The importance of timing differentiation during limb muscle development

AbstractBackground: Skeletal muscle of trunk, limbs and tongue develops from a small population of cells that originates from somites. Although promoters and inhibitors of muscle differentiation have been isolated, nothing is known about how the amplification of the muscle precursor pool is regulated; this amplification provides muscle mass during development. Furthermore, little is known about how cells accumulate in the pre-muscle masses in the limbs. We investigated the role of bone morphogenetic proteins (BMPs) and Sonic hedgehog (Shh) during proliferation, differentiation and positioning of muscle.Results: The proliferation of muscle precursors in limbs was linked to Pax-3 expression. Ectoderm removal downregulated Pax-3 expression, arrested proliferation and prematurely initiated muscle differentiation which exhausted the muscle precursor pool and prevented further muscle growth. BMP-2, BMP-4 and BMP-7 had a dose-dependent effect on pre-myogenic cells: low concentrations maintained a Pax-3-expressing proliferative population, substituting for ectoderm-derived proliferative signals and delaying differentiation, whereas high concentrations prevented muscle development, probably by inducing apoptosis. In the limb, Shh upregulated Bmp-2 and Bmp-7 expression which delayed muscle differentiation, upregulated Pax-3, amplified the muscle precursor population and stimulated excessive muscle growth.Conclusions: These data indicate that embryonic muscle growth requires muscle differentiation to be delayed. Muscle differentiation may occur through a default pathway after cells escape proliferative signals. Positioning of muscle is regulated by high concentrations of BMPs, thus a single type of signalling molecule can determine crucial steps in muscle development: when and where to proliferate, and when and where to differentiate

miR126-5p Downregulation Facilitates Axon Degeneration and NMJ Disruption via a Non-Cell-Autonomous Mechanism in ALS.

Axon degeneration and disruption of neuromuscular junctions (NMJs) are key events in amyotrophic lateral sclerosis (ALS) pathology. Although the disease\u27s etiology is not fully understood, it is thought to involve a non-cell-autonomous mechanism and alterations in RNA metabolism. Here, we identified reduced levels of miR126-5p in presymptomatic ALS male mice models, and an increase in its targets: axon destabilizing Type 3 Semaphorins and their coreceptor Neuropilins. Using compartmentalize

Consideration of soil temperature in the modelling of early-age mass concrete slab

Modeling the structural behavior of concrete at early ages is one of the most challenging, yet fundamental, tasks for civil engineers working on mass concrete. To obtain a reasonably accurate model, a number of factors should be taken into account. Considerations should include both external influences as well as the changes occurring in the complex structure itself. The modeling of an early-age concrete massive slab requires the proper assignment of initial conditions, including the initial temperature of the analyzed element and the adjacent structures. The temperature distribution in the subsoil is the factor analyzed in this paper. The aim of the study is the determination of the temperature distribution in the ground, which is useful in the process related to the acquisition of the most accurate model of the analyzed structure and reflects the actual conditions in the numerical model. For this purpose, the analytical method described in the literature was applied and subsequently evaluated on the basis of the numerical calculation. The performed calculations allow the estimation of the depth representing the range of the influence of the temperature in the ground and the values of the temperatures corresponding to the successive layers of the subsoil. Moreover, aiming the optimization of the numerical analysis of the massive foundation slab, the legitimacy of such detailed consideration of the temperature development in the underlying subsoil was evaluated by the comparison with the temperature distribution in the slab obtained with simplified consideration of the constant soil temperature.The publication is financed by BKM-547/RB6/2018 resources. Funding provided by the Portuguese Foundation for Science and Technology (FCT) to the Research Project IntegraCrete PTDC/ECM EST/1056/2014 (POCI-01-0145-FEDER-016841), as well to the Research Unit ISISE (POCI-01- 0145-FEDER-007633) is also gratefully acknowledged

Comparative effectiveness of contact tracing interventions in the context of the COVID-19 pandemic: a systematic review

