4,445 research outputs found
BEN domain protein Elba2 can functionally substitute for linker histone H1 in Drosophila in vivo
Metazoan linker histones are essential for development and play crucial roles in organization of chromatin, modification of epigenetic states and regulation of genetic activity. Vertebrates express multiple linker histone H1 isoforms, which may function redundantly. In contrast, H1 isoforms are not present in Dipterans, including D. melanogaster, except for an embryo-specific, distantly related dBigH1. Here we show that Drosophila BEN domain protein Elba2, which is expressed in early embryos and was hypothesized to have insulator-specific functions, can compensate for the loss of H1 in vivo. Although the Elba2 gene is not essential, its mutation causes a disruption of normal internucleosomal spacing of chromatin and reduced nuclear compaction in syncytial embryos. Elba2 protein is distributed ubiquitously in polytene chromosomes and strongly colocalizes with H1. In H1-depleted animals, ectopic expression of Elba2 rescues the increased lethality and ameliorates abnormalities of chromosome architecture and heterochromatin functions. We also demonstrate that ectopic expression of BigH1 similarly complements the deficiency of H1 protein. Thus, in organisms that do not express redundant H1 isoforms, the structural and biological functions performed by canonical linker histones in later development, may be shared in early embryos by weakly homologous proteins, such as BigH1, or even unrelated, non-homologous proteins, such as Elba2
Global Burden of Sickle Cell Anaemia in Children under Five, 2010-2050: Modelling Based on Demographics, Excess Mortality, and Interventions
The global burden of sickle cell anaemia (SCA) is set to rise as a consequence of improved survival in high-prevalence low- and middle-income countries and population migration to higher-income countries. The host of quantitative evidence documenting these changes has not been assembled at the global level. The purpose of this study is to estimate trends in the future number of newborns with SCA and the number of lives that could be saved in under-five children with SCA by the implementation of different levels of health interventions.First, we calculated projected numbers of newborns with SCA for each 5-y interval between 2010 and 2050 by combining estimates of national SCA frequencies with projected demographic data. We then accounted for under-five mortality (U5m) projections and tested different levels of excess mortality for children with SCA, reflecting the benefits of implementing specific health interventions for under-five patients in 2015, to assess the number of lives that could be saved with appropriate health care services. The estimated number of newborns with SCA globally will increase from 305,800 (confidence interval [CI]: 238,400-398,800) in 2010 to 404,200 (CI: 242,500-657,600) in 2050. It is likely that Nigeria (2010: 91,000 newborns with SCA [CI: 77,900-106,100]; 2050: 140,800 [CI: 95,500-200,600]) and the Democratic Republic of the Congo (2010: 39,700 [CI: 32,600-48,800]; 2050: 44,700 [CI: 27,100-70,500]) will remain the countries most in need of policies for the prevention and management of SCA. We predict a decrease in the annual number of newborns with SCA in India (2010: 44,400 [CI: 33,700-59,100]; 2050: 33,900 [CI: 15,900-64,700]). The implementation of basic health interventions (e.g., prenatal diagnosis, penicillin prophylaxis, and vaccination) for SCA in 2015, leading to significant reductions in excess mortality among under-five children with SCA, could, by 2050, prolong the lives of 5,302,900 [CI: 3,174,800-6,699,100] newborns with SCA. Similarly, large-scale universal screening could save the lives of up to 9,806,000 (CI: 6,745,800-14,232,700) newborns with SCA globally, 85% (CI: 81%-88%) of whom will be born in sub-Saharan Africa. The study findings are limited by the uncertainty in the estimates and the assumptions around mortality reductions associated with interventions.Our quantitative approach confirms that the global burden of SCA is increasing, and highlights the need to develop specific national policies for appropriate public health planning, particularly in low- and middle-income countries. Further empirical collaborative epidemiological studies are vital to assess current and future health care needs, especially in Nigeria, the Democratic Republic of the Congo, and India
Variational Methods for Biomolecular Modeling
