Duchenne muscular dystrophy is the most common neuromuscular genetic disorder. This review describes the identification of the cause of the disorder in the late 1980s—dystrophin deficiency—and the ...emerging therapeutics enabled by increased understanding of dystrophin structure and function. Image from Duchenne, Guillaume‐Benjamin (1868). "De la paralysie musculaire pseudo‐hypertrophique, ou paralysie myo‐sclérosique". Arch. Gen. Med. Bibliothèque nationale de France. 11: 5–25, 179–209, 305–321, 421–443, 552–588.
Duchenne muscular dystrophy was a well‐established medical and genetic enigma by the 1970s. Why was the new mutation rate so high in all world populations? Why were affected boys doing well in early childhood, but then showed relentless progression of muscle wasting? What was wrong with the muscle? The identification of the first fragments of DMD gene cDNA in 1986, prediction of the entire 3685 amino acid protein sequence, and production of antibodies to dystrophin, both in 1987, provided key tools to understand DMD genetics and molecular pathology. The identification of dystrophin nucleated extensive research on myofiber membrane cytoskeleton, membrane repair, muscle regeneration, and failure of regeneration. This in turn led to molecular therapeutics based on understanding of dystrophin structure and function. This historical perspective describes the events surrounding the initial identification of the dystrophin protein.
Geochemical, paleomagnetic, and geochronological data increasingly support the Snowball Earth hypothesis for Cryogenian glaciations. Yet, the fossil record reveals no clear‐cut evolutionary ...bottleneck. Climate models and the modern cryobiosphere offer insights on this paradox. Recent modeling implies that Snowball continents never lacked ice‐free areas. Wind‐blown dust from these areas plus volcanic ash were trapped by snow on ice sheets and sea ice. At a Snowball onset, sea ice was too thin to flow and ablative ice was too cold for dust retention. After a few millenia, sea ice reached 100 s of meters in thickness and began to flow as a ‘sea glacier’ toward an equatorial ablation zone. At first, dust advected to the ablative surface was recycled by winds, but as the surface warmed with rising CO2, dust aka cryoconite began to accumulate. As a sea glacier has no terminus, cryoconite saturated the surface. It absorbed solar radiation, supported cyanobacterial growth, and sank to an equilibrium depth forming holes and decameter‐scale pans of meltwater. As meltwater production rose, drainages developed, connecting pans to moulins, where meltwater was flushed into the subglacial ocean. Flushing cleansed the surface, creating a stabilizing feedback. If the dust flux rose, cryoconite was removed; if the dust flux waned, cryoconite accumulated. In addition to cyanobacteria, modern cryoconite holes are inhabited by green algae, fungi, protists, and certain metazoans. On Snowball Earth, cryoconite pans provided stable interconnected habitats for eukaryotes tolerant of fresh to brackish cold water on an ablation surface 60 million km2 in area. Flushing and burial of organic matter was a potential source of atmospheric oxygen. Dominance of green algae among Ediacaran eukaryotic primary producers is a possible legacy of Cryogenian cryoconite pans, but a schizohaline ocean—supraglacial freshwater and subglacial brine—may have exerted selective stress on early metazoans, or impeded their evolution.
Atherosclerosis is a chronic inflammatory disease that has its origins in childhood. The goal of this study was to explore the relationships of hematologic inflammatory markers to body mass, ...biochemical inflammatory markers and cardiometabolic risk factors.
Healthy, white, non-Hispanic identifying adolescents (n = 75, age 12 to 18 years) were enrolled. Measures studied included body mass index percentile (BMI%), neutrophil and platelet to lymphocyte ratio (NLR, PLR), pan immune inflammation value (PIV), lipids, augmentation index, reactive hyperemia, inflammatory markers (interleukin 6: IL6, c-reactive protein: CRP), complement (C3, C3a, C4, C4a, C5a) insulin secretion and insulin sensitivity (oral glucose tolerance test: Matusda index, and disposition index (DI)).
NLR (r
= 0.31, p < 0.01), PLR (r
= 0.32, p < 0.01), PIV (r
= 0.32, p < 0.01) and CRP (r
= 0.51, p < 0.001) all positively correlated with BMI% but IL-6 did not. NLR, PLR and PIV all positively correlated with each other. NLR correlated with the reactive hyperemia response (r
= 0.29, p < 0.02) but this relationship was lost when BMI% was included. NLR positively correlated with C3a, C4, CRP and IL6 even when BMI% was included.
In healthy adolescents hematologic markers of inflammation increase with increasing body mass and neutrocyte to lymphocyte ratio is associated with increased complement and inflammatory markers independent of obesity.
Hematologic and biochemical markers of inflammation increase with increased body mass in healthy adolescents. Hematologic and biochemical markers of inflammation are positively related independent of body mass in healthy adolescents. Hematologic inflammatory markers are not related to markers of cardiometabolic risk in healthy adolescents.
Patients with Duchenne muscular dystrophy (DMD) show clinically relevant phenotypic variability, despite sharing the same primary biochemical defect (dystrophin deficiency). Factors contributing to ...this clinical variability include allelic heterogeneity (specific DMD mutations), genetic modifiers (trans-acting genetic polymorphisms) and variations in clinical care. Recently, a series of genetic modifiers have been identified, mostly involving genes and/or proteins that regulate inflammation and fibrosis - processes increasingly recognized as being causally linked with physical disability. This article reviews genetic modifier studies in DMD to date and discusses the effect of genetic modifiers on predicting disease trajectories (prognosis), clinical trial design and interpretation (inclusion of genotype-stratified subgroup analyses) and therapeutic approaches. The genetic modifiers identified to date underscore the importance of progressive fibrosis, downstream of dystrophin deficiency, in driving the disease process. As such, genetic modifiers have shown the importance of therapies aimed at slowing this fibrotic process and might point to key drug targets.
