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How cells respond to mechanical forces by converting them into biological signals underlie crucial cellular processes. Our understanding of mechanotransduction has been hindered by technical barriers, including limitations in our ability to effectively apply low range piconewton forces to specific mechanoreceptors on cell membranes without laborious and repetitive trials. To overcome these challenges we introduce the Nano-winch, a robust, easily assembled, programmable DNA origami-based molecular actuator. The Nano-winch is designed to manipulate multiple mechanoreceptors in parallel by exerting fine-tuned, low- piconewton forces in autonomous and remotely activated modes via adjustable single- and double-stranded DNA linkages, respectively. Nano-winches in autonomous mode can land and operate on the cell surface. Targeting the device to integrin stimulated detectable downstream phosphorylation of focal adhesion kinase, an indication that Nano-winches can be applied to study cellular mechanical processes. Remote activation mode allowed finer extension control and greater force exertion. We united remotely activated Nano-winches with single-channel bilayer experiments to directly observe the opening of a channel by mechanical force in the force responsive gated channel protein, BtuB. This customizable origami provides an instrument-free approach that can be applied to control and explore a diversity of mechanotransduction circuits on living cells. Studies on mechanotransduction are limited by our ability to apply low range forces to specific mechanoreceptors on cell membranes. Here the authors report the Nano-winch, a programmable DNA origami-based molecular actuator, to manipulate multiple mechanoreceptors in parallel by exerting piconewton forces.

Alcohol is widely consumed across the world. It is consumed in both social and cultural settings. Until recently, two types of alcohol consumption were recognized: heavy chronic alcohol consumption or light consumption. Today, there is a new pattern of consumption among teenagers and young adults namely: binge drinking. Heavy alcohol consumption is detrimental to many organs and tissues, including bones, and is known to induce secondary osteoporosis. Some studies, however, have reported benefits from light alcohol consumption on bone parameters. To date, little is known regarding the effects of binge drinking on bone health. Here, we review the effects of three different means of alcohol consumption: light, heavy, and binge drinking. We also review the detailed literature on the different mechanisms by which alcohol intake may decrease bone mass and strength. The effects of alcohol on bone are thought to be both direct and indirect. The decrease in bone mass and strength following alcohol consumption is mainly due to a bone remodeling imbalance, with a predominant decrease in bone formation. Recent studies, however, have reported new mechanisms by which alcohol may act on bone remodeling, including osteocyte apoptosis, oxidative stress, and Wnt signalling pathway modulation. The roles of reduced total fat mass, increased lipid content in bone marrow, and a hypoleptinemia are also discussed.

Membrane receptors, key components in signal transduction, often function as dimers. These include some G protein–coupled receptors such as metabotropic glutamate (mGlu) receptors that have large extracellular domains (ECDs) where agonists bind. How agonist binding in dimeric ECDs activates the effector domains remains largely unknown. The structure of the dimeric ECDs of mGlu 1 solved in the presence of agonist revealed two specific conformations in which either one or both protomers are in an agonist-stabilized closed form. Here we examined whether both conformations correspond to an active form of the full-length receptor. Using a system that allows the formation of dimers made of a wild-type and a mutant subunit, we show that the closure of one ECD per dimer is sufficient to activate the receptor, but the closure of both ECDs is required for full activity.

The centrosome is the principal microtubule organization center in cells, giving rise to microtubule-based organelles (e.g., cilia, flagella). The aim was to study the osteocyte centrosome morphology at an ultrastructural level in relation to its mechanosensitive function. Osteocyte centrosomes and cilia in tibial cortical bone were explored by acetylated alpha-tubulin (AαTub) immunostaining under confocal microscopy. For the first time, fine ultrastructure and spatial orientation of the osteocyte centrosome were explored by transmission electron microscopy on serial ultrathin sections. AαTub-positive staining was observed in 94% of the osteocytes examined (222/236). The mother centriole formed a short primary cilium and was longer than the daughter centriole due to an intermediate zone between centriole and cilium. The proximal end of the mother centriole was connected with the surface of daughter centriole by striated rootlets. The mother centriole exhibited distal appendages that interacted with the cell membrane and formed a particular structure called “cilium membrane prolongation.” The primary cilium was mainly oriented perpendicular to the long axis of bone. Mother and daughter centrioles change their original mutual orientation during the osteocyte differentiation process. The short primary cilium is hypothesized as a novel type of fluid-sensing organelle in osteocytes.

