Miracle-dz/UniFAR-FTUs huggingface dataset:
Common Evolutionary Origin for the Unstable Virulence Plasmid pMUM Found in Geographically Diverse Strains of Mycobacterium ulcerans

ABSTRACT The 174-kb virulence plasmid pMUM001 in Mycobacterium ulcerans epidemic strain Agy99 harbors three very large and homologous genes that encode giant polyketide synthases (PKS) responsible for the synthesis of the lipid toxin mycolactone. Deeper investigation of M. ulcerans Agy99 resulted in identification of two types of spontaneous deletion variants of pMUM001 within a population of cells that also contained the intact plasmid. These variants arose from recombination between two 8-kb sections of the same plasmid sequence, resulting in the loss of a 65-kb region bearing two of the three mycolactone PKS genes. Investigation of nine diverse M. ulcerans strains by using PCR and Southern hybridization for eight pMUM001 gene sequences confirmed the presence of pMUM001-like elements (collectively called pMUM) in all M. ulcerans strains. Physical mapping of these plasmids revealed that like M. ulcerans Agy99, three strains had undergone major deletions in their mycolactone PKS loci. Online liquid chromatography-sequential mass spectrometry analysis of lipid extracts confirmed that strains with PKS deletions were unable to produce mycolactone or any related cometabolites. Interstrain comparisons of the plasmid gene sequences revealed greater than 98% nucleotide identity, and the phylogeny inferred from these sequences closely mimicked the phylogeny from a previous multilocus sequence typing study in which chromosomally encoded loci were used, a result that is consistent with the hypothesis that M. ulcerans diverged from the closely related organism Mycobacterium marinum by acquiring pMUM. Our results suggest that pMUM is a defining characteristic of M. ulcerans but that in the absence of purifying selection, deletion of plasmid sequences and a corresponding loss of mycolactone production readily arise.
Pneumococcal vaccines for preventing otitis media.

BACKGROUND Acute otitis media (AOM) is one of the most common diseases in early infancy and childhood. Long term effects of recurrent episodes of otitis media, rapid emergence of drug resistant bacteria associated with AOM worldwide and huge estimated direct and indirect annual costs associated with otitis media have emphasized the need for an effective vaccination program to prevent episodes of AOM. OBJECTIVES The object of this review was to assess the effect of pneumococcal vaccination in preventing AOM in children up to 12 years of age. SEARCH STRATEGY We searched the Cochrane Acute Respiratory Infection Group specialised register (last update, 26th April 2001), the Cochrane Library (Issue 4, 2000), MEDLINE (January 1966-August 2000) and reference list of all studies and review articles retrieved. We also contacted two vaccine manufacturers and first or corresponding authors of some included studies. SELECTION CRITERIA Randomised controlled clinical trials of pneumococcal vaccination with prevention of AOM as outcome in children aged 12 years or younger and a follow-up of at least six months. DATA COLLECTION AND ANALYSIS Five reviewers independently assessed trial quality and two reviewers extracted data. Two study authors were contacted. MAIN RESULTS Eight trials on pneumococcal polysaccharide vaccine (PPV) and two trials on pneumococcal conjugate vaccine (PCV) were included. The highest efficacy of PPV was found in children aged 24 months and older: the rate ratio after adjustment for study was 0.833 [95%CI: 0.625-0.970]. The PPV has little effect on the prevention of AOM in children without documented prior episodes of AOM and only a moderate effect in the group of children with documented AOM episodes prior to vaccination. The results of the two PCV trials in healthy infants, which followed children from the age of two months until two years of age, could not be pooled because of lack of data. Both studies showed that the risk of recurrent disease decreased with 9% in the group of children receiving the PCV together with other childhood vaccinations at 2,4,6 and 14 months of age: Study Black et al 2000 : risk ratio=0.91[95%CI:0.86-0.96]; Study Eskola et al 2001: risk ratio=0.90 [95%CI:0.73-1.12]. REVIEWER'S CONCLUSIONS Based on the currently available results of the effectiveness of pneumococcal vaccination for the prevention of AOM, a large scale use of pneumococcal vaccination for this indication is not recommended. The results of currently ongoing trials could provide more information whether pneumococcal vaccines are effective in specific high-risk (otitis-prone) populations.
Histone Variant HTZ1 Shows Extensive Epistasis with, but Does Not Increase Robustness to, New Mutations

