julilili42/papers huggingface dataset:
Impact on clinical prognosis using DNA methylation of the SLC16A3 promoter and expression of the human lactate transporter MCT4 in renal cancer.
2014-02-01

452 Background: The monocarboxylate transporter 4 (MCT4) is a metabolic target in tumor biology because it mediates lactate transport across membranes resulting in antiapoptotic effects. Cell experiments support the importance of MCT4 in clear cell renal cell carcinoma (ccRCC). In this study, we assessed the prognostic potential of MCT4 expression in ccRCC and its epigenetic regulation by DNA methylation as novel predictive marker for patient outcome using independent ccRCC cohorts. Methods: MCT4 protein expression was quantified in 207 ccRCC and corresponding nontumor tissues. Data of an independent ccRCC cohort from The Cancer Genome Atlas (TCGA) were analyzed on MCT4 mRNA (n = 482) and DNA methylation (n = 283) level. The findings on MCT4 expression and DNA methylation in the SLC16A3 promoter were validated in a third cohort (n = 64). Promoter activity assays were conducted in four RCC cell lines. Results: MCT4 protein expression was upregulated (p &lt; 0.0001) in ccRCC and showed significant association with cancer-related death. Upregulation of MCT4 mRNA expression (p &lt; 0.00001) was confirmed in the TCGA cohort. Single CpG sites correlated inversely with mRNA expression and were associated with overall survival in Kaplan-Meier analyses [HR = 0.39; 95% confidence interval (CI), 0.24-0.64; P[log-rank] = 1.23e(-04)]. Promoter activity studies confirmed MCT4 regulation by DNA methylation. The significant correlation between MCT4 protein and gene expression or DNA methylation at single CpG sites was validated in a third cohort. Again, higher methylation at individual CpG sites was associated with prolonged survival [HR = 0.05; 95% CI, 0.01-0.40; P[log-rank] = 6.91e(-05)]. Conclusions: This study identified SLC16A3 promoter DNA methylation as a novel epigenetic mechanism for MCT4 regulation in ccRCC. First evidence of a biological rationale for prognosis and clinical outcome is supported by this specific SLC16A3 promoter DNA methylation.
Association of reduced GATA1 mRNA expression with clinicopathology and shortened recurrence-free survival in clear cell renal cell carcinoma.
2014-02-01

521 Background: GATA1, a zinc-finger transcription factor and member of the GATA family proteins 1-6, is known to be involved in cell growth and apoptosis, especially in the erythroid lineage. Recent studies demonstrated that GATA1 interacts with p53 and its overexpression leads to an inhibition of the p53 gene function. Increased p53 expression levels have been shown to be associated with prognosis and tumor progression in renal cell carcinoma. Methods: Quantitative real-time reverse-transcribed polymerase chain reaction was applied to measure relative GATA1 mRNA expression levels in 135 kidney tissue samples, including 77 clear cell RCC (ccRCC) tissues and 58 paired adjacent normal renal tissue samples. Relative GATA1 expression levels were determined using the ΔΔCt method. Results: The mean GATA1 expression levels were significantly decreased in tumor tissues compared to adjacent normal tissues (p &lt; 0.001, paired t-test). In univariate logistic regression analysis decreased GATA1 mRNA expression was associated with advanced tumor disease (p = 0.005), positive status of distant metastasis (p = 0.03) and lymph node metastasis (p = 0.011). Reduced GATA1 expression was associated with an increase risk of disease recurrence (p = 0.005, hazard ratio HR = 0.05). Status of distant metastasis remained also a significant independent parameter in the bivariate Cox regression model (p = 0.05, HR = 3.01). Conclusions: GATA1 mRNA expression is reduced in ccRCC and associates with a poor clinical outcome and worse clinicopathology, indicating a possible role of GATA1 in tumor development and aggressiveness of ccRCC. GATA1 could therefore serve as a new biomarker for tumor progression in ccRCC.
Targeted ablation of Crb2 in photoreceptor cells induces retinitis pigmentosa
2014-02-02