Tight relationships exist in the local Universe between the central stellar properties of galaxies and the mass of their supermassive black hole (SMBH) 1 – 3 . These suggest that galaxies and black holes co-evolve, with the main regulation mechanism being energetic feedback from accretion onto the black hole during its quasar phase 4 – 6 . A crucial question is how the relationship between black holes and galaxies evolves with time; a key epoch to examine this relationship is at the peaks of star formation and black hole growth 8–12 billion years ago (redshifts 1–3) 7 . Here we report a dynamical measurement of the mass of the black hole in a luminous quasar at a redshift of 2, with a look back in time of 11 billion years, by spatially resolving the broad-line region (BLR). We detect a 40-μas (0.31-pc) spatial offset between the red and blue photocentres of the Hα line that traces the velocity gradient of a rotating BLR. The flux and differential phase spectra are well reproduced by a thick, moderately inclined disk of gas clouds within the sphere of influence of a central black hole with a mass of 3.2 × 10 8  solar masses. Molecular gas data reveal a dynamical mass for the host galaxy of 6 × 10 11  solar masses, which indicates an undermassive black hole accreting at a super-Eddington rate. This suggests a host galaxy that grew faster than the SMBH, indicating a delay between galaxy and black hole formation for some systems. Using the GRAVITY+ instrument, dynamical measurement of the black hole mass in a quasar at a redshift of 2.3 (11 billion years ago) shows how the relationship between galaxies and black holes evolves with time.

G‐protein‐coupled receptors (GPCRs) have been shown to form dimers, but the relevance of this phenomenon in G‐protein activation is not known. Among the large GPCR family, metabotropic glutamate (mGlu) receptors are constitutive dimers. Here we examined whether both heptahelical domains (HDs) are turned on upon full receptor activation. To that aim, we measured G‐protein coupling efficacy of dimeric mGlu receptors in which one subunit bears specific mutations. We show that a mutation in the third intracellular loop (i3 loop) known to prevent G‐protein activation in a single subunit decreases coupling efficacy. However, when a single HD is blocked in its inactive state using an inverse agonist, 2‐methyl‐6‐(phenylethynyl)pyridine (MPEP), no decrease in receptor activity is observed. Interestingly, in a receptor dimer in which the subunit that binds MPEP is mutated in its i3 loop, MPEP enhances agonist‐induced activity, reflecting a ‘better’ activation of the adjacent HD. These data are consistent with a model in which a single HD is turned on upon activation of such homodimeric receptors and raise important issues in deciphering the functional role of GPCR dimer formation for G‐protein activation.