Biological systems produce phenotypes that appear to be robust to perturbation by mutations and environmental variation. Prior studies identified genes that, when impaired, reveal previously cryptic genetic variation. This result is typically interpreted as evidence that the disrupted gene normally increases robustness to mutations, as such robustness would allow cryptic variants to accumulate. However, revelation of cryptic genetic variation is not necessarily evidence that a mutationally robust state has been made less robust. Demonstrating a difference in robustness requires comparing the ability of each state (with the gene perturbed or intact) to suppress the effects of new mutations. Previous studies used strains in which the existing genetic variation had been filtered by selection. Here, we use mutation accumulation (MA) lines that have experienced minimal selection, to test the ability of histone H2A.Z (HTZ1) to increase robustness to mutations in the yeast Saccharomyces cerevisiae. HTZ1, a regulator of chromatin structure and gene expression, represents a class of genes implicated in mutational robustness. It had previously been shown to increase robustness of yeast cell morphology to fluctuations in the external or internal microenvironment. We measured morphological variation within and among 79 MA lines with and without HTZ1. Analysis of within-line variation confirms that HTZ1 increases microenvironmental robustness. Analysis of between-line variation shows the morphological effects of eliminating HTZ1 to be highly dependent on the line, which implies that HTZ1 interacts with mutations that have accumulated in the lines. However, lines without HTZ1 are, as a group, not more phenotypically diverse than lines with HTZ1 present. The presence of HTZ1, therefore, does not confer greater robustness to mutations than its absence. Our results provide experimental evidence that revelation of cryptic genetic variation cannot be assumed to be caused by loss of robustness, and therefore force reevaluation of prior claims based on that assumption.
Diagnostic Utility of S100P and von Hippel-Lindau Gene Product (pVHL) in Pancreatic Adenocarcinoma—With Implication of Their Roles in Early Tumorigenesis

Recently, we demonstrated von Hippel-Lindau gene product (pVHL) was expressed in normal pancreatic ducts but absent in pancreatic ductal adenocarcinoma (PDA). Previous studies have suggested the diagnostic value of S100P, S100A4, and S100A6 in PDA. In this study, we evaluated pVHL, S100P, S100A4, and S100A6 as potential markers for PDA, pancreatic intraepithelial neoplasia (PanIN), ampullary adenocarcinoma (AAD), and cholangiocarcinoma (CC). Immunostains were performed on 56 PDA cases, 20 AAD cases, and 28 CC cases using antibodies against pVHL, S100P, S100A6, and S100A4. Western blots were also performed on 2 cases of PDA and the matching non-neoplastic pancreatic tissues. Of the 56 PDA cases, immunoreactivity for S100P, S100A6, and S100A4 was observed in 56, 55, and 41 cases, respectively. Non-neoplastic ductal epithelium was negative for S100P in all cases. Ninety percent of PanINs were also positive for S100P. pVHL was not detected in all PDAs and 96% of PanINs by immunohistochemistry. S100P, S100A4, and S100A6 were present in a significant number of AADs and CCs; and pVHL expression was observed in 25% of AADs and 21% of CCs. Our data indicate that (1) S100P and pVHL are a pair of sensitive and specific markers for identifying primary PDA and PanIN; (2) up-regulation of S100P and down-regulation of pVHL may play a role in early tumorigenesis in PDA; and (3) the 4 markers studied have limited value in differentiating among PDA, AAD, and CC.
Debt, Investment, and Product Market Competition

