julilili42/papers huggingface dataset:
Association of Common Genetic Variants in the MAP4K4 Locus with Prediabetic Traits in Humans
2012-10-18

Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is expressed in all diabetes-relevant tissues and mediates cytokine-induced insulin resistance. We investigated whether common single nucleotide polymorphisms (SNPs) in the MAP4K4 locus associate with glucose intolerance, insulin resistance, impaired insulin release, or elevated plasma cytokines. The best hit was tested for association with type 2 diabetes. Subjects (N = 1,769) were recruited from the Tübingen Family (TÜF) study for type 2 diabetes and genotyped for tagging SNPs. In a subgroup, cytokines were measured. Association with type 2 diabetes was tested in a prospective case-cohort study (N = 2,971) derived from the EPIC-Potsdam study. Three SNPs (rs6543087, rs17801985, rs1003376) revealed nominal and two SNPs (rs11674694, rs11678405) significant associations with 2-hour glucose levels. SNPs rs6543087 and rs11674694 were also nominally associated with decreased insulin sensitivity. Another two SNPs (rs2236936, rs2236935) showed associations with reduced insulin release, driven by effects in lean subjects only. Three SNPs (rs11674694, rs13003883, rs2236936) revealed nominal associations with IL-6 levels. SNP rs11674694 was significantly associated with type 2 diabetes. In conclusion, common variation in MAP4K4 is associated with insulin resistance and β-cell dysfunction, possibly via this gene's role in inflammatory signalling. This variation's impact on insulin sensitivity may be more important since its effect on insulin release vanishes with increasing BMI.
Nonadditive potentials between three Rydberg atoms
2012-10-18

We calculate interaction potentials between three rubidium Rydberg atoms in the absence of external fields. Several three-atom states are considered: and . Among the considered states, nonadditive potentials appear in the states if or if is small, and also in states. Interatomic potentials are nonadditive when they induce intensive mixing between three-atom states of the same zero-order energy. The consideration of nonadditive potentials may add a new dimension to the research into Rydberg atoms.
Do we use the right criteria for determining the clinical significance of incidental prostate cancer at radical cystoprostatectomy?
2012-10-18

Prostate-sparing techniques have been advocated to improved functional outcomes after radical cystoprostatectomy (RCP) for invasive bladder cancer, but this may endanger the oncological outcome. This review addresses the current status of risk factors of prostate cancer (PCa) recurrence in patients with incidental PCa after RCP. The overall 7-year risk of PCa recurrence after RCP is approximately 9%. Increased risk has been suggested in the presence of clinically significant PCa as: ≥ pT3a stage, presence of lymph-node metastasis, positive surgical margins, Gleason pattern ≥ 4, tumour multifocality (three or more foci) and tumour volume >0.5 cm(3). However, the prognostic significance of these parameters has not been evaluated within multivariable analyses so far. Preoperatively elevated prostate-specific antigen (PSA) values correlate weakly with the clinical significance of incidental PCa, while prostate biopsy has a limited accuracy for detecting incidental PCa in the preoperative setting. Genetic markers, e.g. the prostate stem cell antigen (PSCA) gene, have recently been associated with risk of recurrence in patients with incidental PCa. Incidental PCa at RCP is usually clinically insignificant. Yet, clinicopathological parameters for clinical significant cancers have not been investigated independently in the literature so far. Consequently, lifelong PSA surveillance should be conducted in all patients with incidental PCa after RCP. In the presence of clinically significant PCa treatment decisions should be based not only on histological criteria but also on patient-centred parameters (e.g. patient age and comorbidities). Assessment of PSCA expression in RCP specimens may enable improved risk assessment for PCa recurrence after RCP.
Radiative properties of magnetic neutron stars with metallic\\n surfaces and thin atmospheres
2012-10-18

