56 research outputs found
Revisiting the β-lactams for tuberculosis therapy with a compound-compound synthetic lethality approach
The suboptimal effectiveness of β-lactam antibiotics against Mycobacterium tuberculosis has hindered the utility of this compound class for tuberculosis treatment. However, the results of treatment with a second-line regimen containing meropenem plus a β-lactamase inhibitor were found to be encouraging in a case study of extensively drug-resistant tuberculosis (M. C. Payen, S. De Wit, C. Martin, R. Sergysels, et al., Int J Tuberc Lung Dis 16:558-560, 2012, https://doi.org/10.5588/ijtld.11.0414). We hypothesized that the innate resistance of M. tuberculosis to β-lactams is mediated in part by noncanonical accessory proteins that are not considered the classic targets of β-lactams and that small-molecule inhibitors of those accessory targets might sensitize M. tuberculosis to β-lactams. In this study, we screened an NIH small-molecule library for the ability to sensitize M. tuberculosis to meropenem. We identified six hit compounds, belonging to either the N-arylindole or benzothiophene chemotype. Verification studies confirmed the synthetic lethality phenotype for three of the N-arylindoles and one benzothiophene derivative. The latter was demonstrated to be partially bioavailable via oral administration in mice. Structure-activity relationship studies of both structural classes identified analogs with potent antitubercular activity, alone or in combination with meropenem. Transcriptional profiling revealed that oxidoreductases, MmpL family proteins, and a 27-kDa benzoquinone methyltransferase could be the targets of the N-arylindole potentiator. In conclusion, our compound-compound synthetic lethality screening revealed novel small molecules that were capable of potentiating the action of meropenem, presumably via inhibition of the innate resistance conferred by β-lactam accessory proteins. β-Lactam compound-compound synthetic lethality may be an alternative approach for drug-resistant tuberculosis
Measurement of the branching fraction for
We have studied the leptonic decay of the resonance into tau
pairs using the CLEO II detector. A clean sample of tau pair events is
identified via events containing two charged particles where exactly one of the
particles is an identified electron. We find . The result is consistent with
expectations from lepton universality.Comment: 9 pages, RevTeX, two Postscript figures available upon request, CLNS
94/1297, CLEO 94-20 (submitted to Physics Letters B
Measurement of the Decay Asymmetry Parameters in and
We have measured the weak decay asymmetry parameters (\aLC ) for two \LC\
decay modes. Our measurements are \aLC = -0.94^{+0.21+0.12}_{-0.06-0.06} for
the decay mode and \aLC = -0.45\pm 0.31 \pm
0.06 for the decay mode . By combining these
measurements with the previously measured decay rates, we have extracted the
parity-violating and parity-conserving amplitudes. These amplitudes are used to
test models of nonleptonic charmed baryon decay.Comment: 11 pages including the figures. Uses REVTEX and psfig macros. Figures
as uuencoded postscript. Also available as
http://w4.lns.cornell.edu/public/CLNS/1995/CLNS95-1319.p
Measurements of Cabibbo Suppressed Hadronic Decay Fractions of Charmed D0 and D+ Mesons
Using data collected with the BESII detector at storage ring
Beijing Electron Positron Collider, the measurements of relative branching
fractions for seven Cabibbo suppressed hadronic weak decays ,
, and , , and are presented.Comment: 11 pages, 5 figure
Study of the B^0 Semileptonic Decay Spectrum at the Upsilon(4S) Resonance
We have made a first measurement of the lepton momentum spectrum in a sample
of events enriched in neutral B's through a partial reconstruction of B0 -->
D*- l+ nu. This spectrum, measured with 2.38 fb**-1 of data collected at the
Upsilon(4S) resonance by the CLEO II detector, is compared directly to the
inclusive lepton spectrum from all Upsilon(4S) events in the same data set.
These two spectra are consistent with having the same shape above 1.5 GeV/c.
From the two spectra and two other CLEO measurements, we obtain the B0 and B+
semileptonic branching fractions, b0 and b+, their ratio, and the production
ratio f+-/f00 of B+ and B0 pairs at the Upsilon(4S). We report b+/b0=0.950
(+0.117-0.080) +- 0.091, b0 = (10.78 +- 0.60 +- 0.69)%, and b+ = (10.25 +- 0.57
+- 0.65)%. b+/b0 is equivalent to the ratio of charged to neutral B lifetimes,
tau+/tau0.Comment: 14 page, postscript file also available at
http://w4.lns.cornell.edu/public/CLN
Observation of the Charmed Baryon Decays to , , and
We have observed two new decay modes of the charmed baryon into
and using data collected with the
CLEO II detector. We also present the first measurement of the branching
fraction for the previously observed decay mode . The branching fractions for these three modes relative to
are measured to be , , and , respectively.Comment: 12 page uuencoded postscript file, postscript file also available
through http://w4.lns.cornell.edu/public/CLN
Radiative Decay Modes of the Meson
Using data recorded by the CLEO-II detector at CESR we have searched for four
radiative decay modes of the meson: ,
, , and . We
obtain 90% CL upper limits on the branching ratios of these modes of , , and
respectively.Comment: 15 page postscript file, postscript file also available through
http://w4.lns.cornell.edu/public/CLN
Studies of the Cabbibo-Suppressed Decays and
Using 4.8 fb of data taken with the CLEO II detector, the branching
fraction for the Cabibbo-suppressed decay measured
relative to the Cabibbo favored decay is found to be
. Using and from unitarity
constraints, we determine We
also present a 90% confidence level upper limit for the branching ratio of the
decay relative to that for of
1.5.Comment: 10 page postscript file, postscript file also available through
http://w4.lns.cornell.edu/public/CLN
Design and construction of the MicroBooNE detector
This paper describes the design and construction of the MicroBooNE liquid
argon time projection chamber and associated systems. MicroBooNE is the first
phase of the Short Baseline Neutrino program, located at Fermilab, and will
utilize the capabilities of liquid argon detectors to examine a rich assortment
of physics topics. In this document details of design specifications, assembly
procedures, and acceptance tests are reported
BCG turns 100: its nontraditional uses against viruses, cancer, and immunologic diseases
First administered to a human subject as a tuberculosis (TB) vaccine on July 18, 1921, Bacillus Calmette-Guérin (BCG) has a long history of use for the prevention of TB and later the immunotherapy of bladder cancer. For TB prevention, BCG is given to infants born globally across over 180 countries and has been in use since the late 1920s. With about 352 million BCG doses procured annually and tens of billions of doses having been administered over the past century, it is estimated to be the most widely used vaccine in human history. While its roles for TB prevention and bladder cancer immunotherapy are widely appreciated, over the past century, BCG has been also studied for nontraditional purposes, which include (a) prevention of viral infections and nontuberculous mycobacterial infections, (b) cancer immunotherapy aside from bladder cancer, and (c) immunologic diseases, including multiple sclerosis, type 1 diabetes, and atopic diseases. The basis for these heterologous effects lies in the ability of BCG to alter immunologic set points via heterologous T cell immunity, as well as epigenetic and metabolomic changes in innate immune cells, a process called "trained immunity." In this Review, we provide an overview of what is known regarding the trained immunity mechanism of heterologous protection, and we describe the current knowledge base for these nontraditional uses of BCG
- …