Contact tracing is a non-pharmaceutical intervention (NPI) widely used in the control of the COVID-19 pandemic. Its effectiveness may depend on a number of factors including the proportion of contacts traced, delays in tracing, the mode of contact tracing (e.g. forward, backward or bidirectional contact training), the types of contacts who are traced (e.g. contacts of index cases or contacts of contacts of index cases), or the setting where contacts are traced (e.g. the household or the workplace). We performed a systematic review of the evidence regarding the comparative effectiveness of contact tracing interventions. 78 studies were included in the review, 12 observational (ten ecological studies, one retrospective cohort study and one pre-post study with two patient cohorts) and 66 mathematical modelling studies. Based on the results from six of the 12 observational studies, contact tracing can be effective at controlling COVID-19. Two high quality ecological studies showed the incremental effectiveness of adding digital contact tracing to manual contact tracing. One ecological study of intermediate quality showed that increases in contact tracing were associated with a drop in COVID-19 mortality, and a pre-post study of acceptable quality showed that prompt contact tracing of contacts of COVID-19 case clusters / symptomatic individuals led to a reduction in the reproduction number R. Within the seven observational studies exploring the effectiveness of contact tracing in the context of the implementation of other non-pharmaceutical interventions, contact tracing was found to have an effect on COVID-19 epidemic control in two studies and not in the remaining five studies. However, a limitation in many of these studies is the lack of description of the extent of implementation of contact tracing interventions. Based on the results from the mathematical modelling studies, we identified the following highly effective policies: (1) manual contact tracing with high tracing coverage and either medium-term immunity, highly efficacious isolation/quarantine and/ or physical distancing (2) hybrid manual and digital contact tracing with high app adoption with highly effective isolation/ quarantine and social distancing, (3) secondary contact tracing, (4) eliminating contact tracing delays, (5) bidirectional contact tracing, (6) contact tracing with high coverage in reopening educational institutions. We also highlighted the role of social distancing to enhance the effectiveness of some of these interventions in the context of 2020 lockdown reopening. While limited, the evidence from observational studies shows a role for manual and digital contact tracing in controlling the COVID-19 epidemic. More empirical studies accounting for the extent of contact tracing implementation are required.Peer Reviewe

Surface integrity of new dry-electropolishing technology on WC-Co cemented carbides

This study is focused on WC-Co dry-electropolished by DryLyte® technology that allows to obtain corrosion-free surfaces with a roughness below 9 nm. The main goal behind this research is to investigate the surface integrity trying to correlate the remanent microstructure after different dry-electropolishing times as a function of the hardness and elastic modulus evolution though massive nanoindentation. The quality of the surfacehas been evaluated by using advanced characterization techniques and the mechanical response treated by using the statistical methodology proposed by Ulm and Constantinides. To sum up, a close correlation is observed between the residual microstructure and the surface integrity in terms of hardness and elastic modulus maps.Peer ReviewedPostprint (published version

3D Time-lapse Imaging and Quantification of Mitochondrial Dynamics

We present a 3D time-lapse imaging method for monitoring mitochondrial dynamics in living HeLa cells based on photothermal optical coherence microscopy and using novel surface functionalization of gold nanoparticles. The biocompatible protein-based biopolymer coating contains multiple functional groups which impart better cellular uptake and mitochondria targeting efficiency. The high stability of the gold nanoparticles allows continuous imaging over an extended time up to 3000 seconds without significant cell damage. By combining temporal autocorrelation analysis with a classical diffusion model, we quantify mitochondrial dynamics and cast these results into 3D maps showing the heterogeneity of diffusion parameters across the whole cell volume

Perturbed actin cap as a new personalized biomarker in primary fibroblasts of Huntington’s disease patients

Primary fibroblasts from patient’s skin biopsies are directly isolated without any alteration in the genome, retaining in culture conditions their endogenous cellular characteristics and biochemical properties. The aim of this study was to identify a distinctive cell phenotype for potential drug evaluation in fibroblasts from Huntington’s Disease (HD) patients, using image-based high content analysis. We show that HD fibroblasts have a distinctive nuclear morphology associated with a nuclear actin cap deficiency. This in turn affects cell motility in a similar manner to fibroblasts from Hutchinson-Gilford progeria syndrome (HGPS) patients used as known actin cap deficient cells. Moreover, treatment of the HD cells with either Latrunculin B, used to disrupt actin cap formation, or the antioxidant agent Mitoquinone, used to improve mitochondrial activity, show expected opposite effects on actin cap associated morphological features and cell motility. Deep data analysis allows strong cluster classification within HD cells according to patients’ disease severity score which is distinct from HGPS and matching controls supporting that actin cap is a biomarker in HD patients’ cells correlated with HD severity status that could be modulated by pharmacological agents as tool for personalized drug evaluation

