580 research outputs found
Mutations in the MutSα interaction interface of MLH1 can abolish DNA mismatch repair
MutLα, a heterodimer of MLH1 and PMS2, plays a central role in human DNA mismatch repair. It interacts ATP-dependently with the mismatch detector MutSα and assembles and controls further repair enzymes. We tested if the interaction of MutLα with DNA-bound MutSα is impaired by cancer-associated mutations in MLH1, and identified one mutation (Ala128Pro) which abolished interaction as well as mismatch repair activity. Further examinations revealed three more residues whose mutation interfered with interaction. Homology modelling of MLH1 showed that all residues clustered in a small accessible surface patch, suggesting that the major interaction interface of MutLα for MutSα is located on the edge of an extensive ÎČ-sheet that backs the MLH1 ATP binding pocket. Bioinformatic analysis confirmed that this patch corresponds to a conserved potential proteinâprotein interaction interface which is present in both human MLH1 and its E.coli homologue MutL. MutL could be site-specifically crosslinked to MutS from this patch, confirming that the bacterial MutLâMutS complex is established by the corresponding interface in MutL. This is the first study that identifies the conserved major MutLαâMutSα interaction interface in MLH1 and demonstrates that mutations in this interface can affect interaction and mismatch repair, and thereby can also contribute to cancer development
Neocolonial Conservation: Is Moving Rhinos to Australia Conservation or Intellectual Property Loss
Towards the virtualization of a sound source localization acuity test to aid the diagnosis of spatial processing disorder in school-aged children: An experimental approach
Spatial hearing is an essential auditory function. It allows us to localize, segregate, and group sound sources in space. Accurate sound source localization is a fundamental ability for understanding and following speech in everyday situations, as it contributes to our capacity to discern between target signal streams and other simultaneous sound sources that can be regarded as noise (cocktail party processing).BMBF, 13FH666IA6, IngenieurNachwuchs 2016: Binaurales Hören in der realen und virtuellen Welt zur Verbesserung der Hör-Erfahrung von Schulkindern (VIWER-S
On chirp stimuli and neural synchrony in the suprathreshold auditory brainstem response
The chirp-evoked ABR has been regarded as a more synchronous response than the click-evoked ABR, referring to the belief that the chirp stimulates lower-, mid-, and higher-frequency regions of the cochlea simultaneously. In this study a variety of tools were used to analyze the synchronicity of ABRs evoked by chirp- and click-stimuli at 40 dB HL in 32 normal hearing subjects aged 18 to 55 years (mean=24.8 years, SD=7.1 years). Compared to the click-evoked ABRs, the chirp-evoked ABRs showed larger wave V amplitudes, but an absence of earlier waves in the grand averages, larger wave V latency variance, smaller FFT magnitudes at the higher component frequencies, and larger phase variance at the higher component frequencies. These results strongly suggest that the chirp-evoked ABRs exhibited less synchrony than the click-evoked ABRs in this study. It is proposed that the temporal compensation offered by chirp stimuli is sufficient to increase neural recruitment (as measured by wave V amplitude), but that destructive phase interactions still exist along the cochlea partition, particularly in the low frequency portions of the cochlea where more latency jitter is expected. The clinical implications of these findings are discussed. (C) 2010 Acoustical Society of America. [DOI: 10.1121/1.3436527
Fermi Large Area Telescope View of the Core of the Radio Galaxy Centaurus A
We present gamma-ray observations with the LAT on board the Fermi Gamma-Ray
Telescope of the nearby radio galaxy Centaurus~A. The previous EGRET detection
is confirmed, and the localization is improved using data from the first 10
months of Fermi science operation. In previous work, we presented the detection
of the lobes by the LAT; in this work, we concentrate on the gamma-ray core of
Cen~A. Flux levels as seen by the LAT are not significantly different from that
found by EGRET, nor is the extremely soft LAT spectrum
(\G=2.67\pm0.10_{stat}\pm0.08_{sys} where the photon flux is \Phi\propto
E^{-\G}). The LAT core spectrum, extrapolated to higher energies, is
marginally consistent with the non-simultaneous HESS spectrum of the source.
The LAT observations are complemented by simultaneous observations from Suzaku,
the Swift Burst Alert Telescope and X-ray Telescope, and radio observations
with the Tracking Active Galactic Nuclei with Austral Milliarcsecond
Interferometry (TANAMI) program, along with a variety of non-simultaneous
archival data from a variety of instruments and wavelengths to produce a
spectral energy distribution (SED). We fit this broadband data set with a
single-zone synchrotron/synchrotron self-Compton model, which describes the
radio through GeV emission well, but fails to account for the non-simultaneous
higher energy TeV emission observed by HESS from 2004-2008. The fit requires a
low Doppler factor, in contrast to BL Lacs which generally require larger
values to fit their broadband SEDs. This indicates the \g-ray emission
originates from a slower region than that from BL Lacs, consistent with
previous modeling results from Cen~A. This slower region could be a slower
moving layer around a fast spine, or a slower region farther out from the black
hole in a decelerating flow.Comment: Accepted by ApJ. 32 pages, 5 figures, 2 tables. J. Finke and Y.
