Adult mammals have lost multi-tissue regenerative capacity, except for the distal digit, which is able to regenerate via mechanisms that remain largely unknown. Here, we show that, after adult mouse ...distal digit removal, nerve-associated Schwann cell precursors (SCPs) dedifferentiate and secrete growth factors that promote expansion of the blastema and digit regeneration. When SCPs were dysregulated or ablated, mesenchymal precursor proliferation in the blastema was decreased and nail and bone regeneration were impaired. Transplantation of exogenous SCPs rescued these regeneration defects. We found that SCPs secrete factors that promote self-renewal of mesenchymal precursors, and we used transcriptomic and proteomic analysis to define candidate factors. Two of these, oncostatin M (OSM) and platelet-derived growth factor AA (PDGF-AA), are made by SCPs in the regenerating digit and rescued the deficits in regeneration caused by loss of SCPs. As all peripheral tissues contain nerves, these results could have broad implications for mammalian tissue repair and regeneration.
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•Schwann cell precursors (SCPs) enter the regenerating digit tip•Ablation of SCPs by inducible deletion or denervation inhibits regeneration•SCPs secrete growth factors to promote mesenchymal cell proliferation•Oncostatin M and PDGF-AA can rescue regeneration in a denervated digit tip
Johnston et al. show that, during regeneration of the mouse digit tip, nerve-associated Schwann cell precursors dedifferentiate and move into the injured tissue, where they secrete paracrine factors, including oncostatin M and PDGF-AA, to promote mesenchymal cell proliferation, expansion of the blastema, and regeneration.
Adiponectin regulates metabolism through blood glucose control and fatty acid oxidation, partly mediated by downstream effects of adiponectin signaling in skeletal muscle. More recently, skeletal ...muscle has been identified as a source of adiponectin expression, fueling interest in the role of adiponectin as both a circulating adipokine and a locally expressed paracrine/autocrine factor. In addition to being metabolically responsive, skeletal muscle functional capacity, calcium handling, growth and maintenance, regenerative capacity, and susceptibility to chronic inflammation are all strongly influenced by adiponectin stimulation. Furthermore, physical exercise has clear links to adiponectin expression and circulating concentrations in healthy and diseased populations. Greater physical activity is generally related to higher adiponectin expression while lower adiponectin levels are found in inactive obese, pre-diabetic, and diabetic populations. Exercise training typically restores plasma adiponectin and is associated with improved insulin sensitivity. Thus, the role of adiponectin signaling in skeletal muscle has expanded beyond that of a metabolic regulator to include several aspects of skeletal muscle function and maintenance critical to muscle health, many of which are responsive to, and mediated by, physical exercise.
The contrasting patterns of lake-level fluctuations across the Tibetan Plateau (TP) are indicators of differences in the water balance over the TP. However, little is known about the key hydrological ...factors controlling this variability. The purpose of this study is to contribute to a more quantitative understanding of these factors for four selected lakes in the southern-central part of the TP: Nam Co and Tangra Yumco (increasing water levels), and Mapam Yumco and Paiku Co (stable or slightly decreasing water levels). We present the results of an integrated approach combining hydrological modeling, atmospheric-model output and remote-sensing data. The J2000g hydrological model was adapted and extended according to the specific characteristics of closed-lake basins on the TP and driven with High Asia Refined analysis (HAR) data at 10 km resolution for the period 2001–2010. Differences in the mean annual water balances among the four basins are primarily related to higher precipitation totals and attributed runoff generation in the Nam Co and Tangra Yumco basins. Precipitation and associated runoff are the main driving forces for inter-annual lake variations. The glacier-meltwater contribution to the total basin runoff volume (between 14 and 30 % averaged over the 10-year period) plays a less important role compared to runoff generation from rainfall and snowmelt in non-glacierized land areas. Nevertheless, using a hypothetical ice-free scenario in the hydrological model, we indicate that ice-melt water constitutes an important water-supply component for Mapam Yumco and Paiku Co, in order to maintain a state close to equilibrium, whereas the water balance in the Nam Co and Tangra Yumco basins remains positive under ice-free conditions. These results highlight the benefits of linking hydrological modeling with atmospheric-model output and satellite-derived data, and the presented approach can be readily transferred to other data-scarce closed lake basins, opening new directions of research. Future work should go towards a better assessment of the model-chain uncertainties, especially in this region where observation data are scarce.