\\n Context. Simple models fail to describe the observed spectra of\\n X-ray-dim isolated neutron stars (XDINSs). Interpretating these spectra requires detailed\\n studies of radiative properties in the outermost layers of neutron stars with strong\\n magnetic fields. Previous studies have shown that the strongly magnetized plasma in the\\n outer envelopes of a neutron star may exhibit a phase transition to a condensed form. In\\n this case thermal radiation can emerge directly from the metallic surface without going\\n through a gaseous atmosphere, or alternatively, it may pass through a “thin” atmosphere\\n above the surface. The multitude of theoretical possibilities complicates modeling the\\n spectra and makes it desirable to have analytic formulae for constructing samples of\\n models without going through computationally expensive, detailed calculations. \\n Aims. The goal of this work is to develop a simple analytic description\\n of the emission properties (spectrum and polarization) of the condensed, strongly\\n magnetized surface of neutron stars.\\n Methods. We have improved our earlier work for calculating the spectral\\n properties of condensed magnetized surfaces. Using the improved method, we calculated the\\n reflectivity of an iron surface at magnetic field strengths\\n B ~ 1012 G–1014 G, with various inclinations of\\n the magnetic field lines and radiation beam with respect to the surface and each other. We\\n constructed analytic expressions for the emissivity of this surface as functions of the\\n photon energy, magnetic field strength, and the three angles that determine the geometry\\n of the local problem. Using these expressions, we calculated X-ray spectra for neutron\\n stars with condensed iron surfaces covered by thin partially ionized hydrogen\\n atmospheres.\\n Results. We develop simple analytic descriptions of the intensity and\\n polarization of radiation emitted or reflected by condensed iron surfaces of neutron stars\\n with the strong magnetic fields typical of isolated neutron stars. This description\\n provides boundary conditions at the bottom of a thin atmosphere, which are more accurate\\n than previously used approximations. The spectra calculated with this improvement show\\n different absorption features from those in simplified models. \\n Conclusions. The approach developed in this paper yields results that\\n can facilitate modeling and interpretation of the X-ray spectra of isolated, strongly\\n magnetized, thermally emitting neutron stars.\\n
Radiogenic Source Identification for the Helium Production-Diffusion Equation
2012-10-18

Abstract Knowledge of helium diffusion kinetics is critical for materials in which helium measurements are made, particulary for thermochronology. In most cases the helium ages were younger than expected, an observation attributes to diffusive loss of helium and the ejection of high energy alpha particles. Therefore it is important to accurately calculate the distribution of the source term within a sample. In this paper, the prediction of the helium concentrations as function of a spatially variable source term are considered. Both the forward and inverse solutions are presented. Under the assumption of radially symmetric geometry, an analytical solution is deduced based on the eigenfunction expansion. Two regularization methods, the Tikhonov regularization and the spectral cutoff regularization, are considered to obtain the regularized solution. Error estimates with optimal convergence order are shown between the exact solution and the regularized solution. Numerical examples are presented to illustrate the validity and effectiveness of the proposed methods
Poly Specific trans-Acyltransferase Machinery Revealed via Engineered Acyl-CoA Synthetases
2012-10-19

Polyketide synthases construct polyketides with diverse structures and biological activities via the condensation of extender units and acyl thioesters. Although a growing body of evidence suggests that polyketide synthases might be tolerant to non-natural extender units, in vitro and in vivo studies aimed at probing and utilizing polyketide synthase specificity are severely limited to only a small number of extender units, owing to the lack of synthetic routes to a broad variety of acyl-CoA extender units. Here, we report the construction of promiscuous malonyl-CoA synthetase variants that can be used to synthesize a broad range of malonyl-CoA extender units substituted at the C2-position, several of which contain handles for chemoselective ligation and are not found in natural biosynthetic systems. We highlighted utility of these enzymes by probing the acyl-CoA specificity of several trans-acyltransferases, leading to the unprecedented discovery of poly specificity toward non-natural extender units, several of which are not found in naturally occurring biosynthetic pathways. These results reveal that polyketide biosynthetic machinery might be more tolerant to non-natural substrates than previously established, and that mutant synthetases are valuable tools for probing the specificity of biosynthetic machinery. Our data suggest new synthetic biology strategies for harnessing this promiscuity and enabling the regioselective modification of polyketides.
Epithelial Mesenchymal Transition and Pancreatic Tumor Initiating CD44+/EpCAM+ Cells Are Inhibited by γ-Secretase Inhibitor IX
2012-10-19