Fukazawa corresponding author
Evaluation of MLH1 variants of unclear significance
Inactivating mutations in the MLH1 gene cause the cancer predisposition Lynch syndrome, but for small coding genetic variants it is mostly unclear if they are inactivating or not. Nine such MLH1 variants have been identified in South American colorectal cancer (CRC) patients (p.Tyr97Asp, p.His112Gln, p.Pro141Ala, p.Arg265Pro, p.Asn338Ser, p.Ile501del, p.Arg575Lys, p.Lys618del, p.Leu676Pro), and evidence of pathogenicity or neutrality was not available for the majority of these variants. We therefore performed biochemical laboratory testing of the variant proteins and compared the results to protein in silico predictions on structure and conservation. Additionally, we collected all available clinical information of the families to come to a conclusion concerning their pathogenic potential and facilitate clinical diagnosis in the affected families. We provide evidence that four of the alterations are causative for Lynch syndrome, four are likely neutral and one shows compromised activity which can currently not be classified with respect to its pathogenic potential. The work demonstrates that biochemical testing, corroborated by congruent evolutionary and structural information, can serve to reliably classify uncertain variants when other data are insufficient.Barretos Cancer Hospital was partially funded by FINEPâCTâINFRA, Grant Number: 02/2010, Radium Hospital Foundation (Oslo, Norway), Helse SĂžrâĂst (Norway); Deutsche Forschungsgemeinschaft, Grant Number: PL688/2â1info:eu-repo/semantics/publishedVersio
Genetic Analyses in Small for Gestational Age Newborns
Context: Small for gestational age (SGA) can be a result of fetal growth restriction, associated with perinatal morbidity and mortality. Mechanisms that control prenatal growth are poorly understood.
Objective: The aim of the present study was to gain more insight into prenatal growth failure and determine an effective diagnostic approach in SGA newborns. We hypothesized that one or more CNVs and disturbed methylation and sequence variants may be present in genes known to be associated with fetal growth.
Design: A prospective cohort study of subjects with a low birthweight for gestational age.
Setting: The study was conducted at an academic pediatric research institute.
Patients:
A total of 21 SGA newborns with a mean birthweight below the 1st centile and a control cohort of 24 appropriate for gestational age newborns were studied.
Intervention:
Array comparative genomic hybridization, genome-wide methylation studies and exome sequencing were performed.
Main Outcome Measures
The numbers of copy number variations, methylation disturbances and sequence variants.
Results:
The genetic analyses demonstrated three CNVs, one systematically disturbed methylation pattern and one sequence variant explaining the SGA. Additional methylation disturbances and sequence variants were present 20 patients. In 19 patients, multiple abnormalities were found.
Conclusion: Our results confirm the influence of a large number of mechanisms explaining dysregulation of fetal growth. We conclude that copy number variations, methylation disturbances and sequence variants all contribute to prenatal growth failure. Such genetic workup can be an effective diagnostic approach in SGA newborns
Polimiosite : investigação clĂnica em duas irmĂŁs
We present an investigation of a case of polymyositis affecting two sisters of one same parenthood. Their cases have been documented for almost two decades, being investigated by means of a diagnostic protocol which combined clinical findings as well as laboratorial, histopathological and image tests. In both cases, clinical manifestations started in childhood, without signs of involvement of the central and peripheral nervous system. Both patients proved to respond to a therapeutics based on corticosteroids. The degree of relatedness between their parents corroborate the notion that genetic factors may contribute to the development of the disease. ___________________________________________________________________________________________________ RESUMOApresentamos a investigação de dois casos de polimiosite, ocorridos entre irmãs de uma mesma
filiação. Seus casos foram documentados ao longo de quase duas décadas, tendo sido diagnosticados utilizando-
se de protocolo diagnĂłstico que combinou achados clĂnicos, exames laboratoriais, histopatolĂłgicos e por
imagem. Em ambos os casos, as manifestaçÔes clĂnicas se iniciaram ainda na infĂąncia, sendo constatada
ausĂȘncia de acometimento do sistema nervoso central ou perifĂ©rico. Ambas as pacientes responderam
satisfatoriamente a terapia baseada em corticosterĂłide. O grau de parentesco entre os genitores das pacientes
sugere que fatores genéticos podem predispor ao desenvolvimento da doença
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