; surprisingly, it was also found expressed in carcinomas of the stomach, biliary tract and pancreas. We have now investigated the expression of this gene in 64 colorectal carcinomas, 31 adenomas and 13 polyps in comparison with their matrix tissues by applying molecular (RNA analysis) and immunohistochemical (pS2 antibody) techniques. Positive pS2 immunostaining (ranging from focal to strong immunoreaction) was noted in 89% of human colon cancers, while 11% remained negative. Furthermore, all 40 transitional mucosae were strongly positive, whereas normal mucosa was negative. Of hyperplastic polyps, 68.2% displayed a significant immunoreaction, and 80.6% of adenomas were focally positive. Finally, 6 out of 16 cases showed significant pS2 transcription in Northern blot analysis. These data clearly indicate that the breast‐cancer‐associated pS2 protein also plays an as yet undetermined role in the tumorigenesis of human colorectal carcinomas. © 1994 Wiley‐Liss, Inc.
Comparative proteomic analysis coupled with conventional protein assay as a strategy to identify predictors of successful testicular sperm extraction in patients with non‐obstructive azoospermia

Among infertile couples, approximately half have to face with male infertility. In men with non‐obstructive azoospermia, surgical retrieval testicular sperm extraction (TESE) of spermatozoa can be attempted, but with low success rates. A specific biomarker that could predict residual spermatogenesis would obviously be of interest before performing TESE. Thus, our aim was to identify biomarkers of residual spermatogenesis in seminal plasma of patients with non‐obstructive azoospermia (NOA) using an isotope‐coded protein label (ICPL)‐based proteomic strategy coupled with conventional protein assay. This retrospective study was conducted in 40 men with NOA at the University Hospital of Nantes and Proteomics Core facility Biogenouest – Inserm U1085 – IRSET, Rennes, France. Comparative ICPL proteomic screening of frozen seminal plasma and correlation with TESE outcome allowed the identification of some differentially expressed proteins. Among them, lectin galactoside‐binding, soluble 3 binding protein (LGALS3BP) expression was further confirmed using conventional protein assay, and its interest as a predictor of TESE outcome was then evaluated and compared with conventional clinical and hormonal markers of residual spermatogenesis. Among the 12 differentially expressed proteins identified with comparative ICPL proteomic strategy, seminal LGALS3BP expression was found to be significantly higher in men with successful TESE. Finally, comparative ICPL proteomic screening of seminal plasma appears to be a promising approach for the identification of biomarkers of residual spermatogenesis. LGALS3BP, associated with clinical and hormonal markers, could potentially be used as a predictive marker of successful TESE outcome in patients with NOA.
Preventing end stage renal disease in diabetic patients — genetic aspect (part I)

Diabetic nephropathy is a major cause of diabetes-related morbidity and mortality; however the clinical course of the disease and the renal prognosis is highly variable among individuals. The current review will discuss the genetic influence on the development of end stage renal disease (ESRD) in diabetic patients and potential improvements to the current treatment strategy to slow the loss of kidney function in these patients. In this first part, the growing evidence that glucose-induced activation of the intra-renal and systemic renin-angiotensin systems plays an essential role in processes leading to destruction of renal function is summarised. Genetic variations, especially the angiotensin-converting enzyme (ACE)/ID polymorphisms in the gene coding for ACE, are involved in activation of the renin-angiotensin system and seem to influence the clinical course of diabetic nephropathy during treatment with ACE inhibitors. In addition, this polymorphism may interact with other polymorphisms within the reninangiotensin system, leading to high risk of ESRD. As new genetic approaches and methods develop, further understanding of diabetic nephropathy will evolve and genotyping will help prevent ESRD in diabetic patients.
Simulating Pulmonary Vein Activity Leading to Atrial Fibrillation Using a Rule-based Approach on Realistic Anatomical Data

Atrial fibrillation (AF) is the most common cardiac arrhythmia leading to a high rate of stroke. The underlying mechanisms of initiation and maintenance of AF are not fully understood. Several findings suggest a multitude of factors to leave the atria vulnerable to AF. In this work, a rule-based approach is taken to simulate the initiation of AF in a computer model for the purpose of generating a model with which the influence of anatomical structures, electrophysiological properties of the atria and arrhythmogenic activity can be evaluated. Pulmonary vein firing has been simulated leading to AF in 65,7 % of all simulations. The excitation pattern generated resemble chaotic excitation behavior, which is characteristic for AF as well as stable reentrant circuits responsible for atrial flutter. The findings compare well with literature. In future, the presented computer model of AF can be used in therapy planning such as ablation therapy or overdrive pacing
Classifying Benign and Malignant Tissues within the Prostate Peripheral Zone using Textons