In humans, the Crumbs homolog-1 (CRB1) gene is mutated in autosomal recessive Leber congenital amaurosis and early-onset retinitis pigmentosa. In mammals, the Crumbs family is composed of: CRB1, CRB2, CRB3A and CRB3B. Recently, we showed that removal of mouse Crb2 from retinal progenitor cells, and consequent removal from Müller glial and photoreceptor cells, results in severe and progressive retinal degeneration with concomitant loss of retinal function that mimics retinitis pigmentosa due to mutations in the CRB1 gene. Here, we studied the effects of cell-type-specific loss of CRB2 from the developing mouse retina using targeted conditional deletion of Crb2 in photoreceptors or Müller cells. We analyzed the consequences of targeted loss of CRB2 in the adult mouse retina using adeno-associated viral vectors encoding Cre recombinase and short hairpin RNA against Crb2. In vivo retinal imaging by means of optical coherence tomography on retinas lacking CRB2 in photoreceptors showed progressive thinning of the photoreceptor layer and cellular mislocalization. Electroretinogram recordings under scotopic conditions showed severe attenuation of the a-wave, confirming the degeneration of photoreceptors. Retinas lacking CRB2 in developing photoreceptors showed early onset of abnormal lamination, whereas retinas lacking CRB2 in developing Müller cells showed late onset retinal disorganization. Our data suggest that in the developing retina, CRB2 has redundant functions in Müller glial cells, while CRB2 has essential functions in photoreceptors. Our data suggest that short-term loss of CRB2 in adult mouse photoreceptors, but not in Müller glial cells, causes sporadic loss of adhesion between photoreceptors and Müller cells.
Assembly of the bacterial type III secretion machinery
2014-02-03

Many bacteria that live in contact with eukaryotic hosts, whether as symbionts or as pathogens, have evolved mechanisms that manipulate host cell behaviour to their benefit. One such mechanism, the type III secretion system, is employed by Gram-negative bacterial species to inject effector proteins into host cells. This function is reflected by the overall shape of the machinery, which resembles a molecular syringe. Despite the simplicity of the concept, the type III secretion system is one of the most complex known bacterial nanomachines, incorporating one to more than hundred copies of up to twenty different proteins into a multi-MDa transmembrane complex. The structural core of the system is the so-called needle complex that spans the bacterial cell envelope as a tripartite ring system and culminates in a needle protruding from the bacterial cell surface. Substrate targeting and translocation are accomplished by an export machinery consisting of various inner membrane embedded and cytoplasmic components. The formation of such a multimembrane-spanning machinery is an intricate task that requires precise orchestration. This review gives an overview of recent findings on the assembly of type III secretion machines, discusses quality control and recycling of the system and proposes an integrated assembly model.
Proteomic Approach to Reveal the Regulatory Function of Aconitase AcnA in Oxidative Stress Response in the Antibiotic Producer Streptomyces viridochromogenes Tü494
2014-02-03

The aconitase AcnA from the phosphinothricin tripeptide producing strain Streptomyces viridochromogenes Tü494 is a bifunctional protein: under iron-sufficiency conditions AcnA functions as an enzyme of the tricarboxylic acid cycle, whereas under iron depletion it is a regulator of iron metabolism and oxidative stress response. As a member of the family of iron regulatory proteins (IRP), AcnA binds to characteristic iron responsive element (IRE) binding motifs and post-transcriptionally controls the expression of respective target genes. A S. viridochromogenes aconitase mutant (MacnA) has previously been shown to be highly sensitive to oxidative stress. In the present paper, we performed a comparative proteomic approach with the S. viridochromogenes wild-type and the MacnA mutant strain under oxidative stress conditions to identify proteins that are under control of the AcnA-mediated regulation. We identified up to 90 differentially expressed proteins in both strains. In silico analysis of the corresponding gene sequences revealed the presence of IRE motifs on some of the respective target mRNAs. From this proteome study we have in vivo evidences for a direct AcnA-mediated regulation upon oxidative stress.
Rare Variants in BMP2 and BMP4 Found in Otosclerosis Patients Reduce Smad Signaling
2014-02-03

Rare variants in BMP2 and BMP4 are not a major genetic component in the otosclerosis population. However, those with functional affect showed decreased Smad signaling. Further analysis of Smad signaling molecules should be performed to determine if these pathways in combination are a major contributor to otosclerosis, which could lead to additional treatment options for otosclerosis patients.
Character building or subversive consequences of employment during high school: Causal effects based on propensity score models for categorical treatments.
2014-02-03

