Impairment of circulating endothelial progenitors in Down syndrome

<p>Abstract</p> <p>Background</p> <p>Pathological angiogenesis represents a critical issue in the progression of many diseases. Down syndrome is postulated to be a systemic anti-angiogenesis disease model, possibly due to increased expression of anti-angiogenic regulators on chromosome 21. The aim of our study was to elucidate some features of circulating endothelial progenitor cells in the context of this syndrome.</p> <p>Methods</p> <p>Circulating endothelial progenitors of Down syndrome affected individuals were isolated, <it>in vitro </it>cultured and analyzed by confocal and transmission electron microscopy. ELISA was performed to measure SDF-1α plasma levels in Down syndrome and euploid individuals. Moreover, qRT-PCR was used to quantify expression levels of <it>CXCL12 </it>gene and of its receptor in progenitor cells. The functional impairment of Down progenitors was evaluated through their susceptibility to hydroperoxide-induced oxidative stress with BODIPY assay and the major vulnerability to the infection with human pathogens. The differential expression of crucial genes in Down progenitor cells was evaluated by microarray analysis.</p> <p>Results</p> <p>We detected a marked decrease of progenitors' number in young Down individuals compared to euploid, cell size increase and some major detrimental morphological changes. Moreover, Down syndrome patients also exhibited decreased SDF-1α plasma levels and their progenitors had a reduced expression of SDF-1α encoding gene and of its membrane receptor. We further demonstrated that their progenitor cells are more susceptible to hydroperoxide-induced oxidative stress and infection with Bartonella henselae. Further, we observed that most of the differentially expressed genes belong to angiogenesis, immune response and inflammation pathways, and that infected progenitors with trisomy 21 have a more pronounced perturbation of immune response genes than infected euploid cells.</p> <p>Conclusions</p> <p>Our data provide evidences for a reduced number and altered morphology of endothelial progenitor cells in Down syndrome, also showing the higher susceptibility to oxidative stress and to pathogen infection compared to euploid cells, thereby confirming the angiogenesis and immune response deficit observed in Down syndrome individuals.</p

Transcriptome Analysis of Neisseria meningitidis in Human Whole Blood and Mutagenesis Studies Identify Virulence Factors Involved in Blood Survival

During infection Neisseria meningitidis (Nm) encounters multiple environments within the host, which makes rapid adaptation a crucial factor for meningococcal survival. Despite the importance of invasion into the bloodstream in the meningococcal disease process, little is known about how Nm adapts to permit survival and growth in blood. To address this, we performed a time-course transcriptome analysis using an ex vivo model of human whole blood infection. We observed that Nm alters the expression of ≈30% of ORFs of the genome and major dynamic changes were observed in the expression of transcriptional regulators, transport and binding proteins, energy metabolism, and surface-exposed virulence factors. In particular, we found that the gene encoding the regulator Fur, as well as all genes encoding iron uptake systems, were significantly up-regulated. Analysis of regulated genes encoding for surface-exposed proteins involved in Nm pathogenesis allowed us to better understand mechanisms used to circumvent host defenses. During blood infection, Nm activates genes encoding for the factor H binding proteins, fHbp and NspA, genes encoding for detoxifying enzymes such as SodC, Kat and AniA, as well as several less characterized surface-exposed proteins that might have a role in blood survival. Through mutagenesis studies of a subset of up-regulated genes we were able to identify new proteins important for survival in human blood and also to identify additional roles of previously known virulence factors in aiding survival in blood. Nm mutant strains lacking the genes encoding the hypothetical protein NMB1483 and the surface-exposed proteins NalP, Mip and NspA, the Fur regulator, the transferrin binding protein TbpB, and the L-lactate permease LctP were sensitive to killing by human blood. This increased knowledge of how Nm responds to adaptation in blood could also be helpful to develop diagnostic and therapeutic strategies to control the devastating disease cause by this microorganism

