julilili42/papers huggingface dataset:
Faculty Opinions recommendation of Cytomegalovirus infection is associated with increased mortality in the older population.
2013-07-07

Cytomegalovirus (CMV) is a common herpesvirus infection and stimulates the expansion of very large numbers of CMV-specific T cells that reduce the CD4/CD8 ratio and suppress the number of naïve T cells. CMV infection has been associated with frailty and impaired survival. We investigated the correlates of CMV and the impact of the CMV infection on mortality within a cohort of 511 individuals aged at least 65 years who were followed up for 18 years. The mean age of the participants was 74 years of which 70% were CMV-seropositive. CMV was strongly linked to socio-economic status, and CMV infection increased the annual mortality rate by 42% (Hazard ratio = 1.42, 95% CI: 1.11-1.76 after adjusting for age, sex and baseline socio-economic and health variables) corresponding to 3.7 years lower life expectancy from age 65. Infection was associated with a near doubling of cardiovascular deaths, whereas there was no increase in mortality from other causes. These results show that CMV infection markedly increases the mortality rate in healthy older individuals due to an excess of vascular deaths. These findings may have significant implications for the study of immune senescence and if confirmed more generally could have important implications for measures to optimize the health of the elderly.© 2013 John Wiley & Sons Ltd and the Anatomical Society. PMID: 23442093 Funding information This work was supported by: Medical Research Council, United Kingdom Medical Research Council, United Kingdom Grant ID: G9901400
Mendelian Randomization Studies Do Not Support a Causal Role for Reduced Circulating Adiponectin Levels in Insulin Resistance and Type 2 Diabetes
2013-07-08

Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics–based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26–0.35) increase in fasting insulin, a 0.34-SD (0.30–0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47–2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI −0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (−0.20 SD; 95% CI −0.38 to −0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75–1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: −0.03 SD; 95% CI −0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95–1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.
Surface CD24 distinguishes between low differentiated and transit‐amplifying cells in the basal layer of human prostate
2013-07-08

Abstract BACKGROUND Benign prostatic hyperplasia (BPH) and prostate cancer (PCa) are common abnormalities in elderly men. It is considered that epithelial stem cells are involved in the etiology and development of both diseases. To distinguish aberrant from normal cells, the knowledge about primary epithelial stem/progenitor cells (ES/P) is essential. The aim of this study was to examine the role of surface markers to distinguish between different subsets of prostate basal epithelium. METHODS The expression pattern of prostate tissue single cell suspensions was analyzed by flow cytometry using different markers. Sorted cell populations were examined for their clonogenic capacity and the resulted colonies were analyzed with flow cytometry, Western blot, and qPCR for stem cell, basal, and luminal epithelium markers. Additionally, the histological localization of the examined markers was determined using immunofluorescence. RESULTS Using the combination of CD49f, Trop‐2, and surface CD24, basal cell subsets with distinct differentiation capacities were dissected (CD49f + Trop‐2 + CD24 − and CD49f + Trop‐2 + CD24 + ). Although cells from the two subsets gave rise to similar basal colonies, qPCR of primary tissue revealed that higher levels of basal marker expression were detected in the CD49f + Trop‐2 + CD24 − subset. Immunofluorescence analysis showed a prominent expression of CD24 by luminal and basal cells. CONCLUSIONS Subsets with distinct differentiation capacities within the basal epithelium (CD49f + Trop‐2 + CD24 − and CD49f + Trop‐2 + CD24 + ) can be distinguished in human prostate. CD24 is a marker expressed on the basal transit‐amplifying cells (transition cells) and may play a role in the differentiation and migration of ES/P cells to the luminal layer. The knowledge of this mechanism is of relevance for treatment of both diseases. Prostate 73: 1576–1590, 2013 © 2013 Wiley Periodicals, Inc.
Calcification intensity in planktonic Foraminifera reflects ambient conditions irrespective of environmental stress
2013-07-08

