Selectivity, ligand deconstruction, and cellular activity analysis of a BPTF bromodomain inhibitor.

Bromodomain and PHD finger containing protein transcription factor (BPTF) is an epigenetic protein involved in chromatin remodelling and is a potential anticancer target. The BPTF bromodomain has one reported small molecule inhibitor (AU1, rac-1). Here, advances made on the structure-activity relationship of a BPTF bromodomain ligand are reported using a combination of experimental and molecular dynamics simulations leading to the active enatiomer (S)-1.

First Evidence for cos2β>0 and Resolution of the Cabibbo-Kobayashi-Maskawa Quark-Mixing Unitarity Triangle Ambiguity.

We present first evidence that the cosine of the CP-violating weak phase 2β is positive, and hence exclude trigonometric multifold solutions of the Cabibbo-Kobayashi-Maskawa (CKM) Unitarity Triangle using a time-dependent Dalitz plot analysis of B^{0}→D^{(*)}h^{0} with D→K_{S}^{0}π^{+}π^{-} decays, where h^{0}∈{π^{0},η,ω} denotes a light unflavored and neutral hadron. The measurement is performed combining the final data sets of the BABAR and Belle experiments collected at the ϒ(4S) resonance at the asymmetric-energy B factories PEP-II at SLAC and KEKB at KEK, respectively. The data samples contain (471±3)×10^{6}BB[over ¯] pairs recorded by the BABAR detector and (772±11)×10^{6}BB[over ¯] pairs recorded by the Belle detector.

Evaluation of clinical significance of decompressive suboccipital craniectomy on the prognosis of cerebellar infarction.

Objective: The decision of whether and/or when to treat cerebellar infarction surgically remains controversial. We investigated the effectiveness of decompressive suboccipital craniectomy (DSC) for treating cerebellar infarction and the prognostic factors that affect the surgical results.

Methods: From October 2006 to June 2017, a total of 14 consecutive patients (12 men, 2 women; mean±SD age 65±12 years, range 42-84 years) were admitted to our hospital and underwent DSC at the time of admission or during their hospitalization.

Current Progress in the Structural and Biochemical Characterization of Proteins Involved in the Assembly of Lipopolysaccharide.

The lipid component of the outer leaflet of the outer membrane of Gram-negative bacteria is primarily composed of the glycolipid lipopolysaccharide (LPS), which serves to form a protective barrier against hydrophobic toxins and many antibiotics. LPS is comprised of three regions: the lipid A membrane anchor, the nonrepeating core oligosaccharide, and the repeating O-antigen polysaccharide. The lipid A portion is also referred to as endotoxin as its overstimulation of the toll-like receptor 4 during systemic infection precipitates potentially fatal septic shock.

Observation of ϒ(2S)→γη_{b}(1S) Decay.

We report the observation of ϒ(2S)→γη_{b}(1S) decay based on an analysis of the inclusive photon spectrum of 24.7  fb^{-1} of e^{+}e^{-} collisions at the ϒ(2S) center-of-mass energy collected with the Belle detector at the KEKB asymmetric-energy e^{+}e^{-} collider. We measure a branching fraction of B[ϒ(2S)→γη_{b}(1S)]=(6.

Triazolopyrimidine and triazolopyridine scaffolds as TDP2 inhibitors.

Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase II (TOP2) mediated DNA damages and causes cellular resistance to clinically used TOP2 poisons. Inhibiting TDP2 can potentially sensitize cancer cells toward TOP2 poisons. Commercial compound P10A10, to which the structure was assigned as 7-phenyl triazolopyrimidine analogue 6a, was previously identified as a TDP2 inhibitor hit in our virtual and fluorescence-based biochemical screening campaign.

Crystal Structure of the Double Homeodomain of DUX4 in Complex with DNA.

Double homeobox (DUX) transcription factors are unique to eutherian mammals. DUX4 regulates expression of repetitive elements during early embryogenesis, but misexpression of DUX4 causes facioscapulohumeral muscular dystrophy (FSHD) and translocations overexpressing the DUX4 double homeodomain cause B cell leukemia. Here, we report the crystal structure of the tandem homeodomains of DUX4 bound to DNA.

Inhibiting APOBEC3 Activity with Single-Stranded DNA Containing 2'-Deoxyzebularine Analogues.

APOBEC3 enzymes form part of the innate immune system by deaminating cytosine to uracil in single-stranded DNA (ssDNA) and thereby preventing the spread of pathogenic genetic information. However, APOBEC mutagenesis is also exploited by viruses and cancer cells to increase rates of evolution, escape adaptive immune responses, and resist drugs. This raises the possibility of APOBEC3 inhibition as a strategy for augmenting existing antiviral and anticancer therapies.

Synthesis of 5-Aryl-3(2 H)-furanones Using Intramolecular Cyclization of Sulfonium Salts.

Base-induced intramolecular cyclization of novel (4-aryl-2,4-dioxobutyl)methylphenylsulfonium salts prepared from the commercially available 1-arylethanone by a cost-effective process is described in this paper. The reaction was completed within 10 min to produce a family of 2-unsubstituted 5-aryl-3(2 H)-furanones in excellent yield. This procedure is simple, and can be carried out under mild conditions and an ambient atmosphere.

Competency assessment for gastric endoscopic submucosal dissection using an endoscopic part-task training box.