Recent empirical literature on the interaction between capital structure, investment, and product market decisions suggests that debt leads to lower investment expenditures and weaker product market competition. Theoretical literature in this area has been unable to fully explain this finding (perhaps because all theoretical papers look only at two of the above decisions). This paper develops a model which examines all three decisions and shows that debt and investment can be substitutes in a model where firms rationally take on debt. Furthermore, it is demonstrated that when firms compete with prices in the product market, an increase in debt leads to lower investment and higher prices.
Structured Query Language Injection (SQLI) Attacks: Detection and Prevention Techniques in Web Application Technologies

paper investigates and reports on web application vulnerabilities with a specific focus on Structured Query Language Injection (SQLI) attacks and measures and how to counter such threats. SQLI attacks cause very serious dangers to web applications, they make it possible for attackers to get unhindered access to the primary source of data which is in the database and possibly the very sensitive information that the database contains. Even though practitioners and researchers in the web application security field have proposed a range of techniques to get to the bottom of the SQLI attack challenge, presently adopted approaches have either resolved the problem to some extent or have inadequacies that prevent their use and adoption. To help address this challenge, this paper presents a broad review of SQL injection attacks. An appraisal of current detection and prevention techniques against SQL injection attacks are also presented. Furthermore, a vulnerability assessment was conducted on the Centre for Computational Intelligence (CCI) Website as a case study. A snippet code that can be used to redesign the CCI website as a protective measure to counter threats of SQLI was proposed. An examination of this paper indicates that current solutions being promoted may not address the problem, and that web application firewalls provides the answer to SQLI attacks.
CD4 CD7 CD28 T Cells Are Expanded in Rheumatoid Arthritis and Are Characterized by Autoreactivity

Clonal expansion of CD4 (cid:49) T cells is a characteristic finding in patients with RA and is only infrequently found in patients with psoriatic arthritis and healthy controls. Expanded CD4 (cid:49) clonotypes are present in the blood, infiltrate into the joint, and persist over years. We have now ad-dressed the question of whether the expanded clonotypes have unique functional and phenotypic properties which may explain the preferential in vivo expansion in RA. In contrast to most CD4 (cid:49) T cells, expanded clonotypes lacked the expression of the CD28 and CD7 cell surface molecules. Accordingly, the subsets of CD4 (cid:49) CD28 (cid:50) (9.7 vs. 1.7, P (cid:53) 0.00002) and CD4 (cid:49) CD7 (cid:50) T cells (21.5 vs. 12.6, P (cid:53) 0.018) were increased in RA patients compared with age-matched normal individuals. Despite the lack of CD28 expression, clonally expanded CD4 (cid:49) T cells were not anergic but proliferated in response to immobilized anti-CD3 and could be maintained in tissue culture. In vivo expanded CD4 (cid:49) T cells were autoreactive to ubiquitously distributed autoantigens. They responded in an autologous mixed lymphocyte reaction, and T cell clones isolated from selected patients proliferated to autologous peripheral blood adherent cells. These data suggest that in RA patients selected CD4 (cid:49) T cells which share the CD7 (cid:50) CD28 (cid:50) phenotype escape from peripheral tolerance. ( J. Clin. Invest. 1996. 97:2027–2037.)
Lifetime cost of care for children with human immunodeficiency virus infection.

BACKGROUND Knowledge of the cost of care for children with HIV infection is necessary to analyze the economic impact of recommendations for universal counseling and voluntary HIV testing of pregnant women. OBJECTIVES To estimate the total cost of care for children with HIV infection. METHODS We performed a retrospective cohort study of all 88 children with (n = 29) or at risk for (n = 59) perinatally acquired HIV infection cared for at Children's Hospital of Wisconsin between February 2, 1987, and June 1, 1995. Review of medical records for all 29 children with perinatally acquired HIV infection or AIDS identified: date of HIV diagnosis; date of classification into Category N, A, B or C; date of AIDS diagnosis; and date of death or transfer of care. The time each subject remained in each CDC category was calculated and the Kaplan-Meier product-limit method was used to calculate survival time for all patients in each CDC category. Hospital-based inpatient and outpatient charges per patient per month in each CDC category (N, A, B, C and AIDS) were calculated with information from the hospital financial services database, and lifetime hospital-based inpatient and outpatient charges were estimated as the sum of the charges for each category. From that, total charges were calculated assuming that hospital-based charges were 83% of total charges. RESULTS Based on a median survival time of 120 months, the mean lifetime charges for hospital-based care for children with HIV infection was $408307 (estimates ranged from $172217 to $498539). If hospital-based care represents 83% of the total charges for care of children with HIV infection, then mean total lifetime charges for care of children with HIV infection were $491936 ($207490 to $600649). CONCLUSIONS The care of children with HIV infections is expensive. This information may be useful in planning for care programs and for analyzing the economic impact of recommendations for universal counseling and voluntary HIV testing of pregnant women.
Investigation into functional large-scale networks in individuals with schizophrenia using fMRI data and Dynamic Causal Modelling