In this paper, we present our preliminary results classifying benign and malignant tissues within the prostate peripheral zone using textons. For this purpose, patches are randomly extracted from malignant and benign regions and we perform k-means clustering to generate textons. All textons are combined to form the texton dictionary which was used to construct a texton map for every peripheral zone region in each training image. Based on the texton map, histogram models for each malignant and benign tissue are constructed which will be used to train our classifiers. We tested the proposed method on 418 T2-W MR images taken from 45 patients and evaluation results of Az = 87% 7% show a comparable performance with the state-of-the-art in the literature.
An HLA-DRB1-Derived Peptide Associated with Protection Against Rheumatoid Arthritis Is Naturally Processed by Human APCs1

Predisposition to rheumatoid arthritis (RA) is thought to be associated with HLA-DR1, -DR4, and -DR10. However, many epidemiological observations are better explained by a model in which the DQ alleles that are linked to these DR alleles, i.e., DQ5, DQ7, and DQ8, predispose to RA, while certain DR alleles have a dominant protective effect. All protective DRB1 alleles, e.g., *0402, *1301, and *1302, encode a unique motif, 70DERAA74. The protection may be explained by the presentation of DRB1-derived peptides by DQ to immunoregulatory T cells, because it was demonstrated in various autoimmune disease models that T cell responses to certain self-Ags can be involved in disease suppression. The aim of this study was to analyze whether peptides carrying the DERAA motif are naturally processed by human APC and presented in the context of the RA-predisposing DQ. Using a synthetic peptide carrying the DRB1*0402-derived sequence 65KDILEDERAAVDTYC79, we generated DERAA peptide-specific DQ-restricted T cell clones (TCC) from a DQ8 homozygous individual carrying DERAA-negative DR4 alleles. By analyzing the proliferation of these TCC, we demonstrated natural processing and presentation of the DERAA sequence by the APC of all the individuals (n = 12) carrying a DERAA-positive DRB1 allele and either DQ8 or the DQ8-related DQ7. Using a panel of truncated synthetic peptides, we identified the sequence 67(I)LEDERAAVD(TY)78 as the minimal determinant for binding to DQ8 and for recognition by the TCC. These findings support a model in which self-MHC-derived peptide can modulate predisposition to autoimmune disease in humans.
Cost-effectiveness of different caries preventive measures in a high-risk population of Swedish adolescents.

OBJECTIVES A total of 3373 12-year-olds agreed to participate in an intervention study evaluating different caries preventive measures. The study, titled 'Evaluation of caries preventive measures', was performed between 1995 and 1999 at 26 dental health clinics throughout Sweden. At the start of the study, the subjects were classified as individuals at high or low risk of developing caries. The high-risk group consisted of 1165 subjects. The children in the high-risk group were randomly assigned to one of four preventive programs. The programs represent a step-wise increase in fluoride content, contact with dental personnel and cost. The aim of the present cost-effectiveness analysis (CEA) study performed from a societal perspective is to compare costs and consequences of caries preventive programs in a caries high-risk population. By 'costs' is meant both treatment costs and costs contributed by the patient and the patient's family. Costs contributed by patients and their families consist of out-of-pocket expenses, transportation costs, and time. Conclusions are that it is important to consider the perspective from which a study is carried out. Costs contributed by the patient and the patient's family have a high impact on total costs for children and younger adolescents but decrease with time as the adolescents get older. The present study shows an incremental cost-effectiveness of 2043 SEK (8.54 SEK = 1 US dollar, December 1999) per averted decayed enamel and dentine missing and filled surface (DeMFS), of which treatment costs represent 1337 SEK using the unit cost for a nurse. This means a yearly cost of approximately 334 SEK.
Tides of Consent

Politics is a trial in which those in government – and those who aspire to serve – make proposals, debate alternatives, and pass laws. Then the jury of public opinion decides. It likes the proposals or actions, or it does not. It trusts the actors, or it doesn’t. It moves, always at the margin, and then those who benefit from the movement are declared winners. This book is about that public opinion response. Its most basic premise is that although public opinion rarely matters in a democracy, public opinion change is the exception. Public opinion rarely matters because the public rarely cares enough to act on its concerns or preferences. Change happens only when the threshold of normal public inattention is crossed. When public opinion changes, governments rise or fall, elections are won or lost, and old realities give way to new demands.
Counterexample-Guided Assume-Guarantee Synthesis through Learning