Structure, function and dynamics of many biomolecular systems can be
characterized by the energetic variational principle and the corresponding
systems of partial differential equations (PDEs). This principle allows us to
focus on the identification of essential energetic components, the optimal
parametrization of energies, and the efficient computational implementation of
energy variation or minimization. Given the fact that complex biomolecular
systems are structurally non-uniform and their interactions occur through
contact interfaces, their free energies are associated with various interfaces
as well, such as solute-solvent interface, molecular binding interface, lipid
domain interface, and membrane surfaces. This fact motivates the inclusion of
interface geometry, particular its curvatures, to the parametrization of free
energies. Applications of such interface geometry based energetic variational
principles are illustrated through three concrete topics: the multiscale
modeling of biomolecular electrostatics and solvation that includes the
curvature energy of the molecular surface, the formation of microdomains on
lipid membrane due to the geometric and molecular mechanics at the lipid
interface, and the mean curvature driven protein localization on membrane
surfaces. By further implicitly representing the interface using a phase field
function over the entire domain, one can simulate the dynamics of the interface
and the corresponding energy variation by evolving the phase field function,
achieving significant reduction of the number of degrees of freedom and
computational complexity. Strategies for improving the efficiency of
computational implementations and for extending applications to coarse-graining
or multiscale molecular simulations are outlined.Comment: 36 page
Unaltered intravenous prion disease pathogenesis in the temporary absence of marginal zone B cells
Functional divergence in the role of N-linked glycosylation in smoothened signaling
The G protein-coupled receptor (GPCR) Smoothened (Smo) is the requisite signal transducer of the evolutionarily conserved Hedgehog (Hh) pathway. Although aspects of Smo signaling are conserved from Drosophila to vertebrates, significant differences have evolved. These include changes in its active sub-cellular localization, and the ability of vertebrate Smo to induce distinct G protein-dependent and independent signals in response to ligand. Whereas the canonical Smo signal to Gli transcriptional effectors occurs in a G protein-independent manner, its non-canonical signal employs Gαi. Whether vertebrate Smo can selectively bias its signal between these routes is not yet known. N-linked glycosylation is a post-translational modification that can influence GPCR trafficking, ligand responsiveness and signal output. Smo proteins in Drosophila and vertebrate systems harbor N-linked glycans, but their role in Smo signaling has not been established. Herein, we present a comprehensive analysis of Drosophila and murine Smo glycosylation that supports a functional divergence in the contribution of N-linked glycans to signaling. Of the seven predicted glycan acceptor sites in Drosophila Smo, one is essential. Loss of N-glycosylation at this site disrupted Smo trafficking and attenuated its signaling capability. In stark contrast, we found that all four predicted N-glycosylation sites on murine Smo were dispensable for proper trafficking, agonist binding and canonical signal induction. However, the under-glycosylated protein was compromised in its ability to induce a non-canonical signal through Gαi, providing for the first time evidence that Smo can bias its signal and that a post-translational modification can impact this process. As such, we postulate a profound shift in N-glycan function from affecting Smo ER exit in flies to influencing its signal output in mice
Association of vitamin D receptor polymorphisms with the risk of prostate cancer in the Han population of Southern China
mRNA expression of the DNA replication-initiation proteins in epithelial dysplasia and squamous cell carcinoma of the tongue
