Miracle-dz/UniFAR-FTUs huggingface dataset:
Phenotypic and transcriptional plasticity directed by a yeast mitogen-activated protein kinase network.

The yeast pheromone/filamentous growth MAPK pathway mediates both mating and invasive-growth responses. The interface between this MAPK module and the transcriptional machinery consists of a network of two MAPKs, Fus3 and Kss1; two regulators, Rst1 and Rst2 (a.k.a. Dig1 and Dig2); and two transcription factors, Ste12 and Tec1. Of 16 possible combinations of gene deletions in FUS3, KSS1, RST1, and RST2 in the sigma1278 background, 10 display constitutive invasive growth. Rst1 was the primary negative regulator of invasive growth, while other components either attenuated or enhanced invasive growth, depending on the genetic context. Despite activation of the invasive response by lesions at the same level in the MAPK pathway, transcriptional profiles of different invasive mutant combinations did not exhibit a unified program of gene expression. The distal MAPK regulatory network is thus capable of generating phenotypically similar invasive-growth states (an attractor) from different molecular architectures (trajectories) that can functionally compensate for one another. This systems-level robustness may also account for the observed diversity of signals that trigger invasive growth.
Intima-media thickness and endothelial dysfunction in GCK and HNF1A-MODY patients.

OBJECTIVE Mutations in the glucokinase (GCK) gene, along with hepatocyte nuclear factor 1A (HNF1A) gene mutations, are the most frequent cause of maturity-onset diabetes of the young (MODY). GCK-MODY patients are typically characterized by a moderate fasting hyperglycemia; however, little is known about atherosclerosis and intermediate-related phenotypes in these subjects. DESIGN To examine carotid artery intima-media thickness (IMT) and endothelial function assessed by brachial artery flow-mediated dilatation (FMD) in GCK gene mutations carriers and HNF1A-MODY. METHODS A total of 64 subjects with GCK gene mutations, and 52 HNF1A gene mutation carriers as well as 53 nondiabetic controls were examined. IMT and FMD were assessed by ultrasonography. Appropriate statistical tests were performed to assess differences between the groups, and multivariate linear regression was done for the association with IMT and FMD. RESULTS The clinical characteristics of all groups were similar with the mean age at examination of 35.1, 41.1, and 39.5 years for GCK, HNF1A and the control group respectively. The highest mean IMT value was in the HNF1A-MODY group: 7.0±1.4 mm, whereas it reached 6.3±1.4 mm in GCK mutation carriers and 6.3±1.3 mm in controls (P=0.008). After adjustment for possible clinical and biochemical cofounders, IMT remained higher in HNF1A-MODY patients as compared with GCK-MODY patients (P=0.02) and controls (P=0.0003). FMD was significantly lower in HNF1A (9.9±4.6%) and GCK-MODY (11.1±4.6%) patients in comparison with controls (13.9±4.7%; P=0.0001). After adjustment, FMD remained lower in HNF1A-MODY (P=0.0005) and GCK-MODY patients (P=0.01) as compared with controls. CONCLUSIONS Both examined MODY groups demonstrated evidence of endothelial dysfunction. In addition, HNF1-MODY patients seem to be more prone to an early atherosclerotic phenotype.
Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort

Mutations in the DMD gene, encoding the dystrophin protein, are responsible for the dystrophinopathies Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), and X‐linked Dilated Cardiomyopathy (XLDC). Mutation analysis has traditionally been challenging, due to the large gene size (79 exons over 2.2 Mb of genomic DNA). We report a very large aggregate data set comprised of DMD mutations detected in samples from patients enrolled in the United Dystrophinopathy Project, a multicenter research consortium, and in referral samples submitted for mutation analysis with a diagnosis of dystrophinopathy. We report 1,111 mutations in the DMD gene, including 891 mutations with associated phenotypes. These results encompass 506 point mutations (including 294 nonsense mutations) and significantly expand the number of mutations associated with the dystrophinopathies, highlighting the utility of modern diagnostic techniques. Our data supports the uniform hypermutability of CGA>TGA mutations, establishes the frequency of polymorphic muscle (Dp427m) protein isoforms and reveals unique genomic haplotypes associated with “private” mutations. We note that 60% of these patients would be predicted to benefit from skipping of a single DMD exon using antisense oligonucleotide therapy, and 62% would be predicted to benefit from an inclusive multiexonskipping approach directed toward exons 45 through 55. Hum Mutat 30:1657–1666, 2009. © 2009 Wiley‐Liss, Inc.
Tail length estimation from sacro-caudal skeletal morphology in catarrhines

Tail morphology in primates is important for interpreting functional adaptation and phylogeny. Tail length is probably the most remarkable trait. Establishing usable methods to predict the tail length of extinct primates is a part of the basis to reconstruct primate evolution, particularly of hominoids. Previous studies revealed that sacral morphology often predicts tail length. However, most of the previous studies have only attempted this by using categories (e.g., short, long, etc.). A problem in those studies is that the range of intermediate tail length is wide (whose tail length is 15.0 through100 percent of head to body length (15.0 < RTL < 100.0 %)). Accordingly, this study aimed to quantitatively estimate tail length in catarrhines with intermediate tail lengths. Sacral and proximal caudal vertebral (first to third) of 89 hybrid individuals between Japanese macaque ( Macaca fuscata ) and Formosan rock macaque ( Macaca cyclopis ) were measured. Fifteen regression formulae were produced to estimate tail length in these species. These hybrid macaques were phylogenetically controlled but varied greatly in their relative tail length (tail length / head and body length = 18.8 - 88.8%), and thus were an excellent sample to obtain general regression formulae to estimate catarrhine tail length. A total of 15 predicting models were devised and five formulae performed well. The utility of these formulae were confirmed by an application to 15 species/subspecies of catarrhine taxa.
Heterosubtypic cross‐protection induced by whole inactivated influenza virus vaccine in mice: influence of the route of vaccine administration

Development of influenza vaccines capable of inducing broad protection against different virus subtypes is necessary given the ever‐changing viral genetic landscape. Previously, we showed that vaccination with whole inactivated virus (WIV) induces heterosubtypic protection against lethal virus infection in mice. Whole inactivated virus‐induced cross‐protection was found to be mediated primarily by flu‐specific CD8+ T cells.
Risk for Irritable Bowel Syndrome in Fibromyalgia Patients

Abstract Various studies have shown that irritable bowel syndrome (IBS) is highly associated with other pathologies, including fibromyalgia (FM). The objective of this study was to analyze the differences among risk factors associated with IBS following FM in a nationwide prospective cohort study. We propose that a relationship exists between FM and IBS. This article presents evidence obtained from a cohort study in which we used data from the Taiwan National Health Insurance Research Database to clarify the relationship between FM and IBS. The follow-up period ran from the start of FM diagnosis to the date of the IBS event, censoring, or December 31, 2011. We analyzed the risk of IBS using Cox proportional hazard regression models, including sex, age, and comorbidities. During the follow-up period, from 2000 to 2011, the overall incidence of IBS was higher in FM patients than in non-FM patients (7.47 vs 4.42 per 1000 person-years), with a crude hazard ratio = 1.69 (95% confidence interval [CI] 1.59–1.79). After adjustment for age, sex, and comorbidities, FM was associated with a 1.54-fold increased risk for IBS. Mutually risk factors may influence the relationship between FM and IBS. We recommend that physiologists conduct annual examinations of FM patients to reduce the incidence of IBS progression.
Analysis of a Gene Regulatory Cascade Mediating Circadian Rhythm in Zebrafish

