236 research outputs found
Electronic structure and time-dependent description of rotational predissociation of LiH
Adiabatic potential energy curves of the and states of
the LiH molecule have been calculated. They correlate asymptotically to atomic
states, like 2s+1s, 2p+1s, 3s+1s, 3p+1s, 3d+1s, 4s+1s, 4p+1s and 4d+1s. Very
good agreement is found between our calculated spectroscopic parameters and
experimental ones. The dynamics of the rotational predissociation process of
the state has been studied by solving the time-dependent
Schr\"{o}dinger equation. The classical experiment of Velasco [Can. J. Phys.
{35}, 1204 (1957)] on dissociation in the state is explained in
detail
Electronic structure and rovibrational predissociation of the 2sPi state in KLi
Adiabatic potential energy curves of the 3sSigma+, 3tSigma+, 2sPi and 2tPi
states correlating for large internuclear distance with the K(4s) + Li(2p)
atomic asymptote were calculated. Very good agreement between the calculated
and the experimental curve of the 2sPi state allowed for a reliable description
of the dissociation process through a small (20 cm-1 for J = 0) potential
energy barrier. The barrier supports several rovibrational quasi-bound states
and explicit time evolution of these states via the time-dependent nuclear
Schroedinger equation, showed that the state populations decay exponentially in
time. We were able to precisely describe the time-dependent dissociation
process of several rovibrational levels and found that our calculated spectrum
match very well with the assigned experimental spectrum. Moreover, our approach
is able to predict the positions of previously unassigned lines despite their
low intensit
Universal scaling of distances in complex networks
Universal scaling of distances between vertices of Erdos-Renyi random graphs,
scale-free Barabasi-Albert models, science collaboration networks, biological
networks, Internet Autonomous Systems and public transport networks are
observed. A mean distance between two nodes of degrees k_i and k_j equals to
=A-B log(k_i k_j). The scaling is valid over several decades. A simple
theory for the appearance of this scaling is presented. Parameters A and B
depend on the mean value of a node degree _nn calculated for the nearest
neighbors and on network clustering coefficients.Comment: 4 pages, 3 figures, 1 tabl
Nonequilibrium phase transition due to social group isolation
We introduce a simple model of a growing system with competing
communities. The model corresponds to the phenomenon of defeats suffered by
social groups living in isolation. A nonequilibrium phase transition is
observed when at critical time the first isolated cluster occurs. In the
one-dimensional system the volume of the new phase, i.e. the number of the
isolated individuals, increases with time as . For a large number
of possible communities the critical density of filled space equals to where is the system size. A similar transition is observed
for Erd\H{o}s-R\'{e}nyi random graphs and Barab\'{a}si-Albert scale-free
networks. Analytic results are in agreement with numerical simulations.Comment: 5 pages, 4 figure
Structure-based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1
The treatment of Human African Trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important and pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp. has been identified as a candidate target and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from T. brucei (J. Med. Chem. 2010, 53, 221-229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared, designed with input from new crystal structures of 23 of these compounds complexed with PTR1, and evaluated in screens for enzyme inhibitory activity against PTR1 and in vitro antitrypanosomal activity. 8 compounds were sufficiently active in both screens to take forward to in vivo evaluation. Thus although evidence for trypanocidal activity in a stage I disease model in mice was obtained, the compounds were too toxic to mice for further development
Solar Model Uncertainties, MSW Analysis, and Future Solar Neutrino Experiments
Various theoretical uncertainties in the standard solar model and in the
Mikheyev-Smirnov-Wolfenstein (MSW) analysis are discussed. It is shown that two
methods of estimating the solar neutrino flux uncertainties are equivalent: (a)
a simple parametrization of the uncertainties using the core temperature and
the nuclear production cross sections; (b) the Monte Carlo method of Bahcall
and Ulrich. In the MSW analysis, we emphasize proper treatments of correlation
of theoretical uncertainties between flux components and between different
detectors, the Earth effect, and multiple solutions in a combined
procedure. The MSW solutions for various standard and nonstandard solar models
are also shown. The MSW predictions of the global solutions for the future
solar neutrino experiments are given, emphasizing the measurement of the energy
spectrum and the day-night effect in Sudbury Neutrino Observatory and
Super-Kamiokande to distinguish the two solutions.Comment: (Revtex 3.0, 43 pages + 26 figures (uuencoded ps files attached),
Easy way: ps files of entire text with embedded figures available by
anonymous ftp://upenn5.hep.upenn.edu/pub/hata/papers/msw_analysis.u
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infectivity by Viral Load, S Gene Variants and Demographic Factors, and the Utility of Lateral Flow Devices to Prevent Transmission