Long-term kidney function recovery and mortality after COVID-19-associated acute kidney injury: An international multi-centre observational cohort study

Background: While acute kidney injury (AKI) is a common complication in COVID-19, data on post-AKI kidney function recovery and the clinical factors associated with poor kidney function recovery is lacking. Methods: A retrospective multi-centre observational cohort study comprising 12,891 hospitalized patients aged 18 years or older with a diagnosis of SARS-CoV-2 infection confirmed by polymerase chain reaction from 1 January 2020 to 10 September 2020, and with at least one serum creatinine value 1–365 days prior to admission. Mortality and serum creatinine values were obtained up to 10 September 2021. Findings: Advanced age (HR 2.77, 95%CI 2.53–3.04, p < 0.0001), severe COVID-19 (HR 2.91, 95%CI 2.03–4.17, p < 0.0001), severe AKI (KDIGO stage 3: HR 4.22, 95%CI 3.55–5.00, p < 0.0001), and ischemic heart disease (HR 1.26, 95%CI 1.14–1.39, p < 0.0001) were associated with worse mortality outcomes. AKI severity (KDIGO stage 3: HR 0.41, 95%CI 0.37–0.46, p < 0.0001) was associated with worse kidney function recovery, whereas remdesivir use (HR 1.34, 95%CI 1.17–1.54, p < 0.0001) was associated with better kidney function recovery. In a subset of patients without chronic kidney disease, advanced age (HR 1.38, 95%CI 1.20–1.58, p < 0.0001), male sex (HR 1.67, 95%CI 1.45–1.93, p < 0.0001), severe AKI (KDIGO stage 3: HR 11.68, 95%CI 9.80–13.91, p < 0.0001), and hypertension (HR 1.22, 95%CI 1.10–1.36, p = 0.0002) were associated with post-AKI kidney function impairment. Furthermore, patients with COVID-19-associated AKI had significant and persistent elevations of baseline serum creatinine 125% or more at 180 days (RR 1.49, 95%CI 1.32–1.67) and 365 days (RR 1.54, 95%CI 1.21–1.96) compared to COVID-19 patients with no AKI. Interpretation: COVID-19-associated AKI was associated with higher mortality, and severe COVID-19-associated AKI was associated with worse long-term post-AKI kidney function recovery. Funding: Authors are supported by various funders, with full details stated in the acknowledgement section

Lagging Adaptation to Climate Supersedes Local Adaptation to Herbivory in an Annual Monkeyflower.

While native populations are often adapted to historical biotic and abiotic conditions at their home site, populations from other locations in the range may be better adapted to current conditions due to changing climates or extreme conditions in a single year. We examine whether local populations of a widespread species maintain a relative advantage over distant populations that have evolved at sites better matching the current climate. Specifically, we grew lines derived from low- and high-elevation annual populations in California and Oregon of the common monkeyflower (Erythranthe guttata) and conducted phenotypic selection analyses in low- and high-elevation common gardens in Oregon to examine relative fitness and the traits mediating relative fitness. Californian low-elevation populations have the highest relative fitness at the low-elevation site, and Californian high-elevation populations have the highest relative fitness at the high-elevation site. Relative fitness differences are mediated by selection for properly timed transitions to flowering, with selection favoring more rapid growth rates at the low-elevation site and greater vegetative biomass prior to flowering at the high-elevation site. Fitness advantages for Californian plants occur despite incurring higher herbivory at both sites than the native Oregonian plants. Our findings suggest that a lag in adaptation causes maladaptation in extreme years that may be more prevalent in future climates, but local populations still have high growth rates and thus are not yet threatened

Lagging Adaptation to Climate Supersedes Local Adaptation to Herbivory in an Annual Monkeyflower.

While native populations are often adapted to historical biotic and abiotic conditions at their home site, populations from other locations in the range may be better adapted to current conditions due to changing climates or extreme conditions in a single year. We examine whether local populations of a widespread species maintain a relative advantage over distant populations that have evolved at sites better matching the current climate. Specifically, we grew lines derived from low- and high-elevation annual populations in California and Oregon of the common monkeyflower (Erythranthe guttata) and conducted phenotypic selection analyses in low- and high-elevation common gardens in Oregon to examine relative fitness and the traits mediating relative fitness. Californian low-elevation populations have the highest relative fitness at the low-elevation site, and Californian high-elevation populations have the highest relative fitness at the high-elevation site. Relative fitness differences are mediated by selection for properly timed transitions to flowering, with selection favoring more rapid growth rates at the low-elevation site and greater vegetative biomass prior to flowering at the high-elevation site. Fitness advantages for Californian plants occur despite incurring higher herbivory at both sites than the native Oregonian plants. Our findings suggest that a lag in adaptation causes maladaptation in extreme years that may be more prevalent in future climates, but local populations still have high growth rates and thus are not yet threatened

RawPhenotypeData

This is a comma delimited file (.csv) which contains phenotype data for 1,745 E. guttata individuals grown in either a low elevation or high elevation common garden in central Oregon. These common gardens included lines derived from collections four populations (low and high elevation populations in California and Oregon) as well as two F4 outbred mapping populations derived from initial crosses between low and high elevation plants from California and Oregon respectively

Lagging Adaptation to Climate Supersedes Local Adaptation to Herbivory in an Annual Monkeyflower.

While native populations are often adapted to historical biotic and abiotic conditions at their home site, populations from other locations in the range may be better adapted to current conditions due to changing climates or extreme conditions in a single year. We examine whether local populations of a widespread species maintain a relative advantage over distant populations that have evolved at sites better matching the current climate. Specifically, we grew lines derived from low- and high-elevation annual populations in California and Oregon of the common monkeyflower (Erythranthe guttata) and conducted phenotypic selection analyses in low- and high-elevation common gardens in Oregon to examine relative fitness and the traits mediating relative fitness. Californian low-elevation populations have the highest relative fitness at the low-elevation site, and Californian high-elevation populations have the highest relative fitness at the high-elevation site. Relative fitness differences are mediated by selection for properly timed transitions to flowering, with selection favoring more rapid growth rates at the low-elevation site and greater vegetative biomass prior to flowering at the high-elevation site. Fitness advantages for Californian plants occur despite incurring higher herbivory at both sites than the native Oregonian plants. Our findings suggest that a lag in adaptation causes maladaptation in extreme years that may be more prevalent in future climates, but local populations still have high growth rates and thus are not yet threatened

Nanoscale Phase Separation of Sulfonated Poly(arylene ether sulfone)/Poly(ether sulfone) Semi-IPNs for DMFC Membrane Applications

Unprecedented improvement in the selectivity (the ratio of proton conductivity to methanol permeability) of DMFC (direct methanol fuel cell) membranes has been demonstrated with a value roughly 16 times higher than that of Nafion117 having been achieved. The novel morphology of semi-interpenetrating polymer network (semi-IPN) membranes characterized by nanometer-sized domains as well as welldeveloped phase cocontinuity is a key factor in enabling such notable progress, which has not been seen in conventional microscale phase separation. The semi-IPN membranes (sIPN-100) consisted of a hydrophilic component acting as a proton conductor, that is, acrylate-terminated fully sulfonated poly(arylene ether sulfone) oligomers (acSPAES-100, degree of sulfonation=100%), and a hydrophobic component functioning as a methanol barrier, that is, poly(ether sulfone) copolymers (RH-2000). We determined the nanoscale phase separation of sIPN-100 by deliberately controlling the kinetics (the change of solvent-evaporation conditions) as well as the thermodynamics (shift of the phase separation boundary to the lower concentration of solvent in the phase diagram, mostly driven by the low molecular weight and the low hydrophilicity of acSPAES-100). Finally, the influence of this unique morphology on the membrane transport properties including the proton conductivity, the methanol permeability, and, more notably, the selectivity, was systematically investigated.close292