N-(3-Bromo-5-methyl-2-pyrid­yl)-4-methyl­benzene­sulfonamide

In the mol­ecule of the title compound, C13H13BrN2O2S, the dihedral angle formed by the pyridine and benzene rings is 66.87 (3)°. An intra­molecular N—H⋯Br hydrogen bond is observed. In the crystal structure, N—H⋯O hydrogen bonds, C—H⋯π inter­actions and aromatic π–π stacking inter­actions [centroid–centroid distance = 3.757 (14) Å] link the mol­ecules into a three-dimensional network

(1R*,5S*)-8-(2-Fluoro-4-nitro­phen­yl)-8-aza­bicyclo­[3.2.1]octan-3-one

In the title compound, C13H13FN2O3, the fused piperidine ring is in a chair conformation. The fused pyrrolidine ring shows an envelope conformation with the N atom displaced by 0.661 (3) Å out of the plane formed by the four C atoms of the pyrrolidine ring. The dihedral angle between this plane and the plane formed by the four attached C atoms of the piperidine ring (not including the carbonyl C atom) is 67.63 (10)°. The F atom is disordered and was refined using a split model with an occupancy ratio of 0.910 (3): 0.080 (3)

Targeting human caseinolytic protease P (ClpP) as a novel therapeutic strategy in ovarian cancer

Abstract Ovarian cancer (OC) is currently one of the most life‐threatening types of gynecological malignancy with limited treatment options and poor clinical outcomes. Human caseinolytic protease P (HsClpP) is located in the mitochondria and plays an important role in several tumors. Moreover, HsClpP is overexpressed in OC and several other tumor cells. Thus, HsClpP modulation is regarded as a potential approach for OC treatment. In this study, we identified and validated a novel boron peptide Compound 43‐8F as a potent HsClpP inhibitor. Upon 43‐8F treatment, mitochondrial damage was observed to be closely correlated with upregulated intracellular reactive oxygen species production, decreasement of membrane potential, and ATP content suppression. Meanwhile, the expression level of SDHB and the ATF4 was increased after 43‐8F treatment, suggesting that 43‐8F treatment induces mitochondrial respiratory disorders and activates the integrated stress response pathway to inhibit tumor cell growth. Further, 43‐8F exhibited a good therapeutic and safety profile in OC xenograft model in nude mice. Together, these results suggest that 43‐8F exerts an anti‐ovarian cancer effect by inhibiting HsClpP pathway

Visualization 1: Parametric distortion-adaptive neighborhood for omnidirectional camera

Video demonstration of human tracking with NEB-HW-PF. Originally published in Applied Optics on 10 August 2015 (ao-54-23-6969

Influence of Dimple Diameter and Depth on Heat Transfer of Impingement-Cooled Turbine Leading Edge with Cross-Flow and Dimple

Today, impingement cooling structures with dimples can effectively ease the burden of turbine blades. This paper investigates the effect of dimple diameter and depth on the heat transfer of the target surface on a laminar-cooled turbine blade with a cross-flow and dimple numerically to find the mechanism behind it so that the dimple can be better used in turbine cooling. The commercial software ANSYS 19.2 and a baseline (BSL) turbulence model is used during the numerical computation. In this paper, the cross-flow Reynolds number varies from 15,000 to 60,000, while the jet Reynolds number remains at 30,000. When the cross-flow Reynolds number changes, due to the location change in vortexes generated inside or around the dimple, the two dimple parameters affect heat transfer differently. When the cross-flow Reynolds number is lower than the jet Reynolds number, dimples with smaller diameters and depths lead to better heat transfer performance. When the cross-flow Reynolds number exceeds the jet Reynolds number, dimples with bigger diameters and depths result in better heat exchange performance. The results also indicate that, while the dimple diameters remain constant, the rise of the cross-flow Reynolds number enhances the heat transfer of the dimple structure

Crystal Structure of Human DNA Methyltransferase 1

DNMT1 (DNA methyltransferase 1) is responsible for propagating the DNA methylation patterns during DNA replication. DNMT1 contains, in addition to a C-terminal methyltransferase domain, a large N-terminal regulatory region that is composed of an RFTS (replication foci targeting sequence) domain, a CXXC zinc finger domain and a pair of BAH (bromo adjacent homology) domains. The regulatory domains of DNMT1 mediate a network of protein-protein and protein-DNA interactions to control the recruitment and enzymatic activity of DNMT1. Here we report the crystal structure of human DNMT1 with all the structural domains (hDNMT1, residues 351-1600) in complex with S-adenosyl-l-homocysteine at 2.62Å resolution. The RFTS domain directly associates with the methyltransferase domain, thereby inhibiting the substrate binding of hDNMT1. Through structural analysis, mutational, biochemical and enzymatic studies, we further identify that a linker sequence between the CXXC and BAH1 domains, aside from its role in the CXXC domain-mediated DNMT1 autoinhibition, serves as an important regulatory element in the RFTS domain-mediated autoinhibition. In comparison with the previously determined structure of mouse DNMT1, this study also reveals a number of distinct structural features that may underlie subtle functional diversity observed for the two orthologues. In addition, this structure provides a framework for understanding the functional consequence of disease-related hDNMT1 mutations

A novel and potent dihydroorotate dehydrogenase inhibitor suppresses the proliferation of colorectal cancer by inducing mitochondrial dysfunction and DNA damage

Abstract Dihydroorotate dehydrogenase (DHODH) is a quite attractive target in cancer therapy. Nevertheless, the antitumor effects of DHODH inhibitors against colorectal cancer (CRC) and the underlying mechanism have seldom been studied. Here, we explored the anti‐CRC efficacy of M62, a novel and potent DHODH inhibitor. In the study, M62 significantly inhibited the proliferation of CRC cells and induced S phase arrest. The antiproliferative effects caused by M62 were rescued by uridine supplementation. Mechanistically, messenger RNA sequencing results showed that M62‐triggered gene changes related to mitochondrial dysfunction, DNA damage, and DNA damage repair. Further validation showed that M62 treatment induced the generation of reactive oxygen species and decreased ΔΨm and ATP production. Meanwhile, M62 induced the accumulation of γ‐H2AX and longer comet tail moment, which were both markers of DNA damage. The downregulated DNA repair proteins and PI3K/ATK pathway were observed after M62 treatment. Furthermore, M62 significantly inhibited CRC xenograft tumor growth without detectable toxicity. Therefore, we conclude that M62 inhibits CRC growth both in vitro and in vivo by causing mitochondrial dysfunction and DNA damage, suggesting that DHODH inhibitors are potential therapeutic strategies for treating CRC