<p>Abstract</p> <p>Background</p> <p>The tongue squamous cell carcinomas (SCCs) are characterized by high mitotic activity, and early detection is desirable. Overexpression of the DNA replication-initiation proteins has been associated with dysplasia and malignancy. Our aim was to determine whether these proteins are useful biomarkers for assessing the development of tongue SCC.</p> <p>Methods</p> <p>We analyzed the mRNA expression of CDC6, CDT1, MCM2 and CDC45 in formalin-fixed, paraffin-embedded benign and malignant tongue tissues using quantitative real-time PCR followed by statistical analysis.</p> <p>Results</p> <p>We found that the expression levels are significantly higher in malignant SCC than mild precancerous epithelial dysplasia, and the expression levels in general increase with increasing grade of precancerous lesions from mild, moderate to severe epithelial dysplasia. CDC6 and CDC45 expression is dependent of the dysplasia grade and lymph node status. CDT1 expression is higher in severe dysplasia than in mild and moderate dysplasia. MCM2 expression is dependent of the dysplasia grade, lymph node status and clinical stage. The expression of the four genes is independent of tumor size or histological grade. A simple linear regression analysis revealed a linear increase in the mRNA levels of the four genes from the mild to severe dysplasia and SCC. A strong association was established between CDC6 and CDT1, and between MCM2 and CDC45 expression. The nonparametric receiver operating characteristic analysis suggested that MCM2 and CDC45 had a higher accuracy than CDC6 and CDT1 for distinguishing dysplasia from tongue SCC.</p> <p>Conclusion</p> <p>These proteins can be used as biomarkers to distinguish precancerous dysplasia from SCC and are useful for early detection and diagnosis of SCC as an adjunct to clinicopathological parameters.</p
Search for the pentaquark in the reaction
A search for the \thp in the reaction was completed
using the CLAS detector at Jefferson Lab. A study of the same reaction,
published earlier, reported the observation of a narrow \thp resonance. The
present experiment, with more than 30 times the integrated luminosity of our
earlier measurement, does not show any evidence for a narrow pentaquark
resonance. The angle-integrated upper limit on \thp production in the mass
range of 1.52 to 1.56 GeV/c for the reaction is
0.3 nb (95% CL). This upper limit depends on assumptions made for the mass and
angular distribution of \thp production. Using \lamstar production as an
empirical measure of rescattering in the deuteron, the cross section upper
limit for the elementary reaction is estimated to be
a factor of 10 higher, {\it i.e.}, nb (95% CL).Comment: 5 figures, submitted to PRL, revised for referee comment
Exclusive electroproduction on the proton at CLAS
The reaction has been measured, using the 5.754
GeV electron beam of Jefferson Lab and the CLAS detector. This represents the
largest ever set of data for this reaction in the valence region. Integrated
and differential cross sections are presented. The , and
dependences of the cross section are compared to theoretical calculations based
on -channel meson-exchange Regge theory on the one hand and on quark handbag
diagrams related to Generalized Parton Distributions (GPDs) on the other hand.
The Regge approach can describe at the 30% level most of the features
of the present data while the two GPD calculations that are presented in this
article which succesfully reproduce the high energy data strongly underestimate
the present data. The question is then raised whether this discrepancy
originates from an incomplete or inexact way of modelling the GPDs or the
associated hard scattering amplitude or whether the GPD formalism is simply
inapplicable in this region due to higher-twists contributions, incalculable at
present.Comment: 29 pages, 29 figure
Photodisintegration of He into p+t
The two-body photodisintegration of He into a proton and a triton has
been studied using the CEBAF Large-Acceptance Spectrometer (CLAS) at Jefferson
Laboratory. Real photons produced with the Hall-B bremsstrahlung-tagging system
in the energy range from 0.35 to 1.55 GeV were incident on a liquid He
target. This is the first measurement of the photodisintegration of He
above 0.4 GeV. The differential cross sections for the He
reaction have been measured as a function of photon-beam energy and
proton-scattering angle, and are compared with the latest model calculations by
J.-M. Laget. At 0.6-1.2 GeV, our data are in good agreement only with the
calculations that include three-body mechanisms, thus confirming their
importance. These results reinforce the conclusion of our previous study of the
three-body breakup of He that demonstrated the great importance of
three-body mechanisms in the energy region 0.5-0.8 GeV .Comment: 13 pages submitted in one tgz file containing 2 tex file and 22
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