A guide to mechanobiology: Where biology and physics meet

AbstractCells actively sense and process mechanical information that is provided by the extracellular environment to make decisions about growth, motility and differentiation. It is important to understand the underlying mechanisms given that deregulation of the mechanical properties of the extracellular matrix (ECM) is implicated in various diseases, such as cancer and fibrosis. Moreover, matrix mechanics can be exploited to program stem cell differentiation for organ-on-chip and regenerative medicine applications. Mechanobiology is an emerging multidisciplinary field that encompasses cell and developmental biology, bioengineering and biophysics. Here we provide an introductory overview of the key players important to cellular mechanobiology, taking a biophysical perspective and focusing on a comparison between flat versus three dimensional substrates. This article is part of a Special Issue entitled: Mechanobiology

Factors influencing participation in a randomized controlled resistance exercise intervention study in breast cancer patients during radiotherapy

Background: Over the past years knowledge about benefits of physical activity after cancer is evolving from randomized exercise intervention trials. However, it has been argued that results may be biased by selective participation. Therefore, we investigated factors influencing participation in a randomized exercise intervention trial for breast cancer patients. Methods: Non-metastatic breast cancer patients were systematically screened for a randomized exercise intervention trial on cancer-related fatigue. Participants and nonparticipants were compared concerning sociodemographic characteristics (age, marital status, living status, travel time to the training facility), clinical data (body-mass-index, tumor stage, tumor size and lymph node status, comorbidities, chemotherapy), fatigue, and physical activity. Reasons for participation or declination were recorded. Results 117 patients (52 participants, 65 nonparticipants) were evaluable for analysis. Multiple regression analyses revealed significantly higher odds to decline participation among patients with longer travel time (p = 0.0012), living alone (p = 0.039), with more comorbidities (0.031), previous chemotherapy (p = 0.0066), of age ≥ 70 years (p = 0.025), or being free of fatigue (p = 0.0007). No associations were found with BMI or physical activity. By far the most frequently reported reason for declination of participation was too long commuting time to the training facility. Conclusions: Willingness of breast cancer patients to participate in a randomized exercise intervention study differed by sociodemographic factors and health status. Neither current physical activity level nor BMI appeared to be selective for participation. Reduction of personal inconveniences and time effort, e.g. by decentralized training facilities or flexible training schedules, seem most promising for enhancing participation in exercise intervention trials. Trial registration: Registered at ClinicalTrials.gov: NCT01468766 (October 2011)

High-Resolution Spectroscopic Study of Extremely Metal-Poor Star Candidates from the SkyMapper Survey

The SkyMapper Southern Sky Survey is carrying out a search for the most metal-poor stars in the Galaxy. It identifies candidates by way of its unique filter set that allows for estimation of stellar atmospheric parameters. The set includes a narrow filter centered on the Ca II K 3933A line, enabling a robust estimate of stellar metallicity. Promising candidates are then confirmed with spectroscopy. We present the analysis of Magellan-MIKE high-resolution spectroscopy of 122 metal-poor stars found by SkyMapper in the first two years of commissioning observations. 41 stars have [Fe/H] <= -3.0. Nine have [Fe/H] <= -3.5, with three at [Fe/H] ~ -4. A 1D LTE abundance analysis of the elements Li, C, Na, Mg, Al, Si, Ca, Sc, Ti, Cr, Mn, Co, Ni, Zn, Sr, Ba and Eu shows these stars have [X/Fe] ratios typical of other halo stars. One star with low [X/Fe] [X/Fe values appears to be "Fe-enhanced," while another star has an extremely large [Sr/Ba] ratio: >2. Only one other star is known to have a comparable value. Seven stars are "CEMP-no" stars ([C/Fe] > 0.7, [Ba/Fe] < 0). 21 stars exhibit mild r-process element enhancements (0.3 <=[Eu/Fe] < 1.0), while four stars have [Eu/Fe] >= 1.0. These results demonstrate the ability to identify extremely metal-poor stars from SkyMapper photometry, pointing to increased sample sizes and a better characterization of the metal-poor tail of the halo metallicity distribution function in the future.Comment: Minor corrections to text, missing data added to Tables 3 and 4; updated to match published version. Complete tables included in sourc

