Skeletal muscle is one of the most dynamic and plastic tissues of the human body. In humans, skeletal muscle comprises approximately 40 % of total body weight and contains 50–75 % of all body ...proteins. In general, muscle mass depends on the balance between protein synthesis and degradation and both processes are sensitive to factors such as nutritional status, hormonal balance, physical activity/exercise, and injury or disease, among others. In this review, we discuss the various domains of muscle structure and function including its cytoskeletal architecture, excitation-contraction coupling, energy metabolism, and force and power generation. We will limit the discussion to human skeletal muscle and emphasize recent scientific literature on single muscle fibers.
Nuclear compartments have diverse roles in regulating gene expression, yet the molecular forces and components that drive compartment formation remain largely unclear
. The long non-coding RNA Xist ...establishes an intra-chromosomal compartment by localizing at a high concentration in a territory spatially close to its transcription locus
and binding diverse proteins
to achieve X-chromosome inactivation (XCI)
. The XCI process therefore serves as a paradigm for understanding how RNA-mediated recruitment of various proteins induces a functional compartment. The properties of the inactive X (Xi)-compartment are known to change over time, because after initial Xist spreading and transcriptional shutoff a state is reached in which gene silencing remains stable even if Xist is turned off
. Here we show that the Xist RNA-binding proteins PTBP1
, MATR3
, TDP-43
and CELF1
assemble on the multivalent E-repeat element of Xist
and, via self-aggregation and heterotypic protein-protein interactions, form a condensate
in the Xi. This condensate is required for gene silencing and for the anchoring of Xist to the Xi territory, and can be sustained in the absence of Xist. Notably, these E-repeat-binding proteins become essential coincident with transition to the Xist-independent XCI phase
, indicating that the condensate seeded by the E-repeat underlies the developmental switch from Xist-dependence to Xist-independence. Taken together, our data show that Xist forms the Xi compartment by seeding a heteromeric condensate that consists of ubiquitous RNA-binding proteins, revealing an unanticipated mechanism for heritable gene silencing.
Western Cambodia is recognized as the epicenter of Plasmodium falciparum multidrug resistance. Recent reports of the efficacy of dihydroartemisinin (DHA)-piperaquine (PP), the latest of the ...artemisinin-based combination therapies (ACTs) recommended by the WHO, have prompted further investigations. The clinical efficacy of dihydroartemisinin-piperaquine in uncomplicated falciparum malaria was assessed in western and eastern Cambodia over 42 days. Day 7 plasma piperaquine concentrations were measured and day 0 isolates tested for in vitro susceptibilities to piperaquine and mefloquine, polymorphisms in the K13 gene, and the copy number of the Pfmdr-1 gene. A total of 425 patients were recruited in 2011 to 2013. The proportion of patients with recrudescent infections was significantly higher in western (15.4%) than in eastern (2.5%) Cambodia (P <10(-3)). Day 7 plasma PP concentrations and median 50% inhibitory concentrations (IC50) of PP were independent of treatment outcomes, in contrast to median mefloquine IC50, which were found to be lower for isolates from patients with recrudescent infections (18.7 versus 39.7 nM; P = 0.005). The most significant risk factor associated with DHA-PP treatment failure was infection by parasites carrying the K13 mutant allele (odds ratio OR, 17.5; 95% confidence interval CI, 1 to 308; P = 0.04). Our data show evidence of P. falciparum resistance to PP in western Cambodia, an area of widespread artemisinin resistance. New therapeutic strategies, such as the use of triple ACTs, are urgently needed and must be tested. (This study has been registered at the Australian New Zealand Clinical Trials Registry under registration no. ACTRN12614000344695.).
Interferons (IFNs) are a family of cytokines with the unique ability to induce cell intrinsic programs that enhance resistance to viral infection. Induction of an antiviral state at the cell, tissue, ...organ, and organismal level is performed by three distinct IFN families, designated as Type-I, Type-II, and Type-III IFNs. Overall, there are 21 human IFNs, (16 type-I, 12 IFNαs, IFNβ, IFNϵ, IFNκ, and IFNω; 1 type-II, IFNγ; and 4 type-III, IFNλ1, IFNλ2, IFNλ3, and IFNλ4), that induce pleotropic cellular activities essential for innate and adaptive immune responses against virus and other pathogens. IFN signaling is initiated by binding to distinct heterodimeric receptor complexes. The three-dimensional structures of the type-I (IFNα/IFNAR1/IFNAR2), type-II (IFNγ/IFNGR1/IFNGR2), and type-III (IFNλ3/IFNλR1/IL10R2) signaling complexes have been determined. Here, we highlight similar and unique features of the IFNs, their cell surface complexes and discuss their role in inducing downstream IFN signaling responses.