High frequency of central nervous system involvement in transformed Waldenstrom macroglobulinemia

Histologicaltransformation (HT) to diffuse large B-cell lymphoma (DLBCL) is a rare event in Waldenström macroglobulinemia (WM) and is associated with a poor prognosis.1-4 It confers an inferior outcome compared with WM patients without HT.2,3 Most transformed WM patients present with elevated serum lactate dehydrogenase (LDH) levels and extranodal disease.1 Among extranodal sites, the central nervous system (CNS) is one of the most frequently involved sites identified at diagnosis of transformed WM (ranging from 13% to 18%).1,3 However, the prognostic value of CNS involvement is unknown, and the rate of CNS involvement at relapse has not been previously reported in this setting.This work was supported by Cancer Research UK [C355/A26819], FC AECC, and AIRC under the “Accelerator Award Program” [EDITOR] to M.A. and R.G.-S

National institutions and subnational development in Africa

Few issues have received more inquiry in the social sciences than “”what are the fundamental determinants of comparative development?”” The institutional view asserts that the ultimate causes of underdevelopment are poorly performing institutional structures, such as lack of constraints on the executive, poor property-rights protection, as well as inefficient legal and court systems (see Acemoglu, Johnson and Robinson 2005 for a review and Acemoglu and Robinson 2012 for an influential popular argument). Other works downplay the role of formal institutions, emphasising instead the importance of geographical features, informal cultural norms, genetic, and epidemiological traits (see Spolaore and Wacziarg 2013 for a review, and Diamond 1997 and Landes 1998 on popular arguments on the importance of geography and culture, respectively)

A pre-intervention study of malaria vector abundance in Rio Muni, Equatorial Guinea: Their role in malaria transmission and the incidence of insecticide resistance alleles

BACKGROUND: Following the success of the malaria control intervention on the island of Bioko, malaria control by the use of indoor residual spraying (IRS) and long-lasting insecticide-treated nets (LLITN) was extended to Rio Muni, on the mainland part of Equatorial Guinea. This manuscript reports on the malaria vectors present and the incidence of insecticide resistant alleles prior to the onset of the programme. METHODS: Anopheles mosquitoes were captured daily using window traps at 30 sentinel sites in Rio Muni, from December 2006 to July 2007. The mosquitoes were identified to species and their sporozoite rates, knockdown resistance (kdr) and acetylcholinesterase (AChE) sensitivity measured, to define the role of vector species in malaria transmission and their potential susceptibility to insecticides. RESULTS: A total of 6,162 Anopheles mosquitoes were collected of which 4,808 were morphologically identified as Anopheles gambiae s.l., 120 Anopheles funestus, 1,069 Anopheles moucheti, and 165 Anopheles nili s.l.. Both M and S molecular forms of Anopheles gambiae s.s. and Anopheles melas were identified. Anopheles ovengensis and Anopheles carnevalei were the only two members of the An. nili group to be identified. Using the species-specific sporozoite rates and the average number of mosquitoes per night, the number of infective mosquitoes per trap per 100 nights for each species complex was calculated as a measure of transmission risk. Both kdr-w and kdr-e alleles were present in the S-form of An. gambiae s.s. (59% and 19% respectively) and at much lower frequencies in the M-form (9.7% and 1.8% respectively). The kdr-w and kdr-e alleles co-occurred in 103 S-form and 1 M-form specimens. No insensitive AChE was detected. CONCLUSION: Anopheles gambiae s.s, a member of the Anopheles gambiae complex was shown to be the major vector in Rio Muni with the other three groups playing a relatively minor role in transmission. The demonstration of a high frequency of kdr alleles in mosquito populations before the onset of a malaria control programme shows that continuous entomological surveillance including resistance monitoring will be of critical importance to ensure the chosen insecticide remains effective