In the study of circadian rhythms, it has been a puzzle how a limited number of circadian clock genes can control diverse aspects of physiology. Here we investigate circadian gene expression genome-wide using larval zebrafish as a model system. We made use of a spatial gene expression atlas to investigate the expression of circadian genes in various tissues and cell types. Comparison of genome-wide circadian gene expression data between zebrafish and mouse revealed a nearly anti-phase relationship and allowed us to detect novel evolutionarily conserved circadian genes in vertebrates. We identified three groups of zebrafish genes with distinct responses to light entrainment: fast light-induced genes, slow light-induced genes, and dark-induced genes. Our computational analysis of the circadian gene regulatory network revealed several transcription factors (TFs) involved in diverse aspects of circadian physiology through transcriptional cascade. Of these, microphthalmia-associated transcription factor a (mitfa), a dark-induced TF, mediates a circadian rhythm of melanin synthesis, which may be involved in zebrafish's adaptation to daily light cycling. Our study describes a systematic method to discover previously unidentified TFs involved in circadian physiology in complex organisms.
Labor Force Diversity and the Survival and Growth of New Firms

Our paper investigates how diversity of the labor force influences the rate of new firm formation and the performance of new firms in urban areas. A diversified labor force within the firm and in the external environment influences the formation, survival and growth of firms. We explore these issues with both aggregate data at the municipal level and individual data at the firm level for the years 1993-2010. We measure diversity using entropy measures that account for a wider range of differences than is typically used. Our empirical analysis finds a positive influence of diversity of the labor force on the rate of new firm formation at the municipal level. At the level of an individual firm, we find that the diversity of the firm’s own labor force is positively associated with its survival, but not its growth. Our results add to the literature on the workings of agglomeration economies through variations in human capital, information spillovers and innovation.
Prevalence and Antimicrobial Agent Susceptibility of Methicillin-resistant Staphylococcus aureus in Healthy Pediatric Outpatients in Las Vegas

Colonization and infection by communityassociated resistant strains of Staphylococcus aureus are being reported in epidemic proportions. The purpose of this study was to determine the local prevalence of methicillin-resistant Staphylococcus aureus (MRSA) colonization in children and to characterize the MRSA isolates in the laboratory with regard to antimicrobial agent susceptibility patterns, and the presence of the mecA and the PantonValentine leukocidin (PVL) genes. Nasal swabs were collected at two pediatric clinics from a total of 505 children during health maintenance visits. A brief questionnaire was administered to collect demographic data and pertinent medical, family, and social history. Samples were cultured onto 2 selective media for S. aureus and MRSA. Potential MRSA isolates were further evaluated by real-time polymerase chain reaction (PCR), and for susceptibility to eight antibiotics by disk diffusion. Culture results showed that MRSA was present in 15 of the 505 specimens (3.0%). Six different antimicrobial susceptibility profiles were observed among the MRSA isolates. PCR amplification results showed that all 15 MRSA isolates were positive for the presence of the mecA gene, and 10 MRSA isolates contained the PVL gene. Understanding local prevalence rates and the role of colonization in infection are needed to develop effective interventions to reduce MRSA infections
Photon inner product and the Gauss-linking number

It is shown that there is an interesting interplay between self-duality, loop representation and knot invariants in the quantum theory of Maxwell fields in Minkowski spacetime. Specifically, in the loop representation based on self-dual connections, the measure that dictates the inner product can be expressed in terms of the Gauss-linking number of thickened loops.
Carnap, Kuhn, and the history of science

The purpose of this article is to respond to Thomas Uebel´s criticisms of my comments regarding the current revisionism of Carnap´s work and its relations to Kuhn. I begin by pointing out some misunderstandings in the interpretation of my article. I then discuss some aspects related to Carnap´s view of the history of science. First, I emphasize that it was not due to a supposed affinity between Kuhn´s conceptions and those of logical positivism that Kuhn was invited to write the monograph on the history of science for the Encyclopedia. Three other authors had been invited first, including George Sarton whose conception was entirely different from Kuhn´s. In addition, I try to show that Carnap attributes little importance to history of science. He seldom refers to it and, when he does, he clearly defends (like Sarton) a Whig or an “old” historiography of science, to which Kuhn opposes his “new historiography of science”. It is argued that this raises serious difficulties for those, like Uebel, who hold the view that Carnap includes the historical or the social within the rational.
p53 Is Necessary for the Apoptotic Response Mediated by a Transient Increase of Ras Activity

