415 research outputs found
On hit-and-miss hyperspace topologies
summary:The Vietoris topology and Fell topologies on the closed subsets of a Hausdorff uniform space are prototypes for hit-and-miss hyperspace topologies, having as a subbase all closed sets that hit a variable open set, plus all closed sets that miss (= fail to intersect) a variable closed set belonging to a prescribed family of closed sets. In the case of the Fell topology, where consists of the compact sets, a closed set misses a member of if and only if is far from in a uniform sense. With the Fell topology as a point of departure, one can consider proximal hit-and-miss hyperspace topologies, where ``miss'' is replaced by ``far from'' in the above formulation. Interest in these objects has been driven by their applicability to convex analysis, where the Mosco topology, the slice topology, and the linear topology have received close scrutiny in recent years. In this article we look closely at the relationship between hit-and-miss and proximal hit-and-miss topologies determined by a class . In the setting of metric spaces, necessary and sufficient conditions on are given for one to contain the other. Particular attention is given to these topologies when consists of the family of closed balls in a metric space, and their interplay with the Wijsman topology is considered in some detail
Understanding the limits to generalizability of experimental evolutionary models.
Post print version of article deposited in accordance with SHERPA RoMEO guidelines. The final definitive version is available online at: http://www.nature.com/nature/journal/v455/n7210/abs/nature07152.htmlGiven the difficulty of testing evolutionary and ecological theory in situ, in vitro model systems are attractive alternatives; however, can we appraise whether an experimental result is particular to the in vitro model, and, if so, characterize the systems likely to behave differently and understand why? Here we examine these issues using the relationship between phenotypic diversity and resource input in the T7-Escherichia coli co-evolving system as a case history. We establish a mathematical model of this interaction, framed as one instance of a super-class of host-parasite co-evolutionary models, and show that it captures experimental results. By tuning this model, we then ask how diversity as a function of resource input could behave for alternative co-evolving partners (for example, E. coli with lambda bacteriophages). In contrast to populations lacking bacteriophages, variation in diversity with differences in resources is always found for co-evolving populations, supporting the geographic mosaic theory of co-evolution. The form of this variation is not, however, universal. Details of infectivity are pivotal: in T7-E. coli with a modified gene-for-gene interaction, diversity is low at high resource input, whereas, for matching-allele interactions, maximal diversity is found at high resource input. A combination of in vitro systems and appropriately configured mathematical models is an effective means to isolate results particular to the in vitro system, to characterize systems likely to behave differently and to understand the biology underpinning those alternatives
Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target
[Image: see text] With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes
Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs
Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold
Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis
Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage; Plasmodium falciparum; and; Cryptosporidium parvum; in cell-culture studies. Target deconvolution in; P. falciparum; has shown that cladosporin inhibits lysyl-tRNA synthetase (; Pf; KRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both; Pf; KRS1 and; C. parvum; KRS (; Cp; KRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED; 90; = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between; Pf; KRS1 and; Cp; KRS. This series of compounds inhibit; Cp; KRS and; C. parvum; and; Cryptosporidium hominis; in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for; Pf; KRS1 and; Cp; KRS vs. (human); Hs; KRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis
Behavioural observations in gunn rats
The Gunn rat is a hooded mutant of albino rat with various biochemical defects, including a low UDP-glucuronosyl-transferase activity. As a consequence, about half of their offspring are jaundiced from birth, due to high free bilirubin levels, and develop widespread brain damage. The behaviour of both jaundiced and nonjaundiced Gunn rats was studied in four different tests in a shuttle-box and in a stepthrough passive avoidance situation, and compared with that of normal hooded rats. No differences among groups were found in performance of shuttle responses to a tone in a pseudoconditioning paradigm in which tones and shocks were given at random. However, rats from the two Gunn groups made less shuttlings to the tone in two tests that involved an avoidance contingency (each response cancelled one shock). In addition, nonicteric Gunn rats also performed poorly in a classical conditioning test in the shuttle-box (tones and shocks paired on every trial regardless of responses). This last deficiency of non-icteric Gunn rats may be explained by their higher tendency to freeze in situations involving stimulus-stimulus interactions. They also showed a higher latency than that of the two other groups to enter the dark side of the step-through apparatus on their first exposure to it. All animals seemed to learn the passive-avoidance task to the same extent, however, as shown in a retest carried out 48 h later. Both Gunn groups were hypersensitive to the stereotyped-behaviour-inducing action of apomorphine (0.125–1.0 mg/kg, i.p.), but all groups were about equally sensitive to that of d -amphetamine sulfate (0.5–4.0 mg/kg). Since apomorphine is disposed of by glucuronidation, this might be explained by the low UDP-glucuronosyl-transferase activity known to exist in the Gunn animals. The present results show that additional genetic defects have developed by in-breeding in the Gunn population, which are unrelated to brain damage caused by bilirubin, and which can be well characterized from a behavioural standpoint.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46403/1/213_2004_Article_BF00426881.pd
Multidifferential study of identified charged hadron distributions in -tagged jets in proton-proton collisions at 13 TeV
Jet fragmentation functions are measured for the first time in proton-proton
collisions for charged pions, kaons, and protons within jets recoiling against
a boson. The charged-hadron distributions are studied longitudinally and
transversely to the jet direction for jets with transverse momentum 20 GeV and in the pseudorapidity range . The
data sample was collected with the LHCb experiment at a center-of-mass energy
of 13 TeV, corresponding to an integrated luminosity of 1.64 fb. Triple
differential distributions as a function of the hadron longitudinal momentum
fraction, hadron transverse momentum, and jet transverse momentum are also
measured for the first time. This helps constrain transverse-momentum-dependent
fragmentation functions. Differences in the shapes and magnitudes of the
measured distributions for the different hadron species provide insights into
the hadronization process for jets predominantly initiated by light quarks.Comment: All figures and tables, along with machine-readable versions and any
supplementary material and additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-013.html (LHCb
public pages
Study of the decay
The decay is studied
in proton-proton collisions at a center-of-mass energy of TeV
using data corresponding to an integrated luminosity of 5
collected by the LHCb experiment. In the system, the
state observed at the BaBar and Belle experiments is
resolved into two narrower states, and ,
whose masses and widths are measured to be where the first uncertainties are statistical and the second
systematic. The results are consistent with a previous LHCb measurement using a
prompt sample. Evidence of a new
state is found with a local significance of , whose mass and width
are measured to be and , respectively. In addition, evidence of a new decay mode
is found with a significance of
. The relative branching fraction of with respect to the
decay is measured to be , where the first
uncertainty is statistical, the second systematic and the third originates from
the branching fractions of charm hadron decays.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-028.html (LHCb
public pages
Measurement of the ratios of branching fractions and
The ratios of branching fractions
and are measured, assuming isospin symmetry, using a
sample of proton-proton collision data corresponding to 3.0 fb of
integrated luminosity recorded by the LHCb experiment during 2011 and 2012. The
tau lepton is identified in the decay mode
. The measured values are
and
, where the first uncertainty is
statistical and the second is systematic. The correlation between these
measurements is . Results are consistent with the current average
of these quantities and are at a combined 1.9 standard deviations from the
predictions based on lepton flavor universality in the Standard Model.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-039.html (LHCb
public pages
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