Abstract. Planktonic Foraminifera are important marine calcifiers, and the ongoing change in the oceanic carbon system makes it essential to understand the influence of environmental factors on the biomineralisation of their shells. The amount of calcite deposited by planktonic Foraminifera during calcification has been hypothesized to reflect a range of environmental factors. However, it has never been assessed whether their calcification only passively responds to the conditions of the ambient seawater or whether it reflects changes in resource allocation due to physiological stress. To disentangle these two end-member scenarios, an experiment is required where the two processes are separated. A natural analogue to such an experiment occurred during the deposition of the Mediterranean sapropels, where large changes in surface water composition and stratification at the onset of the sapropel deposition were decoupled from local extinctions of planktonic Foraminifera species. We take advantage of this natural experiment and investigate the reaction of calcification intensity, expressed as size-normalized weight (SNW), of four species of planktonic Foraminifera to changing conditions during the onset of Sapropel S5 (126–121 ka) in a sediment core from the Levantine Basin. We observe a significant relationship between SNW and surface water properties, as reflected by stable isotopes in the calcite of Foraminifera shells, but we failed to observe any reaction of calcification intensity on ecological stress during times of decreasing abundance culminating in local extinction. The reaction of calcification intensity to surface water perturbation at the onset of the sapropel was observed only in surface dwelling species, but all species calcified more strongly prior to the sapropel deposition and less strongly within the sapropel than at comparable conditions during the present day. These results indicate that the high-salinity environment of the glacial Mediterranean Sea prior to sapropel deposition induced a more intense calcification, whereas the freshwater injection to the surface waters associated with sapropel deposition inhibited calcification. The results are robust to changes in carbonate preservation and collectively imply that changes in normalized shell weight in planktonic Foraminifera should reflect mainly abiotic forcing.
Proteins of the Nuclear Membrane and Matrix
2013-07-08

Most diseases dealt with in this chapter are linked to the phenotype of Emery–Dreifuss muscular dystrophy. The causative genes that are mutated in these conditions encode for proteins of the nuclear matrix, the nuclear envelope, and components of the LINC complex. The first gene to be identified was EMD, encoding emerin, causing the X-linked form of the disease. LMNA, encoding lamins A/C, was found to cause the autosomal dominant and rare recessive variants of Emery–Dreifuss muscular dystrophy. In addition, LMNA mutations cause limb-girdle muscular dystrophy type 1B, a congenital muscular dystrophy, fetal akinesia, and an autosomal dominant spinal muscular atrophy-like disorder. Mutations of the SYNE1, SYNE2, and TMEM43 genes were identified after systematic searches in patients who displayed the Emery–Dreifuss muscular dystrophy phenotype. By contrast, the mutation of the MATR3 gene encoding the nuclear matrix protein matrin 3 leads to autosomal dominant vocal cord and pharyngeal weakness and distal myopathy.
Oxytocin Reduces Reward-Driven Food Intake in Humans
2013-07-09

Experiments in animals suggest that the neuropeptide oxytocin acts as an anorexigenic signal in the central nervous control of food intake. In humans, however, research has almost exclusively focused on the involvement of oxytocin in the regulation of social behavior. We investigated the effect of intranasal oxytocin on ingestion and metabolic function in healthy men. Food intake in the fasted state was examined 45 min after neuropeptide administration, followed by the assessment of olfaction and reward-driven snack intake in the absence of hunger. Energy expenditure was registered by indirect calorimetry, and blood was repeatedly sampled to determine concentrations of blood glucose and hormones. Oxytocin markedly reduced snack consumption, restraining, in particular, the intake of chocolate cookies by 25%. Oxytocin, moreover, attenuated basal and postprandial levels of adrenocorticotropic hormone and cortisol and curbed the meal-related rise in plasma glucose. Energy expenditure and hunger-driven food intake as well as olfactory function were not affected. Our results indicate that oxytocin, beyond its role in social bonding, regulates nonhomeostatic, reward-related energy intake, hypothalamic-pituitary-adrenal axis activity, and the glucoregulatory response to food intake in humans. These effects can be assumed to converge with the psychosocial function of oxytocin and imply possible applications in the treatment of metabolic disorders.
Polymorphism rs3123554 in CNR2 reveals gender‐specific effects on body weight and affects loss of body weight and cerebral insulin action
2013-07-09