ABSTRACT The tumor suppressor p53 eliminates cancer-prone cells via multiple mechanisms, including apoptosis. Ras elicits apoptosis in cells after protein kinase C (PKC) downregulation. However, the role of p53 in Ras-mediated apoptosis has not been fully investigated. Here, we demonstrate that mouse fibroblasts that express wild-type p53 are more susceptible to apoptosis elicited by PKC inhibition if Ras is transiently expressed or upregulated as opposed to stably expressed. In the latter case, p53 is frequently mutated. Transiently increased Ras activity induces Bax, and PKC inhibition augments this induction. Overexpression of E6 inactivates p53 and thereby suppresses both Bax induction and apoptosis. In contrast, Bax is not induced in stable ras transfectants, regardless of PKC inhibition. The data suggest that short- and long-term activation of Ras use a different mechanism(s) to initiate apoptosis. The status of p53 may contribute to such differences.
Arterial Hemodynamics in Hypertension

This paper reports mechanisms responsible for alterations in arterial hemodynamics in hypertension. Hypertension results from increased peripheral resistance, but the major changes in the pulse are a consequence of the accompanying decrease in arterial distensibility, whether this is due to the elevated mean pressure per se or to degeneration of the normal components of the arterial wall. Decreased distensibility increases characteristic impedance in the ascending aorta and through its effects on wave velocity causes shift of impedance curves to higher frequencies. This disturbs the normally favorable relationship between the components of the ventricular ejection wave and the impedance presented to the ventricle and results in increased pulsatile energy losses in the vascular system. At the same time there are changes in the harmonic components of the ascending aortic pressure wave which lead to increase in amplitude and characteristic alterations in contour. Decreased arterial distensibility causes a shift of peripheral/central pressure amplification curves to higher frequencies. As a result of this and the altered harmonic content of the ascending aortic pressure wave, there is little amplification or change in contour of the pressure wave between the ascending aorta and peripheral arteries.
Madeus: Database Live Migration Middleware under Heavy Workloads for Cloud Environment

Database-as-a-service has been gaining popularity in cloud computing because multitenant databases can reduce costs by sharing off-the-shelf resources. However, due to heavy workloads, resource sharing often causes a hot spot; one node is overloaded even while others are not. Unfortunately, a hot spot can lead to violation of service level agreements and destroy customer satisfaction. To efficiently address the hot spot problem, we propose a middleware approach called Madeus that conducts database live migration. To make efficient database live migration possible, we also introduce the lazy snapshot isolation rule (LSIR) that enables concurrently propagating syncsets, which are the datasets needed to synchronize slave with master databases. Madeus provides efficient database live migration by implementing the LSIR under snapshot isolation. Unlike current approaches, Madeus is pure middleware that is transparent to the database management system and based on commodity hardware and software. To demonstrate the superiority of our approach over current approaches, we experimentally evaluated Madeus by using PostgreSQL with the TPC-W benchmark. The results indicate that Madeus achieves more efficient live migration than three other types of middleware approaches, especially under heavy workloads; therefore, it can effectively resolve hot spots.
Extremely low genotypic diversity and sexual reproduction in isolated populations of the self-incompatible lily-of-the-valley (Convallaria majalis) and the role of the local forest environment.