NADPH oxidase, NOX1, mediates vascular injury in ischemic retinopathy

&lt;b&gt;Aims:&lt;/b&gt; Ischemic retinal diseases such as retinopathy of prematurity are major causes of blindness due to damage to the retinal microvasculature. Despite this clinical situation, retinopathy of prematurity is mechanistically poorly understood. Therefore, effective preventative therapies are not available. However, hypoxic-induced increases in reactive oxygen species (ROS) have been suggested to be involved with NADPH oxidases (NOX), the only known dedicated enzymatic source of ROS. Our major aim was to determine the contribution of NOX isoforms (1, 2, and 4) to a rodent model of retinopathy of prematurity. &lt;b&gt;Results:&lt;/b&gt; Using a genetic approach, we determined that only mice with a deletion of NOX1, but not NOX2 or NOX4, were protected from retinal neovascularization and vaso-obliteration, adhesion of leukocytes, microglial accumulation, and the increased generation of proangiogenic and proinflammatory factors and ROS. We complemented these studies by showing that the specific NOX inhibitor, GKT137831, reduced vasculopathy and ROS levels in retina. The source of NOX isoforms was evaluated in retinal vascular cells and neuro-glial elements. Microglia, the immune cells of the retina, expressed NOX1, 2, and 4 and responded to hypoxia with increased ROS formation, which was reduced by GKT137831. &lt;b&gt;Innovation:&lt;/b&gt; Our studies are the first to identify the NOX1 isoform as having an important role in the pathogenesis of retinopathy of prematurity. &lt;b&gt;Conclusions:&lt;/b&gt; Our findings suggest that strategies targeting NOX1 have the potential to be effective treatments for a range of ischemic retinopathie

The evolution of plasticity at geographic range edges

Acknowledgments This article is the product of a working group funded by a grant from the Quebec Centre for Biodiversity Sciences to J-P.L. and K.E.M. J-P.L. is funded by a Concordia University Research Chair and an NSERC Discovery Grant (RGPIN-2015-06081). D.L. is supported by the Sustainability and Energy Research Initiative PhD grant. K.E.M. is supported by an NSERC Discovery Grant (RGPIN-2019-04239). C.J.G., A.L.A., and C.S. are funded by NSERC Discovery Grants. T.U. is supported by the UBC International Doctoral Fellowship.Peer reviewedPostprin

Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration

Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4(-/-)) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4(-/-) mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy

Inhibition of Ubc13-mediated ubiquitination by GPS2 regulates multiple stages of B cell development

Non-proteolytic ubiquitin signaling mediated by Lys63 ubiquitin chains plays a critical role in multiple pathways that are key to the development and activation of immune cells. Our previous work indicates that GPS2 (G-protein Pathway Suppressor 2) is a multifunctional protein regulating TNF signaling and lipid metabolism in the adipose tissue through modulation of Lys63 ubiquitination events. However, the full extent of GPS2-mediated regulation of ubiquitination and the underlying molecular mechanisms are unknown. Here, we report that GPS2 is required for restricting the activation of TLR and BCR signaling pathways and the AKT/FOXO1 pathway in immune cells based on direct inhibition of Ubc13 enzymatic activity. Relevance of this regulatory strategy is confirmed in vivo by B cell-targeted deletion of GPS2, resulting in developmental defects at multiple stages of B cell differentiation. Together, these findings reveal that GPS2 genomic and non-genomic functions are critical for the development and cellular homeostasis of B cells

Correlation between Targeted qPCR Assays and Untargeted DNA Shotgun Metagenomic Sequencing for Assessing the Fecal Microbiota in Dogs

