293 research outputs found
TERTp mutations and p53 expression in head and neck cutaneous basal cell carcinomas with different aggressive features
Cutaneous basal cell carcinoma (cBCC) is an economic burden to health services, due to its great morbidity and increasing incidence in old people. Infiltrative cBCCs and cBCCs with micronodular pattern are considered as more aggressive. The role of p53 expression and TERTp mutation on cBCC behavior remains to be clarified. We aimed to assess TERTp mutations and p53 expression in relation to the cBCC histological subtype in a cohort of patients referred to an ENT Department of a tertiary Hospital of Northern Portugal. We performed a retrospective clinicopathological and histological review of the head and neck cBCCs followed-up at the otorhinolaryngology department of Trás-os-Montes e Alto Douro hospital (January 2007–June 2018). We assessed TERTp mutations in 142 cBCCs and p53 protein expression, through immunohistochemistry, in 157 cBCCs. We detected TERTp mutations in 43.7% of cBCCs and p53 overexpression in 60.5% of cBCCs. We spotted association of p53 overexpression and TERTp mutation with necrosis. In the infitrative-growth pattern cBCCs, there was no significant association with the clinical and histological features evaluated, except for necrosis. In the indolent-growth cBCCs, we identified a significant association of TERTp mutation status with female sex, necrosis, multiple cBCCs, and p53 positive expression. Our results suggest that TERTp mutation may be useful to identify more aggressive features in the indolent-growth pattern cBCCs (nodular and superficial subtypes). Further studies with larger cohorts are warranted to clarify the relevance of TERTp mutation in cBCCs.This study was supported by FCT, the Portuguese Foundation for Science and Technology through a Ph.D. Grant to SM (SFRH/BD/137802/2018). This work was financed by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through FCT-Fundação para a Ciência e a Tecnolo-gia/Ministério da Ciência, Tecnologia e Inovação in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274). Additional funding by the European Regional Development Fund (ERDF) through the Operational Programme for Competitiveness and Internationalization—COMPETE2020, and Portuguese national funds via FCT, under project POCI-01-0145-FEDER-016390: CANCEL STEM and from the FCT, under the project POCI-01-0145-FEDER-031438: The other faces of telomerase: Looking beyond tumour immortalization (PDTC/MED-ONC/31438/2017)
Understanding the relationship between egg- and antigen-based diagnostics of Schistosoma mansoni infection pre- and post-treatment in Uganda.
BACKGROUND: Schistosomiasis is a major socio-economic and public health problem in many sub-Saharan African countries. After large mass drug administration (MDA) campaigns, prevalence of infection rapidly returns to pre-treatment levels. The traditional egg-based diagnostic for schistosome infections, Kato-Katz, is being substituted in many settings by circulating antigen recognition-based diagnostics, usually the point-of-care circulating cathodic antigen test (CCA). The relationship between these diagnostics is poorly understood, particularly after treatment in both drug-efficacy studies and routine monitoring. RESULTS: We created a model of schistosome infections to better understand and quantify the relationship between these two egg- and adult worm antigen-based diagnostics. We focused particularly on the interpretation of "trace" results after CCA testing. Our analyses suggest that CCA is generally a better predictor of prevalence, particularly after treatment, and that trace CCA results are typically associated with truly infected individuals. CONCLUSIONS: Even though prevalence rises to pre-treatment levels only six months after MDAs, our model suggests that the average intensity of infection is much lower, and is probably in part due to a small burden of surviving juveniles from when the treatment occurred. This work helps to better understand CCA diagnostics and the interpretation of post-treatment prevalence estimations
Reversing non-local transport through a superconductor by electromagnetic excitations
Superconductors connected to normal metallic electrodes at the nanoscale
provide a potential source of non-locally entangled electron pairs. Such states
would arise from Cooper pairs splitting into two electrons with opposite spins
tunnelling into different leads. In an actual system the detection of these
processes is hindered by the elastic transmission of individual electrons
between the leads, yielding an opposite contribution to the non-local
conductance. Here we show that electromagnetic excitations on the
superconductor can play an important role in altering the balance between these
two processes, leading to a dominance of one upon the other depending on the
spatial symmetry of these excitations. These findings allow to understand some
intriguing recent experimental results and open the possibility to control
non-local transport through a superconductor by an appropriate design of the
experimental geometry.Comment: 6 pages, 3 figure
On the curvature of vortex moduli spaces
We use algebraic topology to investigate local curvature properties of the
moduli spaces of gauged vortices on a closed Riemann surface. After computing
the homotopy type of the universal cover of the moduli spaces (which are
symmetric powers of the surface), we prove that, for genus g>1, the holomorphic
bisectional curvature of the vortex metrics cannot always be nonnegative in the
multivortex case, and this property extends to all Kaehler metrics on certain
symmetric powers. Our result rules out an established and natural conjecture on
the geometry of the moduli spaces.Comment: 25 pages; final version, to appear in Math.