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high rate of metastasis. Recent studies have indicated that the Notch signalling pathway is important in PDAC initiation and maintenance, although the specific cell biological roles of the pathway remain to be established. Here we sought to examine this question in established pancreatic cancer cell lines using the γ-secretase inhibitor IX (GSI IX) to inactivate Notch. Based on the known roles of Notch in development and stem cell biology, we focused on effects on epithelial mesenchymal transition (EMT) and on pancreatic tumor initiating CD44+/EpCAM+ cells. We analyzed the effect of the GSI IX on growth and epithelial plasticity of human pancreatic cancer cell lines, and on the tumorigenicity of pancreatic tumor initiating CD44+/EpCAM+ cells. Notably, apoptosis was induced after GSI IX treatment and EMT markers were selectively targeted. Furthermore, under GSI IX treatment, decline in the growth of pancreatic tumor initiating CD44+/EpCAM+ cells was observed in vitro and in a xenograft mouse model. This study demonstrates a central role of Notch signalling pathway in pancreatic cancer pathogenesis and identifies an effective approach to inhibit selectively EMT and suppress tumorigenesis by eliminating pancreatic tumor initiating CD44+/EpCAM+ cells.
Kohlschütter-Tönz Syndrome: Mutations inROGDIand Evidence of Genetic Heterogeneity
2012-10-19

Kohlschütter-Tönz syndrome (KTS) is a rare autosomal recessive disorder characterized by amelogenesis imperfecta, psychomotor delay or regression and seizures starting early in childhood. KTS was established as a distinct clinical entity after the first report by Kohlschütter in 1974, and to date, only a total of 20 pedigrees have been reported. The genetic etiology of KTS remained elusive until recently when mutations in ROGDI were independently identified in three unrelated families and in five likely related Druze families. Herein, we report a clinical and genetic study of 10 KTS families. By using a combination of whole exome sequencing, linkage analysis, and Sanger sequencing, we identify novel homozygous or compound heterozygous ROGDI mutations in five families, all presenting with a typical KTS phenotype. The other families, mostly presenting with additional atypical features, were negative for ROGDI mutations, suggesting genetic heterogeneity of atypical forms of the disease.
RNA isolation from fetal and adult human tissues for transcriptional profiling
2012-10-19

Abstract Investigations involving rare human tissues that are difficult to acquire due to their scarcity are highly challenging. The need to verify microarray analysis data by additional methods such as immunohistochemical staining and quantitative PCR creates an even greater demand for these valuable tissues. Furthermore, since rare human tissues may come from different sources and may have been processed by variable methods, the comparability of these samples must be verified. The aim of this study was to determine and validate a processing method that allows the analysis of human fetal and adult cardiovascular tissues from different sources that were preserved using varying methods. Due to restricted access to fresh human tissues and the need to accumulate these samples over an extended period of time, we used formalin‐fixed paraffin‐embedded tissues for gene expression analyses. We analyzed RNA levels from four different age groups: fetal first and second trimester, adolescents, and adults. In this study, we present an improved standard processing procedure for tissue sample processing and analysis of rare human cardiovascular tissues.
A preliminary assessment of the effectiveness of the Mesoamerican Biological Corridor for protecting potential Baird's tapir (Tapirus bairdii) habitat in southern Mexico
2012-10-20