Borrelia miyamotoi is a relapsing fever Borrelia group spirochete that is transmitted by the same hard-bodied (ixodid) tick species that transmit the agents of Lyme disease. It was discovered in 1994 ...in Ixodes persulcatus ticks in Japan. B. miyamotoi species phylogenetically cluster with the relapsing fever group spirochetes, which usually are transmitted by soft-bodied (argasid) ticks or lice. B. miyamotoi infects at least six Ixodes tick species in North America and Eurasia that transmit Lyme disease group spirochetes and may use small rodents and birds as reservoirs. Human cases of B. miyamotoi infection were first reported in 2011 in Russia and subsequently in the United States, Europe and Japan. These reports document the public health importance of B. miyamotoi, as human B. miyamotoi infection appears to be comparable in frequency to babesiosis or human granulocytic anaplasmosis in some areas and may cause severe disease, including meningoencephalitis. The most common clinical manifestations of B. miyamotoi infection are fever, fatigue, headache, chills, myalgia, arthralgia, and nausea. Symptoms of B. miyamotoi infection generally resolve within a week of the start of antibiotic therapy. B. miyamotoi infection should be considered in patients with acute febrile illness who have been exposed to Ixodes ticks in a region where Lyme disease occurs. Because clinical manifestations are nonspecific, etiologic diagnosis requires confirmation by blood smear examination, PCR, antibody assay, in vitro cultivation, and/or isolation by animal inoculation. Antibiotics that have been used effectively include doxycycline for uncomplicated B. miyamotoi infection in adults and ceftriaxone or penicillin G for meningoencephalitis.
Detectors based on liquid argon (LAr) often require surfaces that can shift vacuum ultraviolet (VUV) light and reflect the visible shifted light. For the LAr instrumentation of the LEGEND-200 ...neutrinoless double beta decay experiment, several square meters of wavelength-shifting reflectors (WLSR) were prepared: the reflector Tetratex® (TTX) was in-situ evaporated with the wavelength shifter tetraphenyl butadiene (TPB). For even larger detectors, TPB evaporation will be more challenging and plastic films of polyethylene naphthalate (PEN) are considered as an option to ease scalability. In this work, we first characterized the absorption (and reflectivity) of PEN, TPB (and TTX) films in response to visible light. We then measured TPB and PEN coupled to TTX in a LAr setup equipped with a VUV sensitive photomultiplier tube. The effective VUV photon yield in the setup was first measured using an absorbing reference sample, and the VUV reflectivity of TTX quantified. The characterization and simulation of the setup along with the measurements and modelling of the optical parameters of TPB, PEN and TTX allowed to estimate the absolute quantum efficiency (QE) of TPB and PEN in LAr (at 87K) for the first time: these were found to be above 67 and 49%, respectively (at 90% CL). These results provide relevant input for the optical simulations of experiments that use TPB in LAr, such as LEGEND-200, and for experiments that plan to use TPB or PEN to shift VUV scintillation light.
Ankrd11 is a potential chromatin regulator implicated in neural development and autism spectrum disorder (ASD) with no known function in the brain. Here, we show that knockdown of Ankrd11 in ...developing murine or human cortical neural precursors caused decreased proliferation, reduced neurogenesis, and aberrant neuronal positioning. Similar cellular phenotypes and aberrant ASD-like behaviors were observed in Yoda mice carrying a point mutation in the Ankrd11 HDAC-binding domain. Consistent with a role for Ankrd11 in histone acetylation, Ankrd11 was associated with chromatin and colocalized with HDAC3, and expression and histone acetylation of Ankrd11 target genes were altered in Yoda neural precursors. Moreover, the Ankrd11 knockdown-mediated decrease in precursor proliferation was rescued by inhibiting histone acetyltransferase activity or expressing HDAC3. Thus, Ankrd11 is a crucial chromatin regulator that controls histone acetylation and gene expression during neural development, thereby providing a likely explanation for its association with cognitive dysfunction and ASD.
•Ankrd11 regulates proliferation and neurogenesis in the embryonic brain•Ankrd11 mutation causes cortical abnormalities and ASD-like behavior•Ankrd11 is associated with chromatin and colocalizes with HDAC3•Ankrd11 mutation alters histone acetylation and gene expression in neural precursors
Gallagher et al. identify the ASD-associated protein Ankrd11 as a transcriptional coregulator essential for embryonic cortical development. Ankrd11 regulates histone acetylation and gene expression and thus controls precursor proliferation and neuronal genesis and positioning. Ankrd11 mutant mice display abnormal cortical development and ASD-like behaviors, thereby modeling the human situation.
...the initial trials comparing COVID-19 vaccines versus placebo should seek reliable evidence not only of some efficacy but of worthwhile efficacy. ...although efficacy far greater than 50% would be ...better, efficacy of about 50% would represent substantial progress. Evaluation of multiple COVID-19 vaccines with standardised methodology will facilitate regulatory and deployment decisions.7 Unless such decisions are informed by reliable randomised evidence, the effect on public acceptance of COVID-19 vaccines could adversely affect COVID-19 control and the uptake of vaccines against other diseases.8 The WHO Solidarity Vaccines Trial9 (figure) aims to evaluate efficiently and rapidly (within 3–6 months of each vaccine's introduction into the study) the efficacy of multiple vaccines,10 helping to ensure that weakly effective vaccines are not deployed.
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