Berryman, N, Maurel, D, and Bosquet, L. Effect of plyometric vs. dynamic weight training on the energy cost of running. J Strength Cond Res 24(7)1818-1825, 2010-The purpose of this study is to compare the effects of 2 strength training methods on the energy cost of running (Cr). Thirty-five moderately to well-trained male endurance runners were randomly assigned to either a control group (C) or 2 intervention groups. All groups performed the same endurance-training program during an 8-week period. Intervention groups added a weekly strength training session designed to improve neuromuscular qualities. Sessions were matched for volume and intensity using either plyometric training (PT) or purely concentric contractions with added weight (dynamic weight training [DWT]). We found an interaction between time and group (p < 0.05) and an effect of time (p < 0.01) for Cr. Plyometric training induced a larger decrease of Cr (218 ± 16 to 203 ± 13 ml·kg·km) than DWT (207 ± 15 to 199 ± 12 ml·kg·km), whereas it remained unchanged in C. Pre-post changes in Cr were correlated with initial Cr (r = −0.57, p < 0.05). Peak vertical jump height (VJHpeak) increased significantly (p < 0.01) for both experimental groups (DWT = 33.4 ± 6.2 to 34.9 ± 6.1 cm, PT = 33.3 ± 4.0 to 35.3 ± 3.6 cm) but not for C. All groups showed improvements (p < 0.05) in Perf3000 (C = 711 ± 107 to 690 ± 109 seconds, DWT = 755 ± 87 to 724 ± 77 seconds, PT = 748 ± 81 to 712 ± 76 seconds). Plyometric training were more effective than DWT in improving Cr in moderately to well-trained male endurance runners showing that athletes and coaches should include explosive strength training in their practices with a particular attention on plyometric exercises. Future research is needed to establish the origin of this adaptation.

Axitinib (AG-013736) is a potent and selective oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, which have an important role in pancreatic cancer. The aim of this study was to assess the safety and efficacy of gemcitabine plus axitinib versus gemcitabine alone. Between January and August, 2006, 103 patients with unresectable, locally advanced, or metastatic pancreatic cancer were randomly assigned in a two to one ratio to receive gemcitabine (1000 mg/m 2) plus axitinib 5 mg twice daily (n=69) or gemcitabine (1000 mg/m 2) alone (n=34) by a centralised registration system. The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00219557. All randomised patients were included in the efficacy analyses. Median overall survival was longer with gemcitabine plus axitinib than with gemcitabine alone (6·9 [95% CI 5·3–10·1] months vs 5·6 [3·9–8·8] months). The hazard ratio for survival with gemcitabine plus axitinib versus with gemcitabine alone, adjusted for stratification factors, was 0·71 (95% CI 0·44–1·13). The most common grade 3 or worse adverse events were fatigue (15 [22%] patients in the gemcitabine plus axitinib group vs one [3%] in the gemcitabine alone group), abdominal pain (eight [12%] vs five [16%]), and asthenia (eight [12%] vs one [3%]). Gemcitabine plus axitinib showed a similar safety profile to gemcitabine alone; the small, non-statistically significant gain in overall survival needs to be assessed in a randomised phase III trial. Pfizer Inc.

Debris disks are usually detected through the infrared excess over the photospheric level of their host star. The most favorable stars for disk detection are those with spectral types between A and K, while the statistics for debris disks detected around low-mass M-type stars is very low, either because they are rare or because they are more difficult to detect. Terrestrial planets, on the other hand, may be common around M-type stars. Here, we report on the discovery of an extended (likely) debris disk around the M-dwarf GSC 07396-00759. The star is a wide companion of the close accreting binary V4046 Sgr. The system probably is a member of the \\(\\beta\\) Pictoris Moving Group. We resolve the disk in scattered light, exploiting high-contrast, high-resolution imagery with the two near-infrared subsystems of the VLT/SPHERE instrument, operating in the YJ bands and the H2H3 doublet. The disk is clearly detected up to 1.5\" (\\(\\sim110\\) au) from the star and appears as a ring, with an inclination \\(i\\sim83\\) degree, and a peak density position at \\(\\sim 70\\) au. The spatial extension of the disk suggests that the dust dynamics is affected by a strong stellar wind, showing similarities with the AU Mic system that has also been resolved with SPHERE. The images show faint asymmetric structures at the widest separation in the northwest side. We also set an upper limit for the presence of giant planets to \\(2 M_J\\). Finally, we note that the 2 resolved disks around M-type stars of 30 such stars observed with SPHERE are viewed close to edge-on, suggesting that a significant population of debris disks around M dwarfs could remain undetected because of an unfavorable orientation.