On the Mechanistic Origins of Toughness in Bone

One of the most intriguing protein materials found in nature is bone, a material composed of assemblies of tropocollagen molecules and tiny hydroxyapatite mineral crystals that form an extremely tough, yet lightweight, adaptive and multifunctional material. Bone has evolved to provide structural support to organisms, and therefore its mechanical properties are of great physiological relevance. In this article, we review the structure and properties of bone, focusing on mechanical deformation and fracture behavior from the perspective of the multidimensional hierarchical nature of its structure. In fact, bone derives its resistance to fracture with a multitude of deformation and toughening mechanisms at many size scales ranging from the nanoscale structure of its protein molecules to the macroscopic physiological scale.United States. Army Research Office (contract number W911NF-06-1-0291)National Science Foundation (U.S.) (CAREER award (contract number 0642545))Lawrence Berkeley National Laboratory (Laboratory Directed Research and Development Program)United States. Dept. of Energy (Office of Science, Office of Basic Energy Sciences, Division of Materials Sciences and Engineering, contract number DE-AC02-05CH11231

No association of alcohol use and the risk of ulcerative colitis or Crohn’s disease: data from a European Prospective cohort study (EPIC)

Background The role of long -term alcohol consumption for the risk of developing ulcerative colitis (UC) and Crohn’s disease (CD) is unclear. Aim s For the first time, t o prospectively assess the role of pre -disease alcohol consumption o n the risk of developing UC or CD. Methods Nested within the European Prospective Investigation into Cancer and Nutrition (EPIC - IBD ), incident UC and CD cases and ma tched controls where included. At recruitment, participants completed validated food frequency and lifestyle questionnaires. Alcohol consumption was classified as either: non -use, former, light ( ≤ 0.5 and 1 drink/week), below the recommended limits (BRL) ( ≤ 1 and 2 drinks/day), moderate ( ≤ 2.5 and 5 drinks/day) , or heavy use (>2.5 and >5 drinks/ day) for women and men, respectively ; and was expressed as consumption at enrolment and during lifetime. Conditional logistic regression was applied adjusting for smoking and education , taking light users as the 3 Abstract Background The role of long -term alcohol consumption for the risk of developing ulcerative colitis (UC) and Crohn’s disease (CD) is unclear. Aim s For the first time, t o prospectively assess the role of pre -disease alcohol consumption o n the risk of developing UC or CD. Methods Nested within the European Prospective Investigation into Cancer and Nutrition (EPIC - IBD ), incident UC and CD cases and ma tched controls where included. At recruitment, participants completed validated food frequency and lifestyle questionnaires. Alcohol consumption was classified as either: non -use, former, light ( ≤ 0.5 and 1 drink/week), below the recommended limits (BRL) ( ≤ 1 and 2 drinks/day), moderate ( ≤ 2.5 and 5 drinks/day) , or heavy use (>2.5 and >5 drinks/ day) for women and men, respectively ; and was expressed as consumption at enrolment and during lifetime. Conditional logistic regression was applied adjusting for smoking and education , taking light users as the reference. Results Out of 262,451 participants in 6 countries, 198 UC incident cases/792 controls and 84 CD cases/336 controls were included. At enrolment, 8%/27%/3 2%/2 3%/1 1% UC cases and 7%/2 9%/4 0%/19%/ 5% C D cases were: non -users, light, BRL, moderate and heavy users, respectively. The corresponding figures for lifetime non -use, former, light, BRL, moderate and heavy use were : 3%/5%/2 3%/44%/19%/6% and 5%/2%/25%/44%/23 %/1% for UC and CD cases , respectively. There were no associations between any categories of alcohol consumption and risk of UC or CD in the una djusted and adjusted odds ratios . Conclusion There was no evidence of association s between alcohol use and the odds of developing either UC or CD

Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing.

Funder: Fondazione Fibrosi Cistica - FFC#1/2017Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. The 3272-26A>G and 3849+10kbC>T CFTR mutations alter the correct splicing of the CFTR gene, generating new acceptor and donor splice sites respectively. Here we develop a genome editing approach to permanently correct these genetic defects, using a single crRNA and the Acidaminococcus sp. BV3L6, AsCas12a. This genetic repair strategy is highly precise, showing very strong discrimination between the wild-type and mutant sequence and a complete absence of detectable off-targets. The efficacy of this gene correction strategy is verified in intestinal organoids and airway epithelial cells derived from CF patients carrying the 3272-26A>G or 3849+10kbC>T mutations, showing efficient repair and complete functional recovery of the CFTR channel. These results demonstrate that allele-specific genome editing with AsCas12a can correct aberrant CFTR splicing mutations, paving the way for a permanent splicing correction in genetic diseases

Comparing the Invasibility of Experimental “Reefs” with Field Observations of Natural Reefs and Artificial Structures