Introduction Dynamic Causal Modelling is an established method for the computation of synaptic plasticity from fMRI data (Stephan et al., 2006, 2009a). Bilinear DCM provides for the inference of causal mechanisms, which at the regional neuronal level give estimations of how the rate of change of neuronal activity in one region influences neuronal activity in other regions (Friston, 2009; Friston et al., 2003; Stephan et al., 2008). Nonlinear DCM is an extension of bilinear DCM, which assesses inhibitions of a neuronal connection and provides a means to model nonlinearities in fMRI data (Stephan et al., 2008). It is assumed that these nonlinear effects originate from activity-dependent synaptic plasticity processes (Abbott et al., 1997; Rothman et al., 2009; Salinas and Sejnowski, 2001; Shu et al., 2003). Furthermore, it has been suggested that altered gain control (i.e. nonlinear modulation of neuronal connections) of the thalamocortical connection could be the underlying factor for altered synaptic plasticity and cortical dysconnectivity in schizophrenia (Andreasen et al., 1997; Negyessy and Goldman-Rakic, 2005). We know from neurophysiological studies that nonlinear mechanisms are integral to short-term synaptic plasticity. Nonlinear modulation has been shown to regulate synaptic plasticity modulated by neurotransmitters (Berends et al., 2005; Neher and Sakaba, 2008; Pan and Zucker, 2009; Sun and Beierlein, 2011). Also thalamocortical NeuroImage 73 (2013) 16–29 Abbreviations: ACC, Anterior cingulate cortex; BMA, Bayesian Model Averaging; BMS, Bayesian Model Selection; DCM, Dynamic Causal Modelling; EHRS, Edinburgh High Risk Study; IFG, Inferior frontal gyrus; IPS, Intra parietal sulcus; HR+, High risk subjects with psychotic symptoms; HR−, High risk subjects without psychotic symptoms; HRall, All high risk subjects (high risk subjects with psychotic symptoms and without psychotic symptoms); HSCT, Hayling Sentence Completion Task; MD thalamus, Mediodorsal thalamus; mGluR, Metabotropic glutamate receptors; MTG, Middle temporal gyrus; NART, National Adult Reading Test; NMDA, N-methyl-D-aspartate; PSE, Present State Examination; Xp, Exceedance probability. ⁎ Corresponding author at: Division of Psychiatry, University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Edinburgh, EH10 5HF, UK. Fax: +44 1315376691. E-mail address: M.R. Dauvermann@sms.ed.ac.uk (M.R. Dauvermann). 1053-8119/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi. org/10.1016/j.neuroimage. 2013.01. 063
Trigger Factor and DnaK possess overlapping substrate pools and binding specificities

Ribosome‐associated Trigger Factor (TF) and the DnaK chaperone system assist the folding of newly synthesized proteins in Escherichia coli. Here, we show that DnaK and TF share a common substrate pool in vivo. In TF‐deficient cells, Δtig, depleted for DnaK and DnaJ the amount of aggregated proteins increases with increasing temperature, amounting to 10% of total soluble protein (approximately 340 protein species) at 37°C. A similar population of proteins aggregated in DnaK depleted tig+ cells, albeit to a much lower extent. Ninety‐four aggregated proteins isolated from DnaK‐ and DnaJ‐depleted Δtig cells were identified by mass spectrometry and found to include essential cytosolic proteins.
A Modern Ampelography: A Genetic Basis for Leaf Shape and Venation Patterning in Grape1[C][W][OPEN]