Objective The cannabinoid‐receptor system is involved in the regulation of food intake. Here, we test whether single nucleotide polymorphisms (SNPs) in CNR2 , encoding the cannabinoid‐receptor 2, are associated with weight in a cross‐sectional cohort. Furthermore, we wanted to investigate if the identified hits influence weight loss during lifestyle intervention; and study a potential involvement of cerebral insulin action. Methods 2006 subjects at increased risk for type 2 diabetes mellitus were genotyped for 5 tagging SNPs in the CNR2 locus. All subjects underwent a 75‐g OGTT. 345 subjects participated in a lifestyle intervention (TUebingen Lifestyle Intervention Programme). Cerebrocortical insulin sensitivity was measured by magnetoencephalography after intranasal insulin application in 43 subjects. Results In the cross‐sectional cohort, the minor allele of rs3123554 was associated with lower BMI ( P add = 0.01, P rec = 0.004), and this was attributable to its effect in women only. Interestingly, during lifestyle intervention, carriers of the same allele lost less body weight ( P add = 0.03, P rec = 0.008). Moreover, carriers of this minor allele showed lower cerebral insulin sensitivity ( P rec = 0.0402). Conclusions The minor allele of rs3123554 is associated cross‐sectionally with lower body weight, whereas during intervention the same allele led to less reduction of body weight. Reduced cerebral insulin sensitivity in carriers of this allele might contribute to these disadvantageous effects during lifestyle intervention.
Fetal mortality at and beyond term in singleton pregnancies in Baden-Wuerttemberg/Germany 2004–2009
2013-07-09

In our study, the risk for IUFD in pregnancies going beyond term is remarkably lower than found in studies published about other countries. Our results do not support current guidelines which recommend a routine induction of labor in low risk pregnancies at 41+0/7 weeks of pregnancy.
RRM1 domain of the splicing oncoprotein SRSF1 is required for MEK1-MAPK-ERK activation and cellular transformation
2013-07-10

Alternative splicing regulators have emerged as new players in cancer development, modulating the activities of many tumor suppressors and oncogenes and regulating the signaling pathways. However, little is known about the mechanisms by which these oncogenic splicing factors lead to cellular transformation. We have shown previously that the splicing factor serine and arginine splicing factor 1 (SRSF1; SF2/ASF) is a proto-oncogene, which is amplified in breast cancer and transforms immortal cells when overexpressed. In this study, we performed a structure-function analysis of SRSF1 and found that the RNA recognition motif 1 (RRM1) domain is required for its oncogenic activity. Deletion of RRM1 eliminated the splicing activity of SRSF1 on some of its endogenous targets. Moreover, we found that SRSF1 elevates the expression of B-Raf and activates the mitogen-activated protein kinase kinase (MEK) extracellular signal-regulated kinase (ERK) pathway and that RRM1 is required for this activation as well. B-Raf-MEK-ERK activation by SRSF1 contributes to transformation as pharmacological inhibition of MEK1 inhibits SRSF1-mediated transformation. In conclusion, RRM1 of SRSF1 is both required (and when tethered to the RS domain) also sufficient to activate the Raf-MEK-ERK pathway and to promote cellular transformation.
Homo floresiensis Contextualized: A Geometric Morphometric Comparative Analysis of Fossil and Pathological Human Samples
2013-07-10