BACKGROUND AND AIMS Clonal growth is a common phenomenon in plants and allows them to persist when sexual life-cycle completion is impeded. Very low levels of recruitment from seed will ultimately result in low levels of genotypic diversity. The situation can be expected to be exacerbated in spatially isolated populations of obligated allogamous species, as low genotypic diversities will result in low availability of compatible genotypes and low reproductive success. Populations of the self-incompatible forest herb lily-of-the-valley (Convallaria majalis) were studied with the aim of inferring the relative importance of sexual and asexual recruitment. Then the aim was to establish a relationship between genotypic diversity, sexual reproduction and the local forest environment. METHODS Highly polymorphic microsatellite markers were used to investigate clonal diversities and population genetic structure of 20 populations of C. majalis in central Belgium. KEY RESULTS Most of the populations studied consisted of a single genotype and linkage disequilibrium within populations was high, manifesting clonal growth as the main mode of reproduction. A population consisting of multiple genotypes mainly occurred in locations with a thin litter layer and high soil phosphorus levels, suggesting environment-mediated sporadic recruitment from seed. Highly significant genetic differentiation indicated that populations are reproductively isolated. In agreement with the self-incompatibility of C. majalis, monoclonal populations showed very low or even absent fruit set. CONCLUSIONS Lack of sexual recruitment in spatially isolated C. majalis populations has resulted in almost monoclonal populations with reduced or absent sexual reproduction, potentially constraining their long-term persistence. The local forest environment may play an important role in mediating sexual recruitment in clonal forest plant species.
Detection of Protein Folding Defects Caused by BRCA1-BRCT Truncation and Missense Mutations*

Most cancer-associated BRCA1 mutations identified to date result in the premature translational termination of the protein, highlighting a crucial role for the C-terminal, BRCT repeat region in mediating BRCA1 tumor suppressor function. However, the molecular and genetic effects of missense mutations that map to the BRCT region remain largely unknown. Using a protease-based assay, we directly assessed the sensitivity of the folding of the BRCT domain to an extensive set of truncation and single amino acid substitutions derived from breast cancer screening programs. The protein can tolerate truncations of up to 8 amino acids, but further deletion results in drastic BRCT folding defects. This molecular phenotype can be correlated with an increased susceptibility to disease. A cross-validated computational assessment of the BRCT mutation data base suggests that as much as half of all BRCT missense mutations contribute to BRCA1 loss of function and disease through protein-destabilizing effects. The coupled use of proteolytic methods and computational predictive methods to detect mutant BRCA1 conformations at the protein level will augment the efficacy of current BRCA1 screening protocols, especially in the absence of clinical data that can be used to discriminate deleterious BRCT missense mutations from benign polymorphisms.
The haemodynamic effects of adjunctive hormone therapy in potential heart donors: a prospective randomized double-blind factorially designed controlled trial.

AIMS The aim of this study was to assess the haemodynamic effects of tri-iodothyronine (T3) and methylprednisolone in potential heart donors. METHODS AND RESULTS In a prospective randomized double-blind trial, 80 potential cardiac donors were allocated to receive T3 (0.8 microg kg(-1) bolus; 0.113 microg kg(-1) h(-1) infusion) (n = 20), methylprednisolone (1000 mg bolus) (n = 19), both drugs (n = 20), or placebo (n = 21) following initial haemodynamic assessment. After hormone or placebo administration, cardiac output-guided optimization was initiated, using vasopressin as a pressor and weaning norepinephrine and inotropes. Treatment was administered for 5.9 +/- 1.3 h until retrieval or end-assessment. Cardiac index increased significantly (P < 0.001) but administration of T3 and methylprednisolone alone or in combination did not affect this change or the heart retrieval rate. Thirty-five per cent (14/40) of initially marginal or dysfunctional hearts were suitable for transplant at end-assessment. At end-assessment, 50% of donor hearts fulfilled criteria for transplant suitability. CONCLUSION Cardiac output-directed donor optimization improves donor circulatory status and has potential to increase the retrieval rate of donor hearts. Tri-iodothyronine and methylprednisolone therapy do not appear to acutely affect cardiovascular function or yield.