Abstract Baird's tapir ( Tapirus bairdii ) is one of the most emblematic mammals of Mesoamerica, but like other large‐bodied animals, it is facing an increasing risk of extinction due primarily to habitat loss. Mexico's ‘ortion of the Mesoamerican Biological Corridor (MBC‐M) is located in one of the main strongholds for Bairds tapir. To assess the MBC‐M's effectiveness for tapir conservation, we estimated the distribution of the species’ potential habitat by applying 2 modelling approaches (random forest and Maxent) to a set of uncorrelated environmental variables and a 157‐point presence dataset. We calculated the extent of tapir habitat in within the MBC‐M and modelled new corridors and conservation areas, which we compared to the MBC‐M. Moreover, we assessed deforestation patterns in the region. Twenty‐seven percent of highly suitable tapir habitat occurred in protected areas, 15% in corridors and 58.3% was outside the MBC‐M and associated reserves. The spatial configuration of the MBC‐M was partially concordant with the modelled set of conservation areas and corridors. The main dissimilarity was that the modelled corridors traversed forests in Belize and Guatemala to connect conservation areas. Analyses of deforestation since 1993 and human population density in the vicinity of the MBC‐M indicated that future conservation efforts should give particular attention to the Montes Azules‐El Triunfo Corridor due to greater habitat threat. The MBC‐M has a great potential to play a prominent role in the conservation of tapir habitat but there is an urgent need to implement management plans that reinforce and complement this conservation initiative.
Identification of Dlk1-Dio3 Imprinted Gene Cluster Noncoding RNAs as Novel Candidate Biomarkers for Liver Tumor Promotion
2012-10-22

The molecular events during nongenotoxic carcinogenesis and their temporal order are poorly understood but thought to include long-lasting perturbations of gene expression. Here, we have investigated the temporal sequence of molecular and pathological perturbations at early stages of phenobarbital (PB) mediated liver tumor promotion in vivo. Molecular profiling (mRNA, microRNA [miRNA], DNA methylation, and proteins) of mouse liver during 13 weeks of PB treatment revealed progressive increases in hepatic expression of long noncoding RNAs and miRNAs originating from the Dlk1-Dio3 imprinted gene cluster, a locus that has recently been associated with stem cell pluripotency in mice and various neoplasms in humans. PB induction of the Dlk1-Dio3 cluster noncoding RNA (ncRNA) Meg3 was localized to glutamine synthetase-positive hypertrophic perivenous hepatocytes, suggesting a role for β-catenin signaling in the dysregulation of Dlk1-Dio3 ncRNAs. The carcinogenic relevance of Dlk1-Dio3 locus ncRNA induction was further supported by in vivo genetic dependence on constitutive androstane receptor and β-catenin pathways. Our data identify Dlk1-Dio3 ncRNAs as novel candidate early biomarkers for mouse liver tumor promotion and provide new opportunities for assessing the carcinogenic potential of novel compounds.
Defining regulatory and phosphoinositide-binding sites in the human WIPI-1 β-propeller responsible for autophagosomal membrane localization downstream of mTORC1 inhibition
2012-10-22

We identified amino acids of the WIPI-1 β-propeller that confer PtdIns(3)P or PtdIns(3,5)P2 binding (S203, S205, G208, T209, R212, R226, R227, G228, S251, T255, H257), and that regulate the localization at autophagosomal membranes (R110, R112, H185) downstream of mTORC1 inhibition.
Conjugative DNA transfer inStreptomycesby TraB: is one protein enough?
2012-10-22