The maintenance of a progenitor cell population as a reservoir of undifferentiated cells is required for organ development and regeneration. However, the mechanisms by which epithelial progenitor ...cells are maintained during organogenesis are poorly understood. We report that removal of the parasympathetic ganglion in mouse explant organ culture decreased the number and morphogenesis of keratin 5-positive epithelial progenitor cells. These effects were rescued with an acetylcholine analog. We demonstrate that acetylcholine signaling, via the muscarinic M1 receptor and epidermal growth factor receptor, increased epithelial morphogenesis and proliferation of the keratin 5-positive progenitor cells. Parasympathetic innervation maintained the epithelial progenitor cell population in an undifferentiated state, which was required for organogenesis. This mechanism for epithelial progenitor cell maintenance may be targeted for organ repair or regeneration.
Within cells, the spatial compartmentalization of thousands of distinct proteins serves a multitude of diverse biochemical needs. Correlative super-resolution (SR) fluorescence and electron ...microscopy (EM) can elucidate protein spatial relationships to global ultrastructure, but has suffered from tradeoffs of structure preservation, fluorescence retention, resolution, and field of view. We developed a platform for three-dimensional cryogenic SR and focused ion beam-milled block-face EM across entire vitreously frozen cells. The approach preserves ultrastructure while enabling independent SR and EM workflow optimization. We discovered unexpected protein-ultrastructure relationships in mammalian cells including intranuclear vesicles containing endoplasmic reticulum-associated proteins, web-like adhesions between cultured neurons, and chromatin domains subclassified on the basis of transcriptional activity. Our findings illustrate the value of a comprehensive multimodal view of ultrastructural variability across whole cells.
Interpretations of major climatic and biological events in Earth history are, in large part, derived from the stable carbon isotope records of carbonate rocks and sedimentary organic matter. ...Neoproterozoic carbonate records contain unusual and large negative isotopic anomalies within long periods (10-100 million years) characterized by δ(13)C in carbonate (δ(13)C(carb)) enriched to more than +5 per mil. Classically, δ(13)C(carb) is interpreted as a metric of the relative fraction of carbon buried as organic matter in marine sediments, which can be linked to oxygen accumulation through the stoichiometry of primary production. If a change in the isotopic composition of marine dissolved inorganic carbon is responsible for these excursions, it is expected that records of δ(13)C(carb) and δ(13)C in organic carbon (δ(13)C(org)) will covary, offset by the fractionation imparted by primary production. The documentation of several Neoproterozoic δ(13)C(carb) excursions that are decoupled from δ(13)C(org), however, indicates that other mechanisms may account for these excursions. Here we present δ(13)C data from Mongolia, northwest Canada and Namibia that capture multiple large-amplitude (over 10 per mil) negative carbon isotope anomalies, and use these data in a new quantitative mixing model to examine the behaviour of the Neoproterozoic carbon cycle. We find that carbonate and organic carbon isotope data from Mongolia and Canada are tightly coupled through multiple δ(13)C(carb) excursions, quantitatively ruling out previously suggested alternative explanations, such as diagenesis or the presence and terminal oxidation of a large marine dissolved organic carbon reservoir. Our data from Namibia, which do not record isotopic covariance, can be explained by simple mixing with a detrital flux of organic matter. We thus interpret δ(13)C(carb) anomalies as recording a primary perturbation to the surface carbon cycle. This interpretation requires the revisiting of models linking drastic isotope excursions to deep ocean oxygenation and the opening of environments capable of supporting animals.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Immunological and inflammatory processes downstream of dystrophin deficiency as well as metabolic abnormalities, defective autophagy, and loss of regenerative capacity all contribute to muscle ...pathology in Duchenne muscular dystrophy (DMD). These downstream cascades offer potential avenues for pharmacological intervention. Modulating the inflammatory response and inducing immunological tolerance to de novo dystrophin expression will be critical to the success of dystrophin-replacement therapies. This Review focuses on the role of the inflammatory response in DMD pathogenesis and opportunities for clinical intervention.
Epithelial-mesenchymal interactions are required to coordinate cell proliferation, patterning, and functional differentiation of multiple cell types in a developing organ. This exquisite coordination ...is dependent on various secreted molecules that provide developmental signals to mediate these tissue interactions. Recently, it was reported that mature mesenchymal-derived microRNAs (miRNAs) in the fetal mouse salivary gland are loaded into exosomes, and transported to the epithelium where they influence progenitor cell proliferation. The exosomal miRNAs regulated epithelial expression of genes involved in DNA methylation in progenitor cells to influence morphogenesis. Thus, exosomal miRNAs are mobile genetic signals that cross tissue boundaries within an organ. These findings raise many questions about how miRNA signals are initiated to coordinate organogenesis and whether they are master regulators of epithelial-mesenchymal interactions. The development of therapeutic applications using exosomal miRNAs for the regeneration of damaged adult organs is a promising area of research.
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