1,675 research outputs found
Potentiation of PBD Dimers by Lipophilicity Manipulation
Background & Introduction: Pyrrolobenzodiazepine (PBD) dimers are highly potent DNA cross-linking agents used as warheads in Antibody Drug Conjugates (ADCs) for cancer therapy. We propose to investigate the correlation existing between the lipophilicity of those molecules and their activity (both in vitro and in vivo) as well as any effect observed during conjugation. /
Materials and Methods: Reaction progress was monitored by Thin-Layer Chromatography (TLC) using Merck Kieselgel 60 F254 silica gel, with a fluorescent indicator on aluminium plates. Visualisation of TLC was achieved with UV light or iodine vapour unless otherwise stated. Flash chromatography was performed using Merck Kieselgel 60 F254 silica gel. /
Results: We have successfully designed and synthesized a novel PBD warhead (SG3312) with enhanced physicochemical properties. The warhead also displayed increased potency in vitro. After overcoming some epimerization issues, the synthesis of enantiomerically pure payload was achieved (SG3259) and fulfilled our criteria for a simplified and more efficient conjugation. No addition of propylene glycol was required, and high DAR and excellent monomeric purity were achieved. /
Conclusion: The ADC (Herceptin-maia-SG3259) has been shown to release the active warhead (SG3312) upon exposure to Cathepsin B and demonstrated encouraging activity both in vitro and in vivo
Constraining parameter space in type-II two-Higgs doublet model in light of a 126 GeV Higgs boson
We explore the implications of a 126 GeV Higgs boson indicated by the recent
LHC results for two-Higgs doublet model (2HDM). Identifying the 126 GeV Higgs
boson as either the lighter or heavier of CP even neutral Higgs bosons in 2HDM,
we examine how the masses of Higgs fields and mixing parameters can be
constrained by the theoretical conditions and experimental constraints. The
theoretical conditions taken into account are the vacuum stability,
perturbativity and unitarity required to be satisfied up to a cut-off scale. We
also show how bounds on the masses of Higgs bosons and mixing parameters depend
on the cut-off scale. In addition, we investigate whether the allowed regions
of parameter space can accommodate particularly the enhanced di-photon signals,
ZZ* and WW* decay modes of the Higgs boson, and examine the prediction of the
signal strength of Z{\gamma} decay mode for the allowed regions of the
parameter space.Comment: To be published in JHEP, 20 pages, 11 figures, Figures and results
are updated for the recent LHC result
Asymmetric Origin for Gravitino Relic Density in the Hybrid Gravity-Gauge Mediated Supersymmetry Breaking
We propose the hybrid gravity-gauge mediated supersymmetry breaking where the
gravitino mass is about several GeV. The strong constraints on supersymmetry
viable parameter space from the CMS and ATLAS experiments at the LHC can be
relaxed due to the heavy colored supersymmetric particles, and it is consistent
with null results in the dark matter (DM) direct search experiments such as
XENON100. In particular, the possible maximal flavor and CP violations from the
relatively small gravity mediation may naturally account for the recent LHCb
anomaly. In addition, because the gravitino mass is around the asymmetric DM
mass, we propose the asymmetric origin of the gravitino relic density and solve
the cosmological coincident problem on the DM and baryon densities \Omega_{\rm
DM}:\Omega_{B}\approx 5:1. The gravitino relic density arises from asymmetric
metastable particle (AMP) late decay. However, we show that there is no AMP
candidate in the minimal supersymmetric Standard Model (SM) due to the robust
gaugino/Higgsino mediated wash-out effects. Interestingly, AMP can be realized
in the well motivated supersymmetric SMs with vector-like particles or
continuous U(1)_R symmetry. Especially, the lightest CP-even Higgs boson mass
can be lifted in the supersymmetric SMs with vector-like particles.Comment: RevTex4, 21 pages, 1 figure, minor corrections, JHEP versio
Hardy's inequality for functions vanishing on a part of the boundary
We develop a geometric framework for Hardy's inequality on a bounded domain
when the functions do vanish only on a closed portion of the boundary.Comment: 26 pages, 2 figures, includes several improvements in Sections 6-8