The present study revisited the unresolved issue of the long-term effects of part-time working intensity during high school on students' achievement, participation in postsecondary education, time allocation, and work-related values and expectations. Using data from the Educational Longitudinal Study of 2002 (N = 14,654), the effects of part-time working in Year 12 on outcomes assessed at graduation from high school and 2 years later were studied with propensity score methods for categorical treatments. Three theoretical perspectives on the effects of part-time working intensity (subversion of academic goals, character building, threshold model) were contrasted. Substantively, there were negative linear effects of working intensity on achievement outcomes. Results for higher education participation partly supported a threshold model. Heterogeneous effects for self-reported time use and work-related values suggested that the negative effects on achievement outcomes were not due to a simple zero-sum game. Ironically, working with high intensity led students to value having a good job more strongly but might undermine their chances of achieving this goal. However, these effects were only recognized 2 years after high school graduation, when occupational expectations were negatively affected by working intensity in Year 12.
Ion channels in cancer: future perspectives and clinical potential
2014-02-04

Ion transport across the cell membrane mediated by channels and carriers participate in the regulation of tumour cell survival, death and motility. Moreover, the altered regulation of channels and carriers is part of neoplastic transformation. Experimental modification of channel and transporter activity impacts tumour cell survival, proliferation, malignant progression, invasive behaviour or therapy resistance of tumour cells. A wide variety of distinct Ca 2+ permeable channels, K + channels, Na + channels and anion channels have been implicated in tumour growth and metastasis. Further experimental information is, however, needed to define the specific role of individual channel isoforms critically important for malignancy. Compelling experimental evidence supports the assumption that the pharmacological inhibition of ion channels or their regulators may be attractive targets to counteract tumour growth, prevent metastasis and overcome therapy resistance of tumour cells. This short review discusses the role of Ca 2+ permeable channels, K + channels, Na + channels and anion channels in tumour growth and metastasis and the therapeutic potential of respective inhibitors.
Modeling neck mobility in fossil turtles
2014-02-04

ABSTRACT Turtles have the unparalleled ability to retract their heads and necks within their shell but little is known about the evolution of this trait. Extensive analysis of neck mobility in turtles using radiographs, CT scans, and morphometry reveals that basal turtles possessed less mobility in the neck relative to their extant relatives, although the anatomical prerequisites for modern mobility were already established. Many extant turtles are able to achieve hypermobility by dislocating the central articulations, which raises cautions about reconstructing the mobility of fossil vertebrates. A 3D‐model of the Late Triassic turtle Proganochelys quenstedti reveals that this early stem turtle was able to retract its head by tucking it sideways below the shell. The simple ventrolateral bend seen in this stem turtle, however, contrasts with the complex double‐bend of extant turtles. The initial evolution of neck retraction therefore occurred in a near‐synchrony with the origin of the turtle shell as a place to hide the unprotected neck. In this early, simplified retraction mode, the conical osteoderms on the neck provided further protection. J. Exp. Zool. (Mol. Dev. Evol.) 324B: 230–243, 2015 . © 2014 Wiley Periodicals, Inc.
Of volatiles and peptides: in search for MHC-dependent olfactory signals in social communication
2014-02-04

Genes of the major histocompatibility complex (MHC), which play a critical role in immune recognition, are considered to influence social behaviors in mice, fish, humans, and other vertebrates via olfactory cues. As studied most extensively in mice, the polymorphism of MHC class I genes is considered to bring about a specific scent signature, which is decoded by the olfactory system resulting in an individual-specific reaction such as mating. On the assumption that this signature resides in volatiles, extensive attempts to identify these MHC-specific components in urine failed. Alternatively, it has been suggested that peptide ligands of MHC class I molecules are released into urine and can elicit an MHC-haplotype-specific behavioral response after uptake into the nose by sniffing. Analysis of the urinary peptide composition of mice shows that MHC-derived peptides are present, albeit in extremely low concentrations. In contrast, urine contains abundant peptides which differ between mouse strains due to genomic variations such as single-nucleotide variations or complex polymorphisms in multigene families as well as in their concentration. Thus, urinary peptides represent a real-time sampling of the expressed genome available for sensory evaluation. It is suggested that peptide variation caused by genomic differences contains sufficient information for individual recognition beyond or instead of an influence of the MHC in mice and other vertebrates.
Synthesis, Antimalarial Properties, and SAR Studies of Alkoxyurea‐Based HDAC Inhibitors
2014-02-04

