Functional, morphological, and apoptotic alterations in skeletal muscle of ARC deficient mice

Apoptotic signaling plays an important role in the development and maintenance of healthy skeletal muscle. However, dysregulation of apoptotic signals in skeletal muscle is associated with atrophy and loss of function. Apoptosis repressor with caspase recruitment domain (ARC) is a potent anti-apoptotic protein that is highly expressed in skeletal muscle; however, its role in this tissue has yet to be elucidated. To investigate whether ARC deficiency has morphological, functional, and apoptotic consequences, skeletal muscle from 18 week-old wild-type and ARC knockout (KO) mice was studied. In red muscle (soleus), we found lower maximum tetanic force, as well as a shift towards a greater proportion of type II fibers in ARC KO mice. Furthermore, the soleus of ARC KO mice exhibited lower total, as well as fiber type-specific cross sectional area in type I and IIA fibers. Interestingly, these changes in ARC KO mice corresponded with increased DNA fragmentation, albeit independent of caspase or calpain activation. However, cytosolic fractions of red muscle from ARC KO mice had higher apoptosis inducing factor content, suggesting increased mitochondrial-mediated, caspase-independent apoptotic signaling. This was confirmed in isolated mitochondrial preparations, as mitochondria from skeletal muscle of ARC KO mice were more susceptible to calcium stress. Interestingly, white muscle from ARC KO mice showed no signs of altered apoptotic signaling or detrimental morphological differences. Results from this study suggest that even under basal conditions ARC influences muscle apoptotic signaling, phenotype, and function, particularly in slow and/or oxidative muscle

At Africa's Expense? Disaggregating the Social Impact of Chinese Mining Operations

Qualitative studies and media reports suggest that the presence of Chinese oil or mining companies generates resentments among local extractive communities due to low wages, poor working conditions, environmental degradation, the employment of foreign labour, and perceived racial discrimination. At the same time, Chinese investment in the extractive sector appears to enhance local infrastructure. So far, these claims have not been empirically tested in a systematic way. Relying on novel data on the control-rights regimes of diamond, gold, and copper mines and geo-referenced information from Afrobarometer surveys, this paper examines whether Chinese-controlled mining promotes anti-Chinese sentiments among the local populations of sub-Saharan African countries. In addition, we test the effect of mining contractors' nationality on socio-economic indicators such as local employment rates and infrastructure levels. Our logistic regression analysis for the period 1997-2014 reveals that the effect of Chinese mining companies on African local development is ambiguous: while proximity to Chinese-operated mines is associated with anti-Chinese sentiments and unemployment, populations living close to Chinese mining areas enjoy better infrastructure, such as paved roads or piped water. Multilevel mixed-effects estimations using district-level data from the Demographic Health Survey for 20 sub-Saharan countries corroborate these findings

Functional and structural insights into Sarcolipin, a regulator of the Sarco-endoplasmic reticulum Ca2+-ATPases

International audienceSarcolipin (SLN), a transmembrane peptide from sarcoplasmic reticulum, is one of the major proteins involved in the muscle contraction/relaxation process. A number of enzymological studies have underlined its regulatory role in connection with the SERCA1a activity. Indeed, SLN folds as a unique transmembrane helix and binds to SERCA1a in a groove close to transmembrane helices M2, M6, and M9, as proposed initially by cross-linking experiments and recently detailed in the 3D structures of the SLN–Ca2+-ATPase complex. In addition, association of SLN with SERCAs may depend on its phosphorylation. SLN possesses a peculiar C-terminus (RSYQY) critical for the regulation of the ATPases. This luminal tail appears to be essential for addressing SLN to the ER membrane. Moreover, we recently demonstrated that some SLN isoforms are acylated on cysteine 9, a feature which remained unnoticed so far even in the recent crystal structures of the SLN–SERCA1a complex. The removal of the fatty acid chain was shown to increase the activity of the membrane-embedded Ca2+-ATPase by about 20 %. The exact functional and structural role of this post-translational modification is presently unknown. Recent data are in favor of a key regulator role of SLN in muscle-based thermogenesis in mammals. The possible link of SLN to heat production could occur through an uncoupling of the SERCA1a-mediated ATP hydrolysis from calcium transport. Considering those particular features and the fact that SLN is not expressed at the same level in different tissues, the role of SLN and its exact mechanism of regulation remain sources of interrogation

Stratified analyses refine association between TLR7 rare variants and severe COVID-19

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10−10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (ORmax = 46.5, p = 1.74 × 10−15). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway