Neurodegeneration and cerebrovascular disease share an underlying microvascular dysfunction that may be remedied by selective transgene delivery. To date, limited options exist in which cellular ...components of the brain vasculature can be effectively targeted by viral vector therapeutics. In this study, we characterize the first engineered adeno-associated virus (AAV) capsid mediating high transduction of cerebral vascular pericytes and smooth muscle cells (SMCs). We performed two rounds of
selection with an AAV capsid scaffold displaying a heptamer peptide library to isolate capsids that traffic to the brain after intravenous delivery. One identified capsid, termed AAV-PR, demonstrated high transduction of the brain vasculature, in contrast to the parental capsid, AAV9, which transduces mainly neurons and astrocytes. Further analysis using tissue clearing, volumetric rendering, and colocalization revealed that AAV-PR enabled high transduction of cerebral pericytes located on small-caliber vessels and SMCs in the larger arterioles and penetrating pial arteries. Analysis of tissues in the periphery indicated that AAV-PR also transduced SMCs in large vessels associated with the systemic vasculature. AAV-PR was also able to transduce primary human brain pericytes with higher efficiency than AAV9. Compared with previously published AAV capsids tropisms, AAV-PR represents the first capsid to allow for effective transduction of brain pericytes and SMCs and offers the possibility of genetically modulating these cell types in the context of neurodegeneration and other neurological diseases.
A subset of CD4 + lymphocytes, regulatory T cells (Tregs), are necessary for central tolerance and function as suppressors of autoimmunity against self-antigens. The SRC-3 coactivator is an oncogene ...in multiple cancers and is capable of potentiating numerous transcription factors in a wide variety of cell types. Src-3 knockout mice display broad lymphoproliferation and hypersensitivity to systemic inflammation. Using publicly available bioinformatics data and directed cellular approaches, we show that SRC-3 also is highly enriched in Tregs in mice and humans. Human Tregs lose phenotypic characteristics when SRC-3 is depleted or pharmacologically inhibited, including failure of induction from resting T cells and loss of the ability to suppress proliferation of stimulated T cells. These data support a model for SRC-3 as a coactivator that actively participates in protection from autoimmunity and may support immune evasion of cancers by contributing to the biology of Tregs.
Organic carbon (C) plays an essential role in the denitrification process as it supplies energy for N2O, N2 and CO2 producing reactions. The objectives of this study were to: (i) rank the reactivity ...of different C compounds found in manures based on their availability for denitrification and (ii) explore C-quality in different C sources based on their capacity to promote denitrification. Evaluation of different C-sources in promoting denitrification was conducted based on the molar ratio of CO2 production to NO3− reduction after incubation. Results of the first experiment (a 12-day investigation) showed that glucose and glucosamine were highly reactive C compounds with all applied NO3− being exhausted by day 3, and glucosamine had significantly high amount of NH4+-N present at end of the experiment. The glucose and glucosamine treatments resulted in significantly greater cumulative CO2 production, compared to the other treatments. In the second experiment (a 9-day investigation), all NO3− had been depleted by day 6 and 9 from acetic acid and glucose, respectively, and the greatest cumulative CO2 production was from acetic acid. The CO2 appearance to NO3− molar ratios revealed that glucose and glucosamine were compounds with highly available C in the first experiment. In the second experiment, the pig slurry and acetic acid were found to be C-sources that promoted potential denitrification. The application of slurry to soil results in the promotion of denitrification and this depends on the availability of the C compounds it contains. Understanding the relationship between C availability and denitrification potential is useful for developing denitrification mitigation strategies for organic soil amendments.
Atmospheric NOx concentrations are declining steadily due to successful abatement strategies predominantly targeting combustion sources. On the European continent, total NOx emissions fell by 55% ...between 1990 and 2017, but only modest reductions were achieved from the agricultural sector; with 7.8% from 20 Eastern European countries and 19.1% from 22 Western European countries. Consequently, the share of agricultural NOx emissions for these 42 European countries have increased from 3.6% to 7.2%. These values are highly uncertain due to serious lack of studies from agricultural soils and manure management. The emission factor (EFNO 1.33%), currently used for calculating soil NOx emissions from European agricultural categories 'N applied to soils' and 'manure management' was evaluated here by including recently published data from temperate climate zones. The newly calculated EFNO (average 0.60%, 0.0625th%/0.5475th%, n = 65 studies) is not notably different from the current value, given the large uncertainties associated with the small pool of studies, and therefore continued use of EFNO (1.33%) is recommended until more data become available. An assessment of the contribution of agricultural and non-agricultural NOx sources found that of the 42 European countries, the 8 most populated countries achieved considerable reductions (1990-2017) from categories 'non-agricultural sources' (55%), 'N applied to soils' (43%) and 'manure management' (1.2%), compared to small reductions from the remaining 34 countries. Forests are also large sources of soil NOx. On average, emissions from Eastern European forests were 4 times larger than from 'N applied agricultural soil', whereas Western European NOx emissions from 'N applied agricultural soil' were two times larger than from forest soils. Given that non-agricultural sources of NOx continue to decline, soil related emissions from agriculture, forests and manure management become more important, and require rigorous investigation in order to improve atmospheric pollution forecasts.
The first record in Mexican waters of albinism and synophthalmia (partial cyclopia) in the Pacific angel shark, Squatina californica is presented. Albinism is not lethal, but synophthalmia may cause ...the death of the individual immediately after birth.
Arterial stiffness is a risk factor for cardiovascular disease, including heart failure with preserved ejection fraction (HFpEF). MGP (matrix Gla protein) is implicated in vascular calcification in ...animal models, and circulating levels of the uncarboxylated, inactive form of MGP (ucMGP) are associated with cardiovascular disease-related and all-cause mortality in human studies. However, the role of MGP in arterial stiffness is uncertain. Approach and Results: We examined the association of ucMGP levels with vascular calcification, arterial stiffness including carotid-femoral pulse wave velocity (PWV), and incident heart failure in community-dwelling adults from the Framingham Heart Study. To further investigate the link between MGP and arterial stiffness, we compared aortic PWV in age- and sex-matched young (4-month-old) and aged (10-month-old) wild-type and Mgp
mice. Among 7066 adults, we observed significant associations between higher levels of ucMGP and measures of arterial stiffness, including higher PWV and pulse pressure. Longitudinal analyses demonstrated an association between higher ucMGP levels and future increases in systolic blood pressure and incident HFpEF. Aortic PWV was increased in older, but not young, female Mgp
mice compared with wild-type mice, and this augmentation in PWV was associated with increased aortic elastin fiber fragmentation and collagen accumulation.
This translational study demonstrates an association between ucMGP levels and arterial stiffness and future HFpEF in a large observational study, findings that are substantiated by experimental studies showing that mice with Mgp heterozygosity develop arterial stiffness. Taken together, these complementary study designs suggest a potential role of therapeutically targeting MGP in HFpEF.
Emerging evidence suggests that males are more susceptible to severe infection by the SARS-CoV-2 virus than females. A variety of mechanisms may underlie the observed gender-related disparities ...including differences in sex hormones. However, the precise mechanisms by which female sex hormones may provide protection against SARS-CoV-2 infectivity remains unknown. Here we report new insights into the molecular basis of the interactions between the SARS-CoV-2 spike (S) protein and the human ACE2 receptor. We further report that glycosylation of the ACE2 receptor enhances SARS-CoV-2 infectivity. Importantly, estrogens can disrupt glycan-glycan interactions and glycan-protein interactions between the human ACE2 and the SARS-CoV-2 thereby blocking its entry into cells. In a mouse model of COVID-19, estrogens reduced ACE2 glycosylation and thereby alveolar uptake of the SARS-CoV-2 spike protein. These results shed light on a putative mechanism whereby female sex hormones may provide protection from developing severe infection and could inform the development of future therapies against COVID-19.
Induced pluripotent stem cells were created from a pancreas agenesis patient with a mutation in GATA6. Using genome-editing technology, additional stem cell lines with mutations in both GATA6 alleles ...were generated and demonstrated a severe block in definitive endoderm induction, which could be rescued by re-expression of several different GATA family members. Using the endodermal progenitor stem cell culture system to bypass the developmental block at the endoderm stage, cell lines with mutations in one or both GATA6 alleles could be differentiated into β-like cells but with reduced efficiency. Use of suboptimal doses of retinoic acid during pancreas specification revealed a more severe phenotype, more closely mimicking the patient’s disease. GATA6 mutant β-like cells fail to secrete insulin upon glucose stimulation and demonstrate defective insulin processing. These data show that GATA6 plays a critical role in endoderm and pancreas specification and β-like cell functionality in humans.
•GATA6 is required for definitive endoderm specification in human ES/iPS cells•Bypassing the endoderm defect allows GATA6 mutants to generate β-like cells•Suboptimal retinoic acid signaling blocks pancreas specification in GATA6 mutants•GATA6 is critical for human β cell function in vitro
In this study, Gadue and colleagues studied GATA6 mutant pluripotent stem cells and demonstrate that GATA6 is necessary for human definitive endoderm specification. GATA6 also plays an important role in pancreas specification which could be partially bypassed by retinoic acid signaling. Furthermore, derivative β cells lacked glucose responsiveness in vitro, showing that GATA6 is vital for appropriate human pancreas development.
Vegetated land areas play a significant role in determining the fate of carbon (C) in the global C cycle. Riparian buffer vegetation is primarily implemented for water quality purposes as they ...attenuate pollutants from immediately adjacent croplands before reaching freashwater systems. However, their prevailing conditions may sometimes promote the production and subsequent emissions of soil carbon dioxide (CO
2
). Despite this, the understanding of soil CO
2
emissions from riparian buffer vegetation and a direct comparison with adjacent croplands they serve remain elusive. In order to quantify the extent of CO
2
emissions in such an agro system, we measured CO
2
emissions simultaneously with soil and environmental variables for six months in a replicated plot-scale facility comprising of maize cropping served by three vegetated riparian buffers, namely: (i) a novel grass riparian buffer; (ii) a willow riparian buffer, and; (iii) a woodland riparian buffer. These buffered treatments were compared with a no-buffer control. The woodland (322.9 ± 3.1 kg ha
− 1
) and grass (285 ± 2.7 kg ha
− 1
) riparian buffer treatments (not significant to each other) generated significantly (
p = < 0.0001
) the largest CO
2
compared to the remainder of the treatments. Our results suggest that during maize production in general, the woodland and grass riparian buffers serving a maize crop pose a CO
2
threat. The results of the current study point to the need to consider the benefits for gaseous emissions of mitigation measures conventionally implemented for improving the sustainability of water resources.
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