Natural systems are increasingly being modified by the addition of artificial habitats which may facilitate invasion. Where invaders are able to disperse from artificial habitats, their impact may spread to surrounding natural communities and therefore it is important to investigate potential factors that reduce or enhance invasibility. We surveyed the distribution of non-indigenous and native invertebrates and algae between artificial habitats and natural reefs in a marine subtidal system. We also deployed sandstone plates as experimental ‘reefs’ and manipulated the orientation, starting assemblage and degree of shading. Invertebrates (non-indigenous and native) appeared to be responding to similar environmental factors (e.g. orientation) and occupied most space on artificial structures and to a lesser extent reef walls. Non-indigenous invertebrates are less successful than native invertebrates on horizontal reefs despite functional similarities. Manipulative experiments revealed that even when non-indigenous invertebrates invade vertical “reefs”, they are unlikely to gain a foothold and never exceed covers of native invertebrates (regardless of space availability). Community ecology suggests that invertebrates will dominate reef walls and algae horizontal reefs due to functional differences, however our surveys revealed that native algae dominate both vertical and horizontal reefs in shallow estuarine systems. Few non-indigenous algae were sampled in the study, however where invasive algal species are present in a system, they may present a threat to reef communities. Our findings suggest that non-indigenous species are less successful at occupying space on reef compared to artificial structures, and manipulations of biotic and abiotic conditions (primarily orientation and to a lesser extent biotic resistance) on experimental “reefs” explained a large portion of this variation, however they could not fully explain the magnitude of differences

Glial Innate Immunity Generated by Non-Aggregated Alpha-Synuclein in Mouse: Differences between Wild-type and Parkinson's Disease-Linked Mutants

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized pathologically by the presence in the brain of intracellular protein inclusions highly enriched in aggregated alpha-synuclein (alpha-Syn). Although it has been established that progression of the disease is accompanied by sustained activation of microglia, the underlying molecules and factors involved in these immune-triggered mechanisms remain largely unexplored. Lately, accumulating evidence has shown the presence of extracellular alpha-Syn both in its aggregated and monomeric forms in cerebrospinal fluid and blood plasma. However, the effect of extracellular alpha-Syn on cellular activation and immune mediators, as well as the impact of familial PD-linked alpha-Syn mutants on this stimulation, are still largely unknown.Methods and Findings: In this work, we have compared the activation profiles of non-aggregated, extracellular wild-type and PD-linked mutant alpha-Syn variants on primary glial and microglial cell cultures. After stimulation of cells with alpha-Syn, we measured the release of Th1- and Th2-type cytokines as well as IP-10/CXCL10, RANTES/CCL5, MCP-1/CCL2 and MIP-1 alpha/CCL3 chemokines. Contrary to what had been observed using cell lines or for the case of aggregated alpha-Syn, we found strong differences in the immune response generated by wild-type alpha-Syn and the familial PD mutants (A30P, E46K and A53T).Conclusions: These findings might contribute to explain the differences in the onset and progression of this highly debilitating disease, which could be of value in the development of rational approaches towards effective control of immune responses that are associated with PD

Microglial activation and chronic neurodegeneration

Microglia, the resident innate immune cells in the brain, have long been implicated in the pathology of neurode-generative diseases. Accumulating evidence points to activated microglia as a chronic source of multiple neurotoxic factors, including tumor necrosis factor-α, nitric oxide, interleukin-1β, and reactive oxygen species (ROS), driving progressive neuron damage. Microglia can become chronically activated by either a single stimulus (e.g., lipopolysaccharide or neuron damage) or multiple stimuli exposures to result in cumulative neuronal loss with time. Although the mechanisms driving these phenomena are just beginning to be understood, reactive microgliosis (the microglial response to neuron damage) and ROS have been implicated as key mechanisms of chronic and neurotoxic microglial activation, particularly in the case of Parkinson’s disease. We review the mechanisms of neurotoxicity associated with chronic microglial activation and discuss the role of neuronal death and microglial ROS driving the chronic and toxic microglial phenotype

Altered processing of sensory stimuli in patients with migraine

Migraine is a cyclic disorder, in which functional and morphological brain changes fluctuate over time, culminating periodically in an attack. In the migrainous brain, temporal processing of external stimuli and sequential recruitment of neuronal networks are often dysfunctional. These changes reflect complex CNS dysfunction patterns. Assessment of multimodal evoked potentials and nociceptive reflex responses can reveal altered patterns of the brain's electrophysiological activity, thereby aiding our understanding of the pathophysiology of migraine. In this Review, we summarize the most important findings on temporal processing of evoked and reflex responses in migraine. Considering these data, we propose that thalamocortical dysrhythmia may be responsible for the altered synchronicity in migraine. To test this hypothesis in future research, electrophysiological recordings should be combined with neuroimaging studies so that the temporal patterns of sensory processing in patients with migraine can be correlated with the accompanying anatomical and functional changes