Assume-guarantee reasoning (AGR) is a promising compositional verification technique that can address the state space explosion problem associated with model checking. Since the construction of assumptions usually requires nontrivial human efforts, a framework was already proposed for generating assumptions automatically using the L* algorithm. However, if the framework shows that a system model does not satisfy a given specification, the designer has to manually refine the system model. To automate this refinement process, we propose a framework that can automatically eliminate all counterexamples from a system model such that the synthesized model satisfies a given safety specification. Further, the framework for synthesis is not only automatic, but is also an iterative L*-based compositional process, i.e., the global state space of the system is never generated in the synthesis process. When a model checker shows that a system model does not satisfy a specification by giving a counterexample, the proposed framework eliminates a class of equivalent counterexamples, that is, the set of counterexamples that transit to the error state through the same final transition. Then, AGR is applied again to check if there is another counterexample. The action of eliminating counterexamples continues until all classes of counterexamples are eliminated from the system model. We prove that the synthesized model satisfies the specification and the synthesis flow terminates after a finite number of iterations. Due to compositional synthesis, our target model for synthesis, namely the component models, is much smaller than the global system state graph.
Trimethoprim‐Sulfamethoxazole‐Induced Tremor in an Immunocompetent Patient

Trimethoprim‐sulfamethoxazole (TMP‐SMX) is a widely administered antibiotic that is well tolerated by most patients. Hypersensitivity reactions and gastrointestinal intolerance are the most common adverse events associated with it. Central nervous system adverse effects such as tremors are less common and occur primarily in patients with acquired immune deficiency syndrome. A 29‐year‐old immunocompetent man developed a tremor while taking TMP‐SMX. The tremor resolved within 2 days after the drug was discontinued.
What matters to seriously ill older persons making end-of-life treatment decisions?: A qualitative study.

BACKGROUND Several methods exist to elicit end-of-life treatment preferences. However, little work has been done to elicit from patients themselves the aspects of treatment decision-making most important to them when making end-of-life treatment decisions. METHODS Participants consisted of 23 patients, 60 years of age and older with a primary diagnosis of congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), or cancer identified by their physicians as having a limited life expectancy. They took part in in-depth semistructured interviews and focus groups in which they were asked to discuss how they had made previous decisions about the treatment of their illness and/or would think about making future decisions. Transcripts were analyzed qualitatively using the constant comparative method. RESULTS There were three major influences on treatment preferences: treatment burden, treatment outcome, and the likelihood of the outcome. Treatment burden was bearable if the outcome of treatment was desirable, but participants were less willing to endure the burden for more marginal outcomes. Certain outcomes were so unacceptable that they determined preference regardless of burden. However, some participants revealed that their willingness to tolerate these adverse outcomes may increase as their illness progresses. Although participants generally believed that physicians know with certainty the outcomes of treatment, most understood the concept of uncertainty, and the likelihood of a given outcome influenced their preferences. CONCLUSIONS A patient-centered approach to advance care planning needs to incorporate a consideration of both treatment burdens and treatment outcomes, including the likelihood of these outcomes. Patients' valuations of these outcomes may change over time.
Repression of Telomerase Activity During In Vitro Differentiation of Osteosarcoma Cells

In this report, we studied the relationship between telomerase activity and in vitro differentiation of osteosarcoma cells. Human osteosarcoma cells (HOS-8603) were treated with all-trans-retinoic acid (RA) and dexamethasone (DEX). Cell cycle phase, alkaline phosphatase (AP) activity, telomerase activity, and human telomerase RNA (hTR) in treated cells were detected. The results showed that the treated cells underwent morphologic differentiation. AP activity of the cells increased significantly. The proportion of the cells in S and G2/M phases was increased. A pronounced decline in telomerase activity was observed, but no significant difference in the amount of hTR expressed, when compared with the control. This study demonstrates that: (1) both RA and DEX can inhibit cell growth and induce morphologic and functional differentiation of HOS-8603 cells; (2) telomerase is an enzyme system regulated during induced differentiation of HOS-8603 cells; (3) significantly decreased telomerase activity may be an indicator of differentiation but does not parallel the expression level of hTR; and (4) the regulation of telomerase is directly linked to cell differentiation not cell cycle.
Novel Role of Nucleostemin in the Maintenance of Nucleolar Architecture and Integrity of Small Nucleolar Ribonucleoproteins and the Telomerase Complex*