Abstract Histone deacetylase (HDAC) inhibitors are an emerging class of potential antimalarial drugs. We investigated the antiplasmodial properties of 16 alkoxyurea‐based HDAC inhibitors containing various cap and zinc binding groups (ZBGs). Ten compounds displayed sub‐micromolar activity against the 3D7 line of Plasmodium falciparum . Structure–activity relationship studies revealed that a hydroxamic acid ZBG is crucial for antiplasmodial activity, and that the introduction of bulky alkyl substituents to cap groups increases potency against asexual blood‐stage parasites. We also demonstrate that selected compounds cause hyperacetylation of P. falciparum histone H4, indicating inhibition of one or more Pf HDACs. To assess the selectivity of alkoxyurea‐based HDAC inhibitors for parasite over normal mammalian cells, the cytotoxicity of representative compounds was evaluated against neonatal foreskin fibroblast (NFF) cells. The most active compound, 6‐((3‐(4‐( tert ‐butyl)phenyl)ureido)oxy)‐ N ‐hydroxyhexanamide ( 1 e , Pf 3D7 IC 50 : 0.16 μ M ) was 31‐fold more toxic against the asexual blood stages than towards normal mammalian cells. Moreover, a subset of four structurally diverse HDAC inhibitors revealed moderate activity against late‐stage (IV–V) gametocytes.
Pupillary Light Reaction during High Altitude Exposure
2014-02-04

Key parameters of the pupillary light reaction are significantly altered at high altitude. We hypothesize that high altitude hypoxia itself as well as known side effects of high altitude exposure such as fatigue or exhaustion after ascent may account for an altered pupillogram. Interestingly, none of these changes are related to AMS.
Dermacozines H–J Isolated from a Deep-Sea Strain of Dermacoccus abyssi from Mariana Trench Sediments
2014-02-05

Dermacoccus abyssi sp. nov. strains MT1.1 and MT1.2 are actinomycetes isolated from a Mariana Trench sediment at a depth of 10 898 m. The fermentation process using complex media led to the production of three new pigmented heteroaromatic (oxidized and reduced) phenazine compounds, dermacozines H-J (1-3). Extensive use was made of 1D and 2D NMR experiments and high-resolution MS to determine the structures of the compounds. The new dermacozines showed radical scavenging activity, and the highest activity was observed for dermacozine H (1), with an IC50 value of 18.8 μM.
Paleoclimate and weathering of the Tokaj (NE Hungary) loess-paleosol sequence: a comparison of geochemical weathering indices and paleoclimate parameters
2014-02-05

Abstract. The Tokaj loess-paleosol sequence in NE Hungary is one of the key sites for detailed paleoclimate reconstructions of the Quaternary in SE Europe. In this study, the geochemical composition of samples from the upper part of the sequence (45–21 ka) was analyzed and a variety of commonly used weathering indices and element ratios were applied to estimate weathering intensity. Further, similarities and differences between these weathering indices and their sensitivity to changes in paleoclimatic conditions were assessed. Results indicate that all of them accurately track changes in weathering intensity and are, with minor exceptions, very similar to each other. Based on different transfer functions for major and trace element concentrations (XRF), magnetic susceptibility (MS) and δ13C data, we calculated mean annual paleotemperature and mean annual paleoprecipitation for the time intervals of paleosol formation (45–27 ka) and dust deposition (27–21 ka). Results differ depending on the respective transfer function and method but largely agree with previously published paleoclimate data of the region. XRF- and δ13C-based results converge to a MAT of 8–10°C (paleosol) and 8–9°C (loess) and show a~MAP range of 685–879 mm a-1 (paleosol) and 572–700 mm a-1 (loess). MS-based results are most reliable with MATs of 8.4°C (paleosol) and 6.7°C (loess) and MAPs of 325–441 mm a-1 (paleosol) and 224 mm a-1 (loess).
Multifrequency study of a new Fe-rich supernova remnant in the Large Magellanic Cloud, MCSNR J0508−6902
2014-02-05