allowing to relax the assumptions in the main results. Final version
published at http://link.springer.com/article/10.1007%2Fs11118-015-9463-
Загадки Велесової книги
Дана публікація розкриває помилки попередніх досліджень «Велесової книги» та надає пояснення важкодоступних висловів тексту.Данная публикация раскрывает ошибки предыдущих исследований «Велесовой книги» и дает объяснение труднодоступных выражений в тексте.This publication reveals the mistakes of the former researches on the «Veles-book» and gives the meanings of some hard-to-understand terms of the text
Cryo-EM structure of a helicase loading intermediate containing ORC-Cdc6-Cdt1-MCM2-7 bound to DNA
In eukaryotes, the Cdt1-bound replicative helicase core MCM2-7 is loaded onto DNA by the ORC-Cdc6 ATPase to form a prereplicative complex (pre-RC) with an MCM2-7 double hexamer encircling DNA. Using purified components in the presence of ATP-γS, we have captured in vitro an intermediate in pre-RC assembly that contains a complex between the ORC-Cdc6 and Cdt1-MCM2-7 heteroheptamers called the OCCM. Cryo-EM studies of this 14-subunit complex reveal that the two separate heptameric complexes are engaged extensively, with the ORC-Cdc6 N-terminal AAA+ domains latching onto the C-terminal AAA+ motor domains of the MCM2-7 hexamer. The conformation of ORC-Cdc6 undergoes a concerted change into a right-handed spiral with helical symmetry that is identical to that of the DNA double helix. The resulting ORC-Cdc6 helicase loader shows a notable structural similarity to the replication factor C clamp loader, suggesting a conserved mechanism of action
Light dark matter and dark force at colliders
Light Dark Matter, GeV, with sizable direct detection rate is an
interesting and less explored scenario. Collider searches can be very powerful,
such as through the channel in which a pair of dark matter particle are
produced in association with a jet. It is a generic possibility that the
mediator of the interaction between DM and the nucleus will also be accessible
at the Tevatron and the LHC. Therefore, collider search of the mediator can
provide a more comprehensive probe of the dark matter and its interactions. In
this article, to demonstrate the complementarity of these two approaches, we
focus on the possibility of the mediator being a new gauge boson, which
is probably the simplest model which allows a large direct detection cross
section for a light dark matter candidate. We combine searches in the
monojet+MET channel and dijet resonance search for the mediator. We find that
for the mass of between 250 GeV and 4 TeV, resonance searches at the
colliders provide stronger constraints on this model than the monojet+MET
searches.Comment: 23 pages and 14 figure
Views and Experiences of Sex, Sexuality and Relationships Following Spinal Cord Injury: A Systematic Review and Narrative Synthesis of the Qualitative Literature
Research examining the effects of spinal cord injury on sexuality has largely focused on physiological functioning and quantification of dysfunction following injury. This paper reports a systematic review of qualitative research that focused on the views and experiences of people with spinal cord injury on sex and relationships. The review addressed the following research question: What are the views and experiences of people with spinal cord injury of sex, sexuality and relationships following injury? Five databases were relevant and employed in the review: CINAHL (1989-2016 only), PsychInfo, PubMed, Scopus and Web of Science, for research published between 1 January 1980 and 30 November 2019. After removing duplicates, 257 records remained and were screened using a two-stage approach to inclusion and quality appraisal. Following screening, 27 met the criteria for inclusion and are reported in the paper. The review includes studies from fifteen countries across five continents. Two main approaches to data analysis summary and thematic synthesis were undertaken to analyze the qualitative data reported in the papers. The analysis revealed four main themes: sexual identity; significant and generalized others, sexual embodiment; and; sexual rehabilitation and education
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