Statistical methods can globally describe the complex shapes of grape leaves, permitting the evaluation of not only the genetic basis of leaf shape but its correlation with traits of economic interest. Terroir, the unique interaction between genotype, environment, and culture, is highly refined in domesticated grape (Vitis vinifera). Toward cultivating terroir, the science of ampelography tried to distinguish thousands of grape cultivars without the aid of genetics. This led to sophisticated phenotypic analyses of natural variation in grape leaves, which within a palmate-lobed framework exhibit diverse patterns of blade outgrowth, hirsuteness, and venation patterning. Here, we provide a morphometric analysis of more than 1,200 grape accessions. Elliptical Fourier descriptors provide a global analysis of leaf outlines and lobe positioning, while a Procrustes analysis quantitatively describes venation patterning. Correlation with previous ampelography suggests an important genetic component, which we confirm with estimates of heritability. We further use RNA-Seq of mutant varieties and perform a genome-wide association study to explore the genetic basis of leaf shape. Meta-analysis reveals a relationship between leaf morphology and hirsuteness, traits known to correlate with climate in the fossil record and extant species. Together, our data demonstrate a genetic basis for the intricate diversity present in grape leaves. We discuss the possibility of using grape leaves as a breeding target to preserve terroir in the face of anticipated climate change, a major problem facing viticulture.
Streaming of Kinect Data for Interactive In-Browser Audio Performances

Distributed audio applications typically follow a server-client model, in which the server produces an audio stream that is sent to the client for consumption. Then, if any modification of the content is needed, it is a product of audio post-processing on the client side, which is computationally expensive. We tackle these challenges by separating the creative (input), from the sound processing (output) part. As a result, the application becomes lightweight in networking and computational metrics, while an extra level of control over the final output is added on the client. In order to demonstrate our solution, we present the architecture of a sample audio application that supports visualizations and uses Kinect as a controller.
Negro Suffrage: The Constitutional Point of View

The Constitution of the United States as amended provides that “The right of citizens of the United States to vote shall not be denied or abridged by the United States or by any State on account of race, color, or previous condition of servitude. ” These words are plain. Everybody understands them. They mean, and every one knows that they mean, that, from the constitutional point of view, one question relative to the suffrage is no longer open. That question is the very one about which I am asked to write. From the political point of view, from the historical point of view, from the social point of view, from the economic point of view, and from the ethical point of view, there is much to be said about negro suffrage. For centuries yet to come there may be much to be said. From the constitutional point of view, accurately defined, there has been nothing to say since March 30, 1870. On that day the Secretary of State of the United States proclaimed that the Fifteenth Amendment had been ratified by the legislatures of twenty-nine out of the then thirty-seven States. The apparent assent of a number of these legislatures, perhaps, had not been a real assent. It might have been given under duress. Still, it had been given. The men who assumed to be the legislatures of other of these States may have had little moral and a very doubtful legal right to speak for them.
Octopamine immunoreactivity in the fruit fly Drosophila melanogaster

Octopamine has been proposed as a neurotransmitter/ modulator/ hormone serving a variety of physiological functions in invertebrates. We have initiated a study of octopamine in the fruit fly Drosophila melanogaster, which provides an excellent system for genetic and molecular analysis of neuroactive molecules. As a first step, the distribution of octopamine immunoreactivity was studied by means of an octopamine‐specific antiserum. We focused on the central nervous system (CNS) and on the innervation of the larval body wall muscles. The larval octopamine neuronal pattern was composed of prominent neurons along the midline of the ventral ganglion, whereas brain lobes were devoid of immunoreactive somata. However, intense immunoreactive neuropil was observed both in the ventral ganglion and in the brain lobes. Some of the immunoreactive neurons sent peripheral fibers that innervated most of the muscles of the larval body wall. Octopamine immunoreactivity was observed at neuromuscular junctions in all larval stages, being present in a well‐defined subset of synaptic boutons, type II. Octopamine immunoreactivity in the adult CNS revealed many additional neurons compared to the larval CNS, indicating that at least a subset of adult octopamine neurons may differentiate during metamorphosis. Major octopamine‐immunoreactive neuronal clusters and neuronal processes were observed in the subesophageal ganglion, deutocerebrum, and dorsal protocerebrum, and intense neuropil staining was detected primarily in the optic lobes and in the central complex. © 1995 Wiley‐Liss, Inc.