The origin of hominins found on the remote Indonesian island of Flores remains highly contentious. These specimens may represent a new hominin species, Homo floresiensis, descended from a local population of Homo erectus or from an earlier (pre-H. erectus) migration of a small-bodied and small-brained hominin out of Africa. Alternatively, some workers suggest that some or all of the specimens recovered from Liang Bua are pathological members of a small-bodied modern human population. Pathological conditions proposed to explain their documented anatomical features include microcephaly, myxoedematous endemic hypothyroidism (âcretinismâ) and Laron syndrome (primary growth hormone insensitivity). This study evaluates evolutionary and pathological hypotheses through comparative analysis of cranial morphology. Geometric morphometric analyses of landmark data show that the sole Flores cranium (LB1) is clearly distinct from healthy modern humans and from those exhibiting hypothyroidism and Laron syndrome. Modern human microcephalic specimens converge, to some extent, on crania of extinct species of Homo. However in the features that distinguish these two groups, LB1 consistently groups with fossil hominins and is most similar to H. erectus. Our study provides further support for recognizing the Flores hominins as a distinct species, H. floresiensis, whose affinities lie with archaic Homo.
Comparative Transcriptome Profiling of Maize Coleoptilar Nodes during Shoot-Borne Root Initiation
2013-07-10

Abstract Maize (Zea mays) develops an extensive shoot-borne root system to secure water and nutrient uptake and to provide anchorage in the soil. In this study, early coleoptilar node (first shoot node) development was subjected to a detailed morphological and histological analysis. Subsequently, microarray profiling via hybridization of oligonucleotide microarrays representing transcripts of 31,355 unique maize genes at three early stages of coleoptilar node development was performed. These pairwise comparisons of wild-type versus mutant rootless concerning crown and seminal roots (rtcs) coleoptilar nodes that do not initiate shoot-borne roots revealed 828 unique transcripts that displayed RTCS-dependent expression. A stage-specific functional analysis revealed overrepresentation of “cell wall,” “stress,” and “development”-related transcripts among the differentially expressed genes. Differential expression of a subset of 15 of 828 genes identified by these microarray experiments was independently confirmed by quantitative real-time-polymerase chain reaction. In silico promoter analyses revealed that 100 differentially expressed genes contained at least one LATERAL ORGAN BOUNDARIES domain (LBD) motif within 1 kb upstream of the ATG start codon. Electrophoretic mobility shift assay experiments demonstrated RTCS binding for four of these promoter sequences, supporting the notion that differentially accumulated genes containing LBD motifs are likely direct downstream targets of RTCS.
The New Homoleptic Tetracyanamidoaluminate LiBa2[Al(CN2)4]
2013-07-10

Abstract The new tetracyanamidoaluminate LiBa 2 [Al(CN 2 ) 4 ] was prepared by solid state metathesis reaction in a fused copper ampoule from a mixture of BaF 2 , AlF 3 , and Li 2 (CN 2 ) at 550 °C. The crystal structure was solved and refined based on single‐crystal X‐ray diffraction data [ P 2 1 2 1 2 1 , Z = 4, a = 6.843(1) Å, b = 11.828(2) Å, c = 11.857(2) Å]. The compound belongs to the known formula type Li M 2 [Al(CN 2 ) 4 ] ( M = Sr, Eu) containing the homoleptic [Al(CN 2 ) 4 ] 5– ion. However, LiBa 2 [Al(CN 2 ) 4 ] forms a distinct crystal structure, containing a two‐dimensional [(NCN) 2/2 Li(NCN) 2 Al(NCN) 2/2 ] network with four‐coordinate Li + and Al 3+ ions. Two crystallographically independent Ba 2+ ions are situated in eightfold environment of terminal nitrogen atoms of cyanamide ions.
Hierarchical Modeling for Rare Event Detection and Cell Subset Alignment across Flow Cytometry Samples
2013-07-11

