We have recently described the development of a series of small-molecule inhibitors of human tumour necrosis factor (TNF) that stabilise an open, asymmetric, signalling-deficient form of the soluble ...TNF trimer. Here, we describe the generation, characterisation, and utility of a monoclonal antibody that selectively binds with high affinity to the asymmetric TNF trimer-small molecule complex. The antibody helps to define the molecular dynamics of the apo TNF trimer, reveals the mode of action and specificity of the small molecule inhibitors, acts as a chaperone in solving the human TNF-TNFR1 complex crystal structure, and facilitates the measurement of small molecule target occupancy in complex biological samples. We believe this work defines a role for monoclonal antibodies as tools to facilitate the discovery and development of small-molecule inhibitors of protein-protein interactions.
The KArlsruhe TRItium Neutrino (KATRIN) experiment will measure the mass of the neutrino with a sensitivity of 0.2 eV (90 % CL). The Forward Beam Monitor (FBM) is a monitoring system which comprises ...of a complex mechanical setup capable of inserting a detector board into the KATRIN beamline at the end of the source and transport section. The detector board contains a Hall sensor, a temperature gauge, and two PIN diodes which can detect electrons from the source with a precision of 0.1 % in less than a minute within an electron flux density of 106 s−1mm−2.
An assessment of the current status of marine anticancer compounds is presented along with a case study on the aquaculture of
Lissodendoryx n. sp. 1, a sponge that produces the antimitotic agents ...halichondrin B and isohomohalichondrin B. The use of polymer therapeutics to enhance the properties of marine natural products is considered.
An antibody specific to small-molecule inhibitor-bound TNF has enabled the development of target occupancy biomarker assays to support the development of novel treatments for autoimmune disorders.
...ELISAs were developed for inhibitor-bound and total TNF to determine the percentage of TNF occupancy in samples from stimulated blood. Inhibitor-saturated samples allowed measurement of total and inhibitor-bound TNF in a single electrochemiluminescence immunoassay.
TNF occupancy was proportional to inhibitor concentration in plasma samples. An electrochemiluminescence method for inhibitor-bound TNF was validated for use as a potential clinical occupancy biomarker assay.
Development of these assays has allowed measurement of a target occupancy biomarker, which has supported progression of the first small-molecule inhibitors of TNF.
ABSTRACT Evidence for an extraterrestrial flux of high-energy neutrinos has now been found in multiple searches with the IceCube detector. The first solid evidence was provided by a search for ...neutrino events with deposited energies TeV and interaction vertices inside the instrumented volume. Recent analyses suggest that the extraterrestrial flux extends to lower energies and is also visible with throughgoing, -induced tracks from the Northern Hemisphere. Here, we combine the results from six different IceCube searches for astrophysical neutrinos in a maximum-likelihood analysis. The combined event sample features high-statistics samples of shower-like and track-like events. The data are fit in up to three observables: energy, zenith angle, and event topology. Assuming the astrophysical neutrino flux to be isotropic and to consist of equal flavors at Earth, the all-flavor spectrum with neutrino energies between 25 TeV and 2.8 PeV is well described by an unbroken power law with best-fit spectral index −2.50 0.09 and a flux at 100 TeV of . Under the same assumptions, an unbroken power law with index −2 is disfavored with a significance of 3.8 (p = 0.0066%) with respect to the best fit. This significance is reduced to 2.1 (p = 1.7%) if instead we compare the best fit to a spectrum with index −2 that has an exponential cut-off at high energies. Allowing the electron-neutrino flux to deviate from the other two flavors, we find a e fraction of 0.18 0.11 at Earth. The sole production of electron neutrinos, which would be characteristic of neutron-decay-dominated sources, is rejected with a significance of 3.6 (p = 0.014%).
We present results from an analysis looking for dark matter annihilation in the Sun with the IceCube neutrino telescope. Gravitationally trapped dark matter in the Sun’s core can annihilate into ...Standard Model particles making the Sun a source of GeV neutrinos. IceCube is able to detect neutrinos with energies >100 GeV while its low-energy infill array DeepCore extends this to >10 GeV. This analysis uses data gathered in the austral winters between May 2011 and May 2014, corresponding to 532 days of livetime when the Sun, being below the horizon, is a source of up-going neutrino events, easiest to discriminate against the dominant background of atmospheric muons. The sensitivity is a factor of two to four better than previous searches due to additional statistics and improved analysis methods involving better background rejection and reconstructions. The resultant upper limits on the spin-dependent dark matter-proton scattering cross section reach down to
1.46
×
10
-
5
pb for a dark matter particle of mass 500 GeV annihilating exclusively into
τ
+
τ
-
particles. These are currently the most stringent limits on the spin-dependent dark matter-proton scattering cross section for WIMP masses above 50 GeV.
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