148 research outputs found
Optimal Drug Regimen and Combined Drug Therapy and its Efficacy in the Treatment of COVID-19 : An Within-Host Modeling Study
The COVID-19 pandemic has resulted in more than 30.35 million infections and
9, 50, 625 deaths in 212 countries over the last few months. Different drug
intervention acting at multiple stages of pathogenesis of COVID-19 can
substantially reduce the infection induced mortality. The current within-host
mathematical modeling studies deals with the optimal drug regimen and the
efficacy of combined therapy in treatment of COVID-19. The drugs/interventions
considered include Arbidol, Remdesivir, Inteferon (INF) and
Lopinavir/Ritonavir. It is concluded that these drug interventions when
administered individually or in combination reduce the infected cells and viral
load. Four scenarios involving administration of single drug intervention, two
drug interventions, three drug interventions and all the four have been
discussed. In all these scenarios the optimal drug regimen is proposed based on
two methods. In the first method these medical interventions are modeled as
control interventions and a corresponding objective function and optimal
control problem is formulated. In this setting the optimal drug regimen is
proposed. Later using the the comparative effectiveness method the optimal drug
regimen is proposed based on basic reproduction number and viral load. The
average infected cell count and viral load decreased the most when all the four
interventions were applied together. On the other hand the average susceptible
cell count decreased the best when Arbidol alone was administered. The basic
reproduction number and viral count decreased the best when all the four
interventions were applied together reinstating the fact obtained earlier in
the optimal control setting. These findings may help physicians with decision
making in treatment of life-threatening COVID-19 pneumonia.Comment: 16 pages, 13 figure
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Fingerprint of volcanic forcing on the ENSO-Indian monsoon coupling
Coupling of the El Niño-Southern Oscillation (ENSO) and Indian monsoon (IM) is central to seasonal summer monsoon rainfall predictions over the Indian subcontinent, although a nonstationary relationship between the two nonlinear phenomena can limit seasonal predictability. Radiative effects of volcanic aerosols injected into the stratosphere during large volcanic eruptions (LVEs) tend to alter ENSO evolution; however, their impact on ENSO-IM coupling remains unclear. Here, we investigate how LVEs influence the nonlinear behavior of the ENSO and IM dynamical systems using historical data, 25 paleoclimate reconstructions, last-millennium climate simulations, large-ensemble targeted climate sensitivity experiments, and advanced analysis techniques. Our findings show that LVEs promote a significantly enhanced phase-synchronization of the ENSO and IM oscillations, due to an increase in the angular frequency of ENSO. The results also shed innovative insights into the physical mechanism underlying the LVE-induced enhancement of ENSO-IM coupling and strengthen the prospects for improved seasonal monsoon predictions
String propagation in four-dimensional dyonic black hole background
We study string propagation in an exact, four-dimensional dyonic black hole
background. The general solutions describing string configurations are obtained
by solving the string equations of motion and constraints. By using the
covariant formalism, we also investigate the propagation of physical
perturbations along the string in the given curved background.Comment: 19 pages, Tex (macro phyzzx is needed
Black hole entropy functions and attractor equations
The entropy and the attractor equations for static extremal black hole
solutions follow from a variational principle based on an entropy function. In
the general case such an entropy function can be derived from the reduced
action evaluated in a near-horizon geometry. BPS black holes constitute special
solutions of this variational principle, but they can also be derived directly
from a different entropy function based on supersymmetry enhancement at the
horizon. Both functions are consistent with electric/magnetic duality and for
BPS black holes their corresponding OSV-type integrals give identical results
at the semi-classical level. We clarify the relation between the two entropy
functions and the corresponding attractor equations for N=2 supergravity
theories with higher-derivative couplings in four space-time dimensions. We
discuss how non-holomorphic corrections will modify these entropy functions.Comment: 21 pages,LaTeX,minor change
Intersecting 6-branes from new 7-manifolds with G_2 holonomy
We discuss a new family of metrics of 7-manifolds with G_2 holonomy, which
are R^3 bundles over a quaternionic space. The metrics depend on five
parameters and have two Abelian isometries. Certain singularities of the G_2
manifolds are related to fixed points of these isometries; there are two
combinations of Killing vectors that possess co-dimension four fixed points
which yield upon compactification only intersecting D6-branes if one also
identifies two parameters. Two of the remaining parameters are quantized and we
argue that they are related to the number of D6-branes, which appear in three
stacks. We perform explicitly the reduction to the type IIA model.Comment: 25 pages, 1 figure, Latex, small changes and add refs, version
appeared in JHE
On the Rotating Charged Black String Solution
A rotating charged black string solution in the low energy effective field
theory describing five dimensional heterotic string theory is constructed. The
solution is labelled by mass, electric charge, axion charge and angular
momentum per unit length. The extremal limit of this solution is also studied.Comment: 12 pages, IMSC-93/6,(Phyzzx macro), January 199
Physics Potential of the ICAL detector at the India-based Neutrino Observatory (INO)
The upcoming 50 kt magnetized iron calorimeter (ICAL) detector at the
India-based Neutrino Observatory (INO) is designed to study the atmospheric
neutrinos and antineutrinos separately over a wide range of energies and path
lengths. The primary focus of this experiment is to explore the Earth matter
effects by observing the energy and zenith angle dependence of the atmospheric
neutrinos in the multi-GeV range. This study will be crucial to address some of