The rapid spread of Zika virus (ZIKV) and its association with abnormal brain development constitute a global health emergency. Congenital ZIKV infection produces a range of mild to severe ...pathologies, including microcephaly. To understand the pathophysiology of ZIKV infection, we used models of the developing brain that faithfully recapitulate the tissue architecture in early to midgestation. We identify the brain cell populations that are most susceptible to ZIKV infection in primary human tissue, provide evidence for a mechanism of viral entry, and show that a commonly used antibiotic protects cultured brain cells by reducing viral proliferation. In the brain, ZIKV preferentially infected neural stem cells, astrocytes, oligodendrocyte precursor cells, and microglia, whereas neurons were less susceptible to infection. These findings suggest mechanisms for microcephaly and other pathologic features of infants with congenital ZIKV infection that are not explained by neural stem cell infection alone, such as calcifications in the cortical plate. Furthermore, we find that blocking the glia-enriched putative viral entry receptor AXL reduced ZIKV infection of astrocytes in vitro, and genetic knockdown of AXL in a glial cell line nearly abolished infection. Finally, we evaluate 2,177 compounds, focusing on drugs safe in pregnancy. We show that the macrolide antibiotic azithromycin reduced viral proliferation and virus-induced cytopathic effects in glial cell lines and human astrocytes. Our characterization of infection in the developing human brain clarifies the pathogenesis of congenital ZIKV infection and provides the basis for investigating possible therapeutic strategies to safely alleviate or prevent the most severe consequences of the epidemic.
•Forty-two publications with analytical data on NCS have been identified.•NCS has nutritionally significant quantities of minerals and vitamins.•It presents antioxidant properties correlated with its ...phenolics content.•These results justify considering NCS a nutritional and functionally important food.
Non-centrifugal cane sugar (NCS) (panela, jaggery, kokuto, etc.) is a traditional sweetener of increasingly economic importance after a long process of displacement by refined sugar. By searching the analytical literature with the different local names of NCS (jaggery, gur, kokuto, panela, chancaca, piloncillo, rapadura, muscovado, unrefined sugar, black sugar) as key-words, this review identified the published data on its content of 7 proximate, 14 minerals, and 13 vitamins so to calculate its average and median values, as well as list its contents of potentially relevant functional components like phenolics, amino acids, complex sugars and others. The forty-two publications on chemical content and properties found to show that NCS has nutritionally and functionally significant quantities of minerals, vitamins and phenolics, among other constituents, as well as antioxidant capacities. This justifies its inclusion in food composition databases and in reviews of antioxidant properties and phenolic contents of foods. Higher awareness of the nutritional and functional properties of NCS could increase scientific, nutritional and health interest in this food.
Summary Background Artemisinin resistance in Plasmodium falciparum lengthens parasite clearance half-life during artemisinin monotherapy or artemisinin-based combination therapy. Absence of in-vitro ...and ex-vivo correlates of artemisinin resistance hinders study of this phenotype. We aimed to assess whether an in-vitro ring-stage survival assay (RSA) can identify culture-adapted P falciparum isolates from patients with slow-clearing or fast-clearing infections, to investigate the stage-dependent susceptibility of parasites to dihydroartemisinin in the in-vitro RSA, and to assess whether an ex-vivo RSA can identify artemisinin-resistant P falciparum infections. Methods We culture-adapted parasites from patients with long and short parasite clearance half-lives from a study done in Pursat, Cambodia, in 2010 (registered with ClinicalTrials.gov , number NCT00341003 ) and used novel in-vitro survival assays to explore the stage-dependent susceptibility of slow-clearing and fast-clearing parasites to dihydroartemisinin. In 2012, we implemented the RSA in prospective parasite clearance studies in Pursat, Preah Vihear, and Ratanakiri, Cambodia ( NCT01736319 ), to measure the ex-vivo responses of parasites from patients with malaria. Continuous variables were compared with the Mann-Whitney U test. Correlations were analysed with the Spearman correlation test. Findings In-vitro survival rates of culture-adapted parasites from 13 slow-clearing and 13 fast-clearing infections differed significantly when assays were done on 0–3 h ring-stage parasites (10·88% vs 0·23%; p=0·007). Ex-vivo survival rates significantly correlated with in-vivo parasite clearance half-lives (n=30, r =0·74, 95% CI 0·50–0·87; p<0·0001). Interpretation The in-vitro RSA of 0–3 h ring-stage parasites provides a platform for the molecular characterisation of artemisinin resistance. The ex-vivo RSA can be easily implemented where surveillance for artemisinin resistance is needed. Funding Institut Pasteur du Cambodge and the Intramural Research Program, NIAID, NIH.
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