We present a detailed radio, X-ray and optical study of a newly discovered Large Magellanic Cloud (LMC) supernova remnant (SNR) which we denote as MCSNR J0508-6902. Observations from the Australia Telescope Compact Array (ATCA) and the XMM-Newton X-ray observatory are complemented by deep Hα images and Anglo-Australian Telescope AAOmega spectroscopic data to study the SNR shell and its shock ionization. Archival data at other wavelengths are also examined. The remnant follows a filled-in shell-type morphology in the radio continuum and has a size of ~74 pc × 57 pc at the LMC distance. The X-ray emission exhibits a faint soft shell morphology with Fe-rich gas in its interior - indicative of a Type Ia origin. The remnant appears to be mostly dissipated at higher radio-continuum frequencies leaving only the south-eastern limb fully detectable while in the optical it is the western side of the SNR shell that is clearly detected. The best-fitting temperature to the shell X-ray emission κT = 0.41 +0.05 -0.06 is consistent with other large LMC SNRs. We determined an O/Fe ratio of &lt;21 and an Fe mass of 0.5-1.8 M⊙ in the interior of the remnant, both of which are consistent with the Type Ia scenario. We find an equipartition magnetic field for the remnant of ~28 μG, a value typical of older SNRs and consistent with other analyses which also infer an older remnant. © 2014 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society.
Analysis of polymorphic sites in the promoter of the nitric oxide synthase 2 gene in Brazilian patients with leprosy
2014-02-05

Summary Leprosy is one of the most neglected infectious tropical diseases of the skin and the nerves caused by the intracellular pathogen Mycobacterium leprae . The inducible NOS isoform encoded by NOS 2A plays a vital role in host defence against bacterial infections. The functional promoter polymorphisms in NOS 2A are associated with various autoimmune and infectious diseases. We investigated the association of NOS 2A variants with progression of leprosy in a Brazilian cohort including 221 clinically classified patients and 103 unrelated healthy controls. We observed a novel variant ss528838018A/G in the promoter region at position −6558. The other functional variants were observed with low frequency of minor allele (&lt;0.005). NOS 2A promoter variant (−954G/C) was not observed in Brazilian populations, and the new observed promoter variant (ss528838018A/G) as well as other promoter variants were not associated with any clinical forms of leprosy in the Brazilian populations.
Spectral-Domain Optical Coherence Tomography Staging and Autofluorescence Imaging in Achromatopsia
2014-02-06

IMPORTANCE Evidence is mounting that achromatopsia is a progressive retinal degeneration, and treatments for this condition are on the horizon. OBJECTIVES To categorize achromatopsia into clinically identifiable stages using spectral-domain optical coherence tomography and to describe fundus autofluorescence imaging in this condition. DESIGN, SETTING, AND PARTICIPANTS A prospective observational study was performed between 2010 and 2012 at the Edward S. Harkness Eye Institute, New York-Presbyterian Hospital. Participants included 17 patients (aged 10-62 years) with full-field electroretinography-confirmed achromatopsia. MAIN OUTCOMES AND MEASURES Spectral-domain optical coherence tomography features and staging system, fundus autofluorescence and near-infrared reflectance features and their correlation to optical coherence tomography, and genetic mutations served as the outcomes and measures. RESULTS Achromatopsia was categorized into 5 stages on spectral-domain optical coherence tomography: stage 1 (2 patients [12%]), intact outer retina; stage 2 (2 patients [12%]), inner segment ellipsoid line disruption; stage 3 (5 patients [29%]), presence of an optically empty space; stage 4 (5 patients [29%]), optically empty space with partial retinal pigment epithelium disruption; and stage 5 (3 patients [18%]), complete retinal pigment epithelium disruption and/or loss of the outer nuclear layer. Stage 1 patients showed isolated hyperreflectivity of the external limiting membrane in the fovea, and the external limiting membrane was hyperreflective above each optically empty space. On near infrared reflectance imaging, the fovea was normal, hyporeflective, or showed both hyporeflective and hyperreflective features. All patients demonstrated autofluorescence abnormalities in the fovea and/or parafovea: 9 participants (53%) had reduced or absent autofluorescence surrounded by increased autofluorescence, 4 individuals (24%) showed only reduced or absent autofluorescence, 3 patients (18%) displayed only increased autofluorescence, and 1 individual (6%) exhibited decreased macular pigment contrast. Inner segment ellipsoid line loss generally correlated with the area of reduced autofluorescence, but hyperautofluorescence extended into this region in 2 patients (12%). Bilateral coloboma-like atrophic macular lesions were observed in 1 patient (6%). Five novel mutations were identified (4 in the CNGA3 gene and 1 in the CNGB3 gene). CONCLUSIONS AND RELEVANCE Achromatopsia often demonstrates hyperautofluorescence suggestive of progressive retinal degeneration. The proposed staging system facilitates classification of the disease into different phases of progression and may have therapeutic implications.