Background: Objective assessment of endoscopist competency is important. Recently, the endoscopic part-task training box (Thompson Endoscopic Skills Trainer [TEST]) was developed to assess endoscopist competency. We aimed to evaluate the ability of the TEST to assess competency during endoscopic procedures, especially endoscopic submucosal dissection (ESD).

Methanol extraction fraction from Citrus Sudachi peel exerts lipid reducing effects in cultured cells.

Ectopic fat accumulation is associated with insulin resistance and type 2 diabetes mellitus. Citrus sudachi is an evergreen tree that is found mainly in Tokushima Prefecture in Japan. Previously, it was demonstrated that Citrus sudachi could inhibit the rising trend of blood glucose and fatty acid in human subjects.

Differential assembly of Rous sarcoma virus tetrameric and octameric intasomes is regulated by the C-terminal domain and tail region of integrase.

Retrovirus integrase (IN) catalyzes the concerted integration of linear viral DNA ends into chromosomes. The atomic structures of five different retrovirus IN-DNA complexes, termed intasomes, have revealed varying IN subunit compositions ranging from tetramers to octamers, dodecamers, and hexadecamers. Intasomes containing two IN-associated viral DNA ends capable of concerted integration are termed stable synaptic complexes (SSC), and those formed with a viral/target DNA substrate representing the product of strand-transfer reactions are strand-transfer complexes (STC).

T4 DNA ligase structure reveals a prototypical ATP-dependent ligase with a unique mode of sliding clamp interaction.

DNA ligases play essential roles in DNA replication and repair. Bacteriophage T4 DNA ligase is the first ATP-dependent ligase enzyme to be discovered and is widely used in molecular biology, but its structure remained unknown. Our crystal structure of T4 DNA ligase bound to DNA shows a compact α-helical DNA-binding domain (DBD), nucleotidyl-transferase (NTase) domain, and OB-fold domain, which together fully encircle DNA.

Development and characterization of 43 microsatellite markers for the critically endangered primrose using MiSeq sequencing.

(Primulaceae), a perennial herb belonging to the section , occurs on wet, shaded rocky cliffs in the mountains of Japan. This threatened species comprises four varieties; these plants are very localized and rare in the wild. In this study, 43 microsatellite markers were developed using MiSeq sequencing to facilitate conservation genetics of these critically endangered primroses.

Suture pulley countertraction method reduces procedure time and technical demand of endoscopic submucosal dissection among novice endoscopists learning endoscopic submucosal dissection: a prospective randomized ex vivo study.

Background And Aims: The lack of reliable countertraction in endoscopic submucosal dissection (ESD) contributes to its technical demand and increased procedure time. We aimed to prospectively evaluate the efficacy of the suture pulley countertraction method in endoscopists new to both suturing and ESD.

Methods: Two 30-mm circular lesions were created in an ex vivo porcine stomach model.

Observation of ϒ(4S)→η^{'}ϒ(1S).

We report the first observation of the hadronic transition ϒ(4S)→η^{'}ϒ(1S), using 496  fb^{-1} data collected at the ϒ(4S) resonance with the Belle detector at the KEKB asymmetric-energy e^{+}e^{-} collider. We reconstruct the η^{'} meson through its decays to ρ^{0}γ and to π^{+}π^{-}η, with η→γγ. We measure B(ϒ(4S)→η^{'}ϒ(1S))=[3.

[Clinical Features and Treatment Strategy of Vertebral Artery Injury Associated with Cervical Spine Trauma].

Objective: Vertebral artery injury(VAI)associated with cervical spine trauma has the potential to cause catastrophic vertebrobasilar stroke. However, there are no well-defined treatment recommendations for VAI. The purpose of this study was to identify an effective treatment strategy for VAI following cervical spine trauma.

Determinants of Oligonucleotide Selectivity of APOBEC3B.

APOBEC3B (A3B) is a prominent source of mutation in many cancers. To date, it has been difficult to capture the native protein-DNA interactions that confer A3B's substrate specificity by crystallography due to the highly dynamic nature of wild-type A3B active site. We use computational tools to restore a recent crystal structure of a DNA-bound A3B C-terminal domain mutant construct to its wild type sequence, and run molecular dynamics simulations to study its substrate recognition mechanisms.

Observation of an Excited Ω^{-} Baryon.

Using data recorded with the Belle detector, we observe a new excited hyperon, an Ω^{*-} candidate decaying into Ξ^{0}K^{-} and Ξ^{-}K_{S}^{0} with a mass of 2012.4±0.7(stat)±0.

Search for B^{-}→μ^{-}ν[over ¯]_{μ} Decays at the Belle Experiment.

We report the results of a search for the rare, purely leptonic decay B^{-}→μ^{-}ν[over ¯]_{μ} performed with a 711  fb^{-1} data sample that contains 772×10^{6}  BB[over ¯] pairs, collected near the ϒ(4S) resonance with the Belle detector at the KEKB asymmetric-energy e^{+}e^{-} collider. The signal events are selected based on the presence of a high momentum muon and the topology of the rest of the event showing properties of a generic B-meson decay, as well as the missing energy and momentum being consistent with the hypothesis of a neutrino from the signal decay. We find a 2.

Choosing the right through-the-scope clip: a rigorous comparison of rotatability, whip, open/close precision, and closure strength (with videos).

Background And Aims: Many new through-the-scope clips are available, and physicians often select clips based on physical characteristics and/or cost. However, functional profiles may be equally important and have not been methodically assessed. We evaluated 5 commercially available clips: Resolution 360, Instinct, Quick Clip Pro, Dura Clip, and SureClip.