the outstanding issues in neutrino oscillation physics, including the
fundamental issue of neutrino mass hierarchy. In this document, we present the
physics potential of the detector as obtained from realistic detector
simulations. We describe the simulation framework, the neutrino interactions in
the detector, and the expected response of the detector to particles traversing
it. The ICAL detector can determine the energy and direction of the muons to a
high precision, and in addition, its sensitivity to multi-GeV hadrons increases
its physics reach substantially. Its charge identification capability, and
hence its ability to distinguish neutrinos from antineutrinos, makes it an
efficient detector for determining the neutrino mass hierarchy. In this report,
we outline the analyses carried out for the determination of neutrino mass
hierarchy and precision measurements of atmospheric neutrino mixing parameters
at ICAL, and give the expected physics reach of the detector with 10 years of
runtime. We also explore the potential of ICAL for probing new physics
scenarios like CPT violation and the presence of magnetic monopoles.Comment: 139 pages, Physics White Paper of the ICAL (INO) Collaboration,
Contents identical with the version published in Pramana - J. Physic
TCF7L2 gene polymorphisms do not predict susceptibility to diabetes in tropical calcific pancreatitis but may interact with SPINK1 and CTSB mutations in predicting diabetes
<p>Abstract</p> <p>Background</p> <p>Tropical calcific pancreatitis (TCP) is a type of chronic pancreatitis unique to developing countries in tropical regions and one of its important features is invariable progression to diabetes, a condition called fibro-calculous pancreatic diabetes (FCPD), but the nature of diabetes in TCP is controversial. We analysed the recently reported type 2 diabetes (T2D) associated polymorphisms in the <it>TCF7L2 </it>gene using a case-control approach, under the hypothesis that <it>TCF7L2 </it>variants should show similar association if diabetes in FCPD is similar to T2D. We also investigated the interaction between the <it>TCF7L2 </it>variants and N34S <it>SPINK1 </it>and L26V <it>CTSB </it>mutations, since they are strong predictors of risk for TCP.</p> <p>Methods</p> <p>Two polymorphisms rs7903146 and rs12255372 in the <it>TCF7L2 </it>gene were analyzed by direct sequencing in 478 well-characterized TCP patients and 661 healthy controls of Dravidian and Indo-European ethnicities. Their association with TCP with diabetes (FCPD) and without diabetes was tested in both populations independently using chi-square test. Finally, a meta analysis was performed on all the cases and controls for assessing the overall significance irrespective of ethnicity. We dichotomized the whole cohort based on the presence or absence of N34S <it>SPINK1 </it>and L26V <it>CTSB </it>mutations and further subdivided them into TCP and FCPD patients and compared the distribution of <it>TCF7L2 </it>variants between them.</p> <p>Results</p> <p>The allelic and genotypic frequencies for both <it>TCF7L2 </it>polymorphisms, did not differ significantly between TCP patients and controls belonging to either of the ethnic groups or taken together. No statistically significant association of the SNPs was observed with TCP or FCPD or between carriers and non-carriers of N34S <it>SPINK1 </it>and L26V <it>CTSB </it>mutations. The minor allele frequency for rs7903146 was different between TCP and FCPD patients carrying the N34S <it>SPINK1 </it>variant but did not reach statistical significance (OR = 1.59, 95% CI = 0.93–2.70, P = 0.09), while, <it>TCF7L2</it><it/>variant showed a statistically significant association between TCP and FCPD patients carrying the 26V allele (OR = 1.69, 95% CI = 1.11–2.56, P = 0.013).</p> <p>Conclusion</p> <p>Type 2 diabetes associated <it>TCF7L2 </it>variants are not associated with diabetes in TCP. Since, <it>TCF7L2 </it>is a major susceptibility gene for T2D, it may be hypothesized that the diabetes in TCP patients may not be similar to T2D. Our data also suggests that co-existence of <it>TCF7L2 </it>variants and the <it>SPINK1 </it>and <it>CTSB </it>mutations, that predict susceptibility to exocrine damage, may interact to determine the onset of diabetes in TCP patients.</p
Embryonic Morphogen Nodal Promotes Breast Cancer Growth and Progression
Breast cancers expressing human embryonic stem cell (hESC)-associated genes are more likely to progress than well-differentiated cancers and are thus associated with poor patient prognosis. Elevated proliferation and evasion of growth control are similarly associated with disease progression, and are classical hallmarks of cancer. In the current study we demonstrate that the hESC-associated factor Nodal promotes breast cancer growth. Specifically, we show that Nodal is elevated in aggressive MDA-MB-231, MDA-MB-468 and Hs578t human breast cancer cell lines, compared to poorly aggressive MCF-7 and T47D breast cancer cell lines. Nodal knockdown in aggressive breast cancer cells via shRNA reduces tumour incidence and significantly blunts tumour growth at primary sites. In vitro, using Trypan Blue exclusion assays, Western blot analysis of phosphorylated histone H3 and cleaved caspase-9, and real time RT-PCR analysis of BAX and BCL2 gene expression, we demonstrate that Nodal promotes expansion of breast cancer cells, likely via a combinatorial mechanism involving increased proliferation and decreased apopotosis. In an experimental model of metastasis using beta-glucuronidase (GUSB)-deficient NOD/SCID/mucopolysaccharidosis type VII (MPSVII) mice, we show that although Nodal is not required for the formation of small (\u3c100 cells) micrometastases at secondary sites, it supports an elevated proliferation:apoptosis ratio (Ki67:TUNEL) in micrometastatic lesions. Indeed, at longer time points (8 weeks), we determined that Nodal is necessary for the subsequent development of macrometastatic lesions. Our findings demonstrate that Nodal supports tumour growth at primary and secondary sites by increasing the ratio of proliferation:apoptosis in breast cancer cells. As Nodal expression is relatively limited to embryonic systems and cancer, this study establishes Nodal as a potential tumour-specific target for the treatment of breast cancer. © 2012 Quail et al
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