Antibiotic-producing soil bacteria of the genus Streptomyces form a huge natural reservoir of antibiotic resistance genes for the dissemination within the soil community. Streptomyces plasmids encode a unique conjugative DNA transfer system clearly distinguished from classical conjugation involving a single-stranded DNA molecule and a type IV protein secretion system. Only a single plasmid-encoded protein, TraB, is sufficient to translocate a double-stranded DNA molecule into the recipient in Streptomyces matings. TraB is a hexameric pore-forming ATPase that resembles the chromosome segregator protein FtsK and translocates DNA by recognizing specific 8-bp repeats present in the plasmid clt locus. Mobilization of chromosomal genes does not require integration of the plasmid, because TraB also recognizes clt-like sequences distributed all over the chromosome.
The Almacık mafic-ultramafic complex: exhumed Sakarya subcrustal mantle adjacent to the İstanbul Zone, NW Turkey
2012-10-22

Abstract The Almacık Mountains in northwestern Turkey expose an upper-amphibolite-facies complex consisting of alternating ultramafic (harzburgitic and websteritic) and mafic (metagabbroic) rock types. In the eastern part of this complex are island arc meta-tholeiites and transitional to calc-alkaline metabasites that are chemically quite similar to those of the Permo-Triassic Çele mafic complex north of Bolu, and this suggests an equivalence. However, much of the section exposes structurally deeper and chemically different mafic and ultramafic rocks, which have no equivalent in the Çele mafic complex, and isotopic dating has suggested that these rocks also formed during the Permian period and underwent Triassic and Jurassic metamorphism. Furthermore, sparse inherited ages, unlike those from İstanbul Zone granitoids, suggest a link with North African-derived Armorican-type basement (and hence the Sakarya Zone), rather than Amazonia-derived Avalonian basement. Alternating mafic and ultramafic rocks suggest structural repetition, supported by the exposure of discrete high-strain zones or poorly exposed shattered rock west of each outcrop of ultramafic rocks. The high grade of metamorphism, and the absence of either extrusive lavas or sheeted dyke rocks, suggests that the Almacık complex was not an ophiolite, but formed instead as subcontinental lower crust and subjacent mantle. Dominantly calc-alkaline geochemistry suggests that it formed the basement to an active continental margin bounding the north side of the Sakarya Continent, with S-dipping subduction of Palaeotethys. The Almacık complex was uplifted as a late result of compression against the southern margin of the İstanbul Zone in the Jurassic period. Lack of coeval high-grade metamorphism in the İstanbul Zone indicates that the latter was overthrust southwards over the Sakarya margin, and that there was therefore a change of subduction polarity in the Triassic period. The evidence further casts doubt on the existence of a Mesozoic Intra-Pontide Ocean in northwestern Turkey and suggests that the latest Permian magmatism, with subsequent Triassic and Jurassic metamorphism, was instead related to the closure of the Palaeotethyan Ocean.
Molecular genetics research in ADHD: Ethical considerations concerning patients' benefit and resource allocation
2012-10-22

Abstract Immense resource allocations have led to great data output in genetic research. Concerning ADHD resources spent on genetic research are less than those spent on clinical research. But there are successful efforts made to increase support for molecular genetics research in ADHD. Concerning genetics no evidence based conclusive results have significant impact on prevention, diagnosis or treatment yet. With regard to ethical aspects like the patients' benefit and limited resources the question arises if it is indicated to think about a new balance of resource allocation between molecular genetics and non‐genetics research in ADHD. An ethical reflection was performed focusing on recent genetic studies and reviews based on a selective literature search. There are plausible reasons why genetic research results in ADHD are somehow disappointing for clinical practice so far. Researchers try to overcome these gaps systematically, without knowing what the potential future benefits for the patients might be. Non‐genetic diagnostic/therapeutic research may lead to clinically relevant findings within a shorter period of time. On the other hand, non‐genetic research in ADHD may be nurtured by genetic approaches. But, with the latter there exist significant risks of harm like stigmatization and concerns regarding data protection. Isolated speeding up resources of genetic research in ADHD seems questionable from an ethical point of view. There is a need to find a new balance of resource allocation between genetic and non‐genetic research in ADHD, probably by integrating genetics more systematically into clinical research. A transdisciplinary debate is recommended. © 2012 Wiley Periodicals, Inc.