BACKGROUND: How SARS-CoV-2 infectivity varies with viral load is incompletely understood. Whether rapid point-of-care antigen lateral flow devices (LFDs) detect most potential transmission sources despite imperfect clinical sensitivity is unknown. METHODS: We combined SARS-CoV-2 testing and contact tracing data from England between 01-September-2020 and 28-February-2021. We used multivariable logistic regression to investigate relationships between PCR-confirmed infection in contacts of community-diagnosed cases and index case viral load, S gene target failure (proxy for B.1.1.7 infection), demographics, SARS-CoV-2 incidence, social deprivation, and contact event type. We used LFD performance to simulate the proportion of cases with a PCR-positive contact expected to be detected using one of four LFDs. RESULTS: 231,498/2,474,066(9%) contacts of 1,064,004 index cases tested PCR-positive. PCR-positive results in contacts independently increased with higher case viral loads (lower Ct values) e.g., 11.7%(95%CI 11.5-12.0%) at Ct=15 and 4.5%(4.4-4.6%) at Ct=30. B.1.1.7 infection increased PCR-positive results by ~50%, (e.g. 1.55-fold, 95%CI 1.49-1.61, at Ct=20). PCR-positive results were most common in household contacts (at Ct=20.1, 8.7%[95%CI 8.6-8.9%]), followed by household visitors (7.1%[6.8-7.3%]), contacts at events/activities (5.2%[4.9-5.4%]), work/education (4.6%[4.4-4.8%]), and least common after outdoor contact (2.9%[2.3-3.8%]). Contacts of children were the least likely to test positive, particularly following contact outdoors or at work/education. The most and least sensitive LFDs would detect 89.5%(89.4-89.6%) and 83.0%(82.8-83.1%) of cases with PCR-positive contacts respectively. CONCLUSIONS: SARS-CoV-2 infectivity varies by case viral load, contact event type, and age. Those with high viral loads are the most infectious. B.1.1.7 increased transmission by ~50%. The best performing LFDs detect most infectious cases
Pyrimidine biosynthesis is not an essential function for trypanosoma brucei bloodstream forms
<p>Background: African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host, but it is unknown whether either process is essential to the parasite.</p>
<p>Methodology/Principal Findings: Pyrimidine requirements for growth were investigated using strictly pyrimidine-free media, with or without single added pyrimidine sources. Growth rates of wild-type bloodstream form Trypanosoma brucei brucei were unchanged in pyrimidine-free medium. The essentiality of the de novo pyrimidine biosynthesis pathway was studied by knocking out the PYR6-5 locus that produces a fusion product of orotate phosphoribosyltransferase (OPRT) and Orotidine Monophosphate Decarboxylase (OMPDCase). The pyrimidine auxotroph was dependent on a suitable extracellular pyrimidine source. Pyrimidine starvation was rapidly lethal and non-reversible, causing incomplete DNA content in new cells. The phenotype could be rescued by addition of uracil; supplementation with uridine, 2′deoxyuridine, and cytidine allowed a diminished growth rate and density. PYR6-5−/− trypanosomes were more sensitive to pyrimidine antimetabolites and displayed increased uracil transport rates and uridine phosphorylase activity. Pyrimidine auxotrophs were able to infect mice although the infection developed much more slowly than infection with the parental, prototrophic trypanosome line.</p>
<p>Conclusions/Significance: Pyrimidine salvage was not an essential function for bloodstream T. b. brucei. However, trypanosomes lacking de novo pyrimidine biosynthesis are completely dependent on an extracellular pyrimidine source, strongly preferring uracil, and display reduced infectivity. As T. brucei are able to salvage sufficient pyrimidines from the host environment, the pyrimidine biosynthesis pathway is not a viable drug target, although any interruption of pyrimidine supply was lethal.</p>
Structure and reactivity of Trypanosoma brucei pteridine reductase: inhibition by the archetypal antifolate methotrexate
The protozoan Trypanosoma brucei has a functional pteridine reductase (TbPTR1), an NADPH-dependent short-chain reductase that participates in the salvage of pterins, which are essential for parasite growth. PTR1 displays broad-spectrum activity with pterins and folates, provides a metabolic bypass for inhibition of the trypanosomatid dihydrofolate reductase and therefore compromises the use of antifolates for treatment of trypanosomiasis. Catalytic properties of recombinant TbPTR1 and inhibition by the archetypal antifolate methotrexate have been characterized and the crystal structure of the ternary complex with cofactor NADP(+) and the inhibitor determined at 2.2 Å resolution. This enzyme shares 50% amino acid sequence identity with Leishmania major PTR1 (LmPTR1) and comparisons show that the architecture of the cofactor binding site, and the catalytic centre are highly conserved, as are most interactions with the inhibitor. However, specific amino acid differences, in particular the placement of Trp221 at the side of the active site, and adjustment of the β6-α6 loop and α6 helix at one side of the substrate-binding cleft significantly reduce the size of the substrate binding site of TbPTR1 and alter the chemical properties compared with LmPTR1. A reactive Cys168, within the active site cleft, in conjunction with the C-terminus carboxyl group and His267 of a partner subunit forms a triad similar to the catalytic component of cysteine proteases. TbPTR1 therefore offers novel structural features to exploit in the search for inhibitors of therapeutic value against African trypanosomiasis
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