Sarcopenia-related Traits, Body Mass Index and Ovarian Cancer Risk: Investigation of Causal Relationships Through Multivariable Mendelian Randomization Analyses

Objective: This study was aimed at exploring the causal relationships of four sarcopenia-related traits (appendicular lean mass, usual walking pace, right hand grip strength, and levels of moderate to vigorous physical activity) with body mass index (BMI) and ovarian cancer risk, by using univariable and multivariable Mendelian randomization (MR) methods. Materials and Methods: Univariable and multivariable MR was performed to estimate causal relationships among sarcopenia-related traits, BMI, and ovarian cancer risk, in aggregated genome-wide association study (GWAS) data from the UK Biobank. Genetic variants associated with each variable (P < 5 × 10−8) were identified as instrumental variables. Three methods—inverse variance weighted (IVW) analysis, weighted median analysis, and MR-Egger regression—were used. Results: Univariable MR analyses revealed positive causal effects of high appendicular lean mass (P = 0.02) and high BMI (P = 0.001) on ovarian cancer occurrence. In contrast, a genetically predicted faster usual walking pace was associated with lower risk of ovarian cancer (P = 0.03). No evidence was found supporting roles of right hand grip strength and levels of moderate to vigorous physical activity in ovarian cancer development (P = 0.56 and P = 0.22, respectively). In multivariable MR analyses, the association between a genetically predicted faster usual walking pace and lower ovarian cancer risk remained significant (P = 0.047). Conclusions: Our study highlights a role of slower usual walking pace in the development of ovarian cancer. Further studies are required to validate our findings and understand the underlying mechanisms

SecA, a remarkable nanomachine

Biological cells harbor a variety of molecular machines that carry out mechanical work at the nanoscale. One of these nanomachines is the bacterial motor protein SecA which translocates secretory proteins through the protein-conducting membrane channel SecYEG. SecA converts chemically stored energy in the form of ATP into a mechanical force to drive polypeptide transport through SecYEG and across the cytoplasmic membrane. In order to accommodate a translocating polypeptide chain and to release transmembrane segments of membrane proteins into the lipid bilayer, SecYEG needs to open its central channel and the lateral gate. Recent crystal structures provide a detailed insight into the rearrangements required for channel opening. Here, we review our current understanding of the mode of operation of the SecA motor protein in concert with the dynamic SecYEG channel. We conclude with a new model for SecA-mediated protein translocation that unifies previous conflicting data

Photo-Chlorination of Linear Alkanes with 2-Position Selectivity Using a Metal-Organic Layer Catalyst

Controlling regioselectivity in activating C−H bonds in linear alkanes is challenging, as their multiple secondary C−H bonds have quite similar dissociation energies with no functional groups to differentiate between the bonds. Amidyl radicals generated from N‒halogen amides were reported to activate C−H bonds with an interesting 2-position selectivity. Here, with a possibility to access the amidyl radical photocatalytically, we coupled ligand-to-metal charge transfer (LMCT)-based radical generation and amide functional group on a tailor-designed metal-organic layer (MOL) material. We achieved efficient photo-chlorination of linear alkanes with 2-position selectivity. For example, with n-hexane as the substrate, 2-chloro-n-hexane was obtained with 85% selectivity and a turnover number of 2200 in 8 hours, together with a high apparent quantum yield of ~7% at room temperature. Transient absorption spectroscopy reveals that a FeIV species is involved in the initial photo-driven process that possibly oxidizes the amide center to an amidyl radical

Long-Term Cardiovascular Mortality among 80,042 Older Patients with Bladder Cancer

Background: To identify the risk of death from cardiovascular disease (CVD) in older patients with bladder cancer (BC). Methods: This population-based study included 80,042 older BC patients (≥65 years) diagnosed between 1975 and 2018, with a mean follow-up of 17.2 years. The proportion of deaths, competing risk models, standardized mortality ratio (SMR), and absolute excess risk (AER) per 10,000 person-years were applied to identify the risk of CVD-related deaths among older BC patients. Results: For older patients with BC, CVD-related death was the chief cause of death, and cumulative CVD-related mortality also exceeded primary BC as the leading cause of death mostly 5–10 years after BC diagnosis, especially in localized-stage and low-grade subgroups. The risk of short- and long-term CVD-related death in older BC patients was higher than in the general older adult population (SMR = 1.30, 95% CI 1.28–1.32; AER = 105.68). The risk of sex-specific CVD-related deaths also increased compared to the general population of older adults, including heart disease, cerebrovascular diseases, hypertension without heart disease, atherosclerosis, aortic aneurysm and dissection, and other diseases of the arteries, arterioles, and capillaries. Conclusions: CVD-related death is an important competing risk among older BC patients and has surpassed primary BC as the chief cause of death, mainly 5–10 years after BC diagnosis. The risk of CVD-related death in older patients with BC was greater than in the general population. The management of older patients with BC should focus not only on the primary cancer but also on CVD-related death

X-ray structure of a protein-conducting channel

A conserved heterotrimeric membrane protein complex, the Sec61 or SecY complex, forms a protein-conducting channel, allowing polypeptides to be transferred across or integrated into membranes. We report the crystal structure of the complex from Methanococcus jannaschii at a resolution of 3.2 Å. The structure suggests that one copy of the heterotrimer serves as a functional translocation channel. The α-subunit has two linked halves, transmembrane segments 1–5 and 6–10, clamped together by the γ-subunit. A cytoplasmic funnel leading into the channel is plugged by a short helix. Plug displacement can open the channel into an ‘hourglass’ with a ring of hydrophobic residues at its constriction. This ring may form a seal around the translocating polypeptide, hindering the permeation of other molecules. The structure also suggests mechanisms for signal-sequence recognition and for the lateral exit of transmembrane segments of nascent membrane proteins into lipid, and indicates binding sites for partners that provide the driving force for translocation