The Energy Landscape, Folding Pathways and the Kinetics of a Knotted Protein
The folding pathway and rate coefficients of the folding of a knotted protein
are calculated for a potential energy function with minimal energetic
frustration. A kinetic transition network is constructed using the discrete
path sampling approach, and the resulting potential energy surface is
visualized by constructing disconnectivity graphs. Owing to topological
constraints, the low-lying portion of the landscape consists of three distinct
regions, corresponding to the native knotted state and to configurations where
either the N- or C-terminus is not yet folded into the knot. The fastest
folding pathways from denatured states exhibit early formation of the
N-terminus portion of the knot and a rate-determining step where the C-terminus
is incorporated. The low-lying minima with the N-terminus knotted and the
C-terminus free therefore constitute an off-pathway intermediate for this
model. The insertion of both the N- and C-termini into the knot occur late in
the folding process, creating large energy barriers that are the rate limiting
steps in the folding process. When compared to other protein folding proteins
of a similar length, this system folds over six orders of magnitude more
slowly.Comment: 19 page
Nel positively regulates the genesis of retinal ganglion cells by promoting their differentiation and survival during development
Peer reviewedPublisher PD
Exploring the Free Energy Landscape: From Dynamics to Networks and Back
The knowledge of the Free Energy Landscape topology is the essential key to
understand many biochemical processes. The determination of the conformers of a
protein and their basins of attraction takes a central role for studying
molecular isomerization reactions. In this work, we present a novel framework
to unveil the features of a Free Energy Landscape answering questions such as
how many meta-stable conformers are, how the hierarchical relationship among
them is, or what the structure and kinetics of the transition paths are.
Exploring the landscape by molecular dynamics simulations, the microscopic data
of the trajectory are encoded into a Conformational Markov Network. The
structure of this graph reveals the regions of the conformational space
corresponding to the basins of attraction. In addition, handling the
Conformational Markov Network, relevant kinetic magnitudes as dwell times or
rate constants, and the hierarchical relationship among basins, complete the
global picture of the landscape. We show the power of the analysis studying a
toy model of a funnel-like potential and computing efficiently the conformers
of a short peptide, the dialanine, paving the way to a systematic study of the
Free Energy Landscape in large peptides.Comment: PLoS Computational Biology (in press
An eclipsing binary distance to the Large Magellanic Cloud accurate to 2 per cent
In the era of precision cosmology it is essential to determine the Hubble
Constant with an accuracy of 3% or better. Currently, its uncertainty is
dominated by the uncertainty in the distance to the Large Magellanic Cloud
(LMC) which as the second nearest galaxy serves as the best anchor point of the
cosmic distance scale. Observations of eclipsing binaries offer a unique
opportunity to precisely and accurately measure stellar parameters and
distances. The eclipsing binary method was previously applied to the LMC but
the accuracy of the distance results was hampered by the need to model the
bright, early-type systems used in these studies. Here, we present distance
determinations to eight long-period, late- type eclipsing systems in the LMC
composed of cool giant stars. For such systems we can accurately measure both
the linear and angular sizes of their components and avoid the most important
problems related to the hot early-type systems. Our LMC distance derived from
these systems is demonstrably accurate to 2.2 % (49.97 +/- 0.19 (statistical)
+/- 1.11 (systematic) kpc) providing a firm base for a 3 % determination of the
Hubble Constant, with prospects for improvement to 2 % in the future.Comment: 34 pages, 5 figures, 13 tables, published in the Nature, a part of
our data comes from new unpublished OGLE-IV photometric dat
Insights from quantitative and mathematical modelling on the proposed WHO 2030 goal for schistosomiasis
Schistosomiasis remains one of the neglected tropical diseases (NTDs) impacting millions of people around the world. The World Health Organization (WHO) recently proposed a goal of elimination as a public health problem (EPHP) for schistosomiasis to be reached by 2030. Current WHO treatment guidelines for achieving EPHP focus on targeting school-aged children. The NTD Modelling Consortium has developed mathematical models to study schistosomiasis transmission dynamics and the impact of control measures. Our modelling insights on Schistosoma mansoni have shown that EPHP is likely to be attainable in low to moderate prevalence settings using the current guidelines. However, as prevalence rises within high prevalence settings, EPHP is less likely to be achieved unless both school-aged children and adults are treated (with coverage levels increasing with the adult burden of infection). We highlight the challenges that are faced by treatment programmes, such as non-adherence to treatment and resurgence, which can hinder progress towards achieving and maintaining EPHP. Additionally, even though EPHP may be reached, prevalence can still be high due to persisting infections. Therefore, without interruption of transmission, treatment will likely have to continue to maintain EPHP. Further modelling work is being carried out, including extending our results to S. haematobium. By providing these modelling insights, we aim to inform discussions on the goals and treatment guidelines for schistosomiasis.</ns4:p
Primary versus secondary source of data in observational studies and heterogeneity in meta-analyses of drug effects: a survey of major medical journals
The data from individual observational studies included in meta-analyses of drug effects are collected either from ad hoc methods (i.e. "primary data") or databases that were established for non-research purposes (i.e. "secondary data"). The use of secondary sources may be prone to measurement bias and confounding due to over-the-counter and out-of-pocket drug consumption, or non-adherence to treatment. In fact, it has been noted that failing to consider the origin of the data as a potential cause of heterogeneity may change the conclusions of a meta-analysis. We aimed to assess to what extent the origin of data is explored as a source of heterogeneity in meta-analyses of observational studies.publishe
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