Nucleostemin (NS) is a nucleolar protein involved in the regulation of cell proliferation. Both overexpression and knockdown of NS increase the activity of the tumor suppressor protein p53, resulting in cell cycle arrest. In addition, NS regulates processing of pre-rRNA and consequently the level of total protein synthesis. Here, we describe a previously uncharacterized function of NS in the maintenance of the tripartite nucleolar structure as well as the integrity of small nucleolar ribonucleoproteins (snoRNPs). NS is also necessary to maintain the telomerase complex which shares common protein subunits with the H/ACA box snoRNPs. First, immunofluorescence microscopy and electron microscopy demonstrated that knockdown of NS disorganized the nucleolar architecture, in particular, the dense fibrillar component where snoRNPs are localized. Second, gel filtration chromatography and immunoprecipitation indicated that NS depletion leads to dissociation of the components of snoRNPs and the telomerase complex. Third, NS depletion reduced both telomerase activity and the cellular level of pseudouridine, an H/ACA snoRNP-mediated modification of rRNA and other RNAs that are important for their folding and stability. These morphological, biochemical and functional studies demonstrate that NS plays an important role to maintain nucleolar structure and function on a more fundamental level than previously thought.
High-Frequency Volatility Estimation and the Relative Importance of Market Microstructure Variables

In this paper we use an autoregressive conditional intensity approach to estimate local high-frequency volatility, and examine to what extent a large universe of market microstructure variables affects local volatility. Our findings support a sequential information arrival hypothesis on the high-frequency level since we show that contemporaneous trading volume is negatively, and lagged trading volume is positively related to local volatility. The use of a penalized likelihood method allows us to obtain a ranking in terms of the relative importance of all market microstructure variables considered. We find that, in a descending order, contemporaneous volume, bid-ask spread, absolute order imbalance, absolute order flow and absolute quote difference carry the most important information for local volatility modelling.
Subtype-selective reconstitution of synaptic transmission in sympathetic ganglion neurons by expression of exogenous calcium channels

Fast cholinergic neurotransmission between superior cervical ganglion neurons (SCGNs) in cell culture is initiated by N-type Ca2+ currents through Cav2.2 channels. To test the ability of different Ca2+-channel subtypes to initiate synaptic transmission in these cells, SCGNs were injected with cDNAs encoding Cav1.2 channels, which conduct L-type currents, Cav2.1 channels, which conduct P/Q-type Ca2+ currents, and Cav2.3 channels, which conduct R-type Ca2+ currents. Exogenously expressed Cav2.1 channels were localized in nerve terminals, as assessed by immunocytochemistry with subtype-specific antibodies, and these channels effectively initiated synaptic transmission. Injection with cDNA encoding Cav2.3 channels yielded a lower level of presynaptic labeling and synaptic transmission, whereas injection with cDNA encoding Cav1.2 channels resulted in no presynaptic labeling and no synaptic transmission. Our results show that exogenously expressed Ca2+ channels can mediate synaptic transmission in SCGNs and that the specificity of reconstitution of neurotransmission (Cav2.1 > Cav2.3 ≫ Cav1.2) follows the same order as in neurons in vivo. The specificity of reconstitution of neurotransmission parallels the specificity of trafficking of these Cav channels to nerve terminals.
Predictive value of routine hematological and biochemical parameters on 30-day fatality in acute stroke.

OBJECTIVE This prospective study was planned to study the prognostic value of routine clinical, hematological and biochemical parameters, including platelet aggregation in patients of acute stroke, on fatality occurring during the first 30 days. MATERIAL AND METHODS In this study 116 consecutive patients (77 males and 39 females) of stroke (within 72 hours of onset) were included. After clinical evaluation and neuroimaging, blood investigations, hemoglobin, total leukocyte count, platelet count, platelet aggregation, erythrocyte sedimentation rate (ESR), blood sugar, urea, creatinine, sodium, potassium, serum cholesterol, serum bilirubin, aspartate aminotransferase (SGOT), alanine aminotransferase (SGPT), albumin, and globulin estimations were performed. The patients were followed up for a maximum period of 30 days from the onset of stroke, and patients who expired were grouped as 'expired' and the rest as 'survivors'. Logistic regression analysis was carried out among the significant parameters to identify independent predictors of 30-day fatality. RESULTS Univariate analysis demonstrated that among hematological parameters, high total leukocyte count and ESR, at admission, correlated significantly with an undesirable outcome during the initial 30 days. Among biochemical parameters, elevated urea, creatinine, serum transaminases (SGOT and SGPT) and globulin levels correlated significantly with death. Logistic regression analysis demonstrated that a low Glasgow Coma Scale (GCS) score along with biochemical parameters such as high serum creatinine, SGPT, ESR and total leukocyte count correlated with death. CONCLUSION Impaired consciousness, high total leukocyte count, raised ESR, elevated creatinine and SGPT levels, estimated within 24 hours of hospitalization, are the most important indicators of 30-day mortality in patients with first-time ischemic stroke.