DNA shotgun sequencing is an untargeted approach for identifying changes in relative abundances, while qPCR allows reproducible quantification of specific bacteria. The canine dysbiosis index (DI) assesses the canine fecal microbiota by using a mathematical algorithm based on qPCR results. We evaluated the correlation between qPCR and shotgun sequencing using fecal samples from 296 dogs with different clinical phenotypes. While significant correlations were found between qPCR and sequencing, certain taxa were only detectable by qPCR and not by sequencing. Based on sequencing, less than 2% of bacterial species (17/1190) were consistently present in all healthy dogs (n = 76). Dogs with an abnormal DI had lower alpha-diversity compared to dogs with normal DI. Increases in the DI correctly predicted the gradual shifts in microbiota observed by sequencing: minor changes (R = 0.19, DI 2, DI > 5, and DI > 8, respectively), compared to dogs with a normal DI (DI < 0, all targets within the RI), as higher R-values indicated larger dissimilarities. In conclusion, the qPCR-based DI is an effective indicator of overall microbiota shifts observed by shotgun sequencing in dogs

The handbook for standardized field and laboratory measurements in terrestrial climate change experiments and observational studies (ClimEx)

Climate change is a world-wide threat to biodiversity and ecosystem structure, functioning and services. To understand the underlying drivers and mechanisms, and to predict the consequences for nature and people, we urgently need better understanding of the direction and magnitude of climate change impacts across the soil-plant-atmosphere continuum. An increasing number of climate change studies are creating new opportunities for meaningful and high-quality generalizations and improved process understanding. However, significant challenges exist related to data availability and/or compatibility across studies, compromising opportunities for data re-use, synthesis and upscaling. Many of these challenges relate to a lack of an established 'best practice' for measuring key impacts and responses. This restrains our current understanding of complex processes and mechanisms in terrestrial ecosystems related to climate change. To overcome these challenges, we collected best-practice methods emerging from major ecological research networks and experiments, as synthesized by 115 experts from across a wide range of scientific disciplines. Our handbook contains guidance on the selection of response variables for different purposes, protocols for standardized measurements of 66 such response variables and advice on data management. Specifically, we recommend a minimum subset of variables that should be collected in all climate change studies to allow data re-use and synthesis, and give guidance on additional variables critical for different types of synthesis and upscaling. The goal of this community effort is to facilitate awareness of the importance and broader application of standardized methods to promote data re-use, availability, compatibility and transparency. We envision improved research practices that will increase returns on investments in individual research projects, facilitate second-order research outputs and create opportunities for collaboration across scientific communities. Ultimately, this should significantly improve the quality and impact of the science, which is required to fulfil society's needs in a changing world.Peer reviewe

The Spin Structure Function g1pg_1^{\rm p} of the Proton and a Test of the Bjorken Sum Rule

New results for the double spin asymmetry $A_1^{\rm p}$ and the proton longitudinal spin structure function $g_1^{\rm p}$ are presented. They were obtained by the COMPASS collaboration using polarised 200 GeV muons scattered off a longitudinally polarised NH$_3$ target. The data were collected in 2011 and complement those recorded in 2007 at 160\,GeV, in particular at lower values of $x$. They improve the statistical precision of $g_1^{\rm p}(x)$ by about a factor of two in the region $x\lesssim 0.02$. A next-to-leading order QCD fit to the $g_1$ world data is performed. It leads to a new determination of the quark spin contribution to the nucleon spin, $\Delta \Sigma$ ranging from 0.26 to 0.36, and to a re-evaluation of the first moment of $g_1^{\rm p}$. The uncertainty of $\Delta \Sigma$ is mostly due to the large uncertainty in the present determinations of the gluon helicity distribution. A new evaluation of the Bjorken sum rule based on the COMPASS results for the non-singlet structure function $g_1^{\rm NS}(x,Q^2)$ yields as ratio of the axial and vector coupling constants $|g_{\rm A}/g_{\rm V}| = 1.22 \pm 0.05~({\rm stat.}) \pm 0.10~({\rm syst.})$, which validates the sum rule to an accuracy of about 9\%.Comment: 19 pages, 8 figures and table