Flow cytometry is the prototypical assay for multi-parameter single cell analysis, and is essential in vaccine and biomarker research for the enumeration of antigen-specific lymphocytes that are often found in extremely low frequencies (0.1% or less). Standard analysis of flow cytometry data relies on visual identification of cell subsets by experts, a process that is subjective and often difficult to reproduce. An alternative and more objective approach is the use of statistical models to identify cell subsets of interest in an automated fashion. Two specific challenges for automated analysis are to detect extremely low frequency event subsets without biasing the estimate by pre-processing enrichment, and the ability to align cell subsets across multiple data samples for comparative analysis. In this manuscript, we develop hierarchical modeling extensions to the Dirichlet Process Gaussian Mixture Model (DPGMM) approach we have previously described for cell subset identification, and show that the hierarchical DPGMM (HDPGMM) naturally generates an aligned data model that captures both commonalities and variations across multiple samples. HDPGMM also increases the sensitivity to extremely low frequency events by sharing information across multiple samples analyzed simultaneously. We validate the accuracy and reproducibility of HDPGMM estimates of antigen-specific T cells on clinically relevant reference peripheral blood mononuclear cell (PBMC) samples with known frequencies of antigen-specific T cells. These cell samples take advantage of retrovirally TCR-transduced T cells spiked into autologous PBMC samples to give a defined number of antigen-specific T cells detectable by HLA-peptide multimer binding. We provide open source software that can take advantage of both multiple processors and GPU-acceleration to perform the numerically-demanding computations. We show that hierarchical modeling is a useful probabilistic approach that can provide a consistent labeling of cell subsets and increase the sensitivity of rare event detection in the context of quantifying antigen-specific immune responses.
Phage P1-Derived Artificial Chromosomes Facilitate Heterologous Expression of the FK506 Gene Cluster
2013-07-11

We describe a procedure for the conjugative transfer of phage P1-derived Artificial Chromosome (PAC) library clones containing large natural product gene clusters (≥70 kilobases) to Streptomyces coelicolor strains that have been engineered for improved heterologous production of natural products. This approach is demonstrated using the gene cluster for FK506 (tacrolimus), a clinically important immunosuppressant of high commercial value. The entire 83.5 kb FK506 gene cluster from Streptomyces tsukubaensis NRRL 18488 present in one 130 kb PAC clone was introduced into four different S. coelicolor derivatives and all produced FK506 and smaller amounts of the related compound FK520. FK506 yields were increased by approximately five-fold (from 1.2 mg L(-1) to 5.5 mg L(-1)) in S. coelicolor M1146 containing the FK506 PAC upon over-expression of the FK506 LuxR regulatory gene fkbN. The PAC-based gene cluster conjugation methodology described here provides a tractable means to evaluate and manipulate FK506 biosynthesis and is readily applicable to other large gene clusters encoding natural products of interest to medicine, agriculture and biotechnology.
Assessment of Motor Function, Sensory Motor Gating and Recognition Memory in a Novel BACHD Transgenic Rat Model for Huntington Disease
2013-07-11

The current BACHD rat model recapitulates certain symptoms from HD patients, especially the marked motor deficits. A subtle neuropsychological phenotype was found and further studies are needed to fully address the sensorimotor phenotype and the potential use of BACHD rats for drug discovery purposes.
Cataract Formation: A Possible Complication of Intra-Arterial Chemotherapy for Retinoblastoma
2013-07-11

Purpose To delineate and discuss a not yet described possible ocular complication of selective intra-arterial chemotherapy (SIAC) for treatment of retinoblastoma. Methods A 23-month-old girl with a large unilateral retinoblastoma was treated with repeated SIAC using 5 mg melphalan between July 2010 and January 2012. Clinical course of tumor and further ocular changes after therapy and histopathologic findings are described. Results In total, 5 SIAC were performed over a time period of 18 months. After the last SIAC, diffuse dense cataract prevented further funduscopy. In addition, anterior chamber seeding was obvious, leading to the decision to enucleate the eye. Histopathologically, nearly complete regression of the main tumor mass with prominent calcifications, but vital tumor seeding in the vitreous, on the lens surface, on the ciliary body, and in the anterior chamber, was observed. Peculiar vacuolation of the lens epithelial cells, liquefaction of the subepithelial lens fibers, and diffuse small vacuoles within the lens were striking. Conclusions Repeated SIAC with melphalan may induce cataract formation, possibly as a toxic effect of the chemotherapeutic to the lens, maybe combined with radiation exposure during fluoroscopy. This ocular complication should be taken into consideration as a limitation of the number of feasible repeated treatments.