To examine the impact of four ambient air pollutants on the COVID-19 mortality rate in the United States of America.
Using publicly accessible data collected by the United States Census Bureau, ...Environmental Protection Agency, and other agencies, county-level mortality rates were regressed on concentration values of ground-level ozone, nitrogen dioxide, carbon monoxide, and sulfur dioxide. Four confounder variables were included in the regression analysis: median household income, rate of hospital beds, population density, and days since first confirmed case.
Regression analysis showed that ground-level ozone is positively correlated with county-level mortality rates regardless of whether confounders are controlled for. Nitrogen dioxide is also shown to have a direct relationship with county-level mortality rates, except when all confounders are included in the analysis.
High ground-level ozone and nitrogen dioxide concentrations contribute to a greater COVID-19 mortality rate. To limit further losses, it is important to reflect research findings in public policies. In the case of air pollution, environmental restrictions should be reinforced, and extra precautions should be taken as facilities start reopening.
G protein-coupled receptors (GPCRs) regulate cellular signaling pathways by coupling to two classes of transducers: heterotrimeric G proteins and β-arrestins. Sarcosine1Ile4Ile8-angiotensin II (SII), ...an analog of the endogenous ligand angiotensin II (AngII) for the angiotensin II type 1 receptor (AT1R), fails to activate G protein in physiologically relevant models. Despite this, SII and several derivatives induce cellular signaling outcomes through β-arrestin-2-dependent mechanisms. However, studies reliant on exogenous AT1R overexpression indicate that SII is a partial agonist for G protein signaling and lacks β-arrestin-exclusive functional specificity. We investigated this apparent discrepancy by profiling changes in functional specificity at increasing expression levels of AT1R using a stably integrated tetracycline-titratable expression system stimulated with AngII, SII, and four other AngII analogs displaying different signaling biases. Unbiased and G protein-biased ligands activated dose-dependent calcium responses at all tested receptor concentrations. In contrast, β-arrestin-biased ligands induced dose-dependent calcium signaling only at higher AT1R overexpression levels. Using inhibitors of G proteins, we demonstrated that both Gi and Gq/11 mediated overexpression-dependent calcium signaling by β-arrestin-biased ligands. Regarding β-arrestin-mediated cellular events, the β-arrestin-biased ligand TRV026 induced receptor internalization at low physiological receptor levels insufficient for it to initiate calcium signaling. In contrast, unbiased AngII exhibited no relative preference between these outcomes under such low receptor conditions. However, with high receptor overexpression, TRV026 lost its functional selectivity. These results suggest receptor overexpression misleadingly distorts the bias of AT1R ligands and highlight the risks of using overexpressed systems to infer the signaling bias of GPCR ligands in physiologically relevant contexts.
Abstract
CMOS-based computing systems that employ the von Neumann architecture are relatively limited when it comes to parallel data storage and processing. In contrast, the human brain is a living ...computational signal processing unit that operates with extreme parallelism and energy efficiency. Although numerous neuromorphic electronic devices have emerged in the last decade, most of them are rigid or contain materials that are toxic to biological systems. In this work, we report on biocompatible bilayer graphene-based artificial synaptic transistors (BLAST) capable of mimicking synaptic behavior. The BLAST devices leverage a dry ion-selective membrane, enabling long-term potentiation, with ~50 aJ/µm
2
switching energy efficiency, at least an order of magnitude lower than previous reports on two-dimensional material-based artificial synapses. The devices show unique metaplasticity, a useful feature for generalizable deep neural networks, and we demonstrate that metaplastic BLASTs outperform ideal linear synapses in classic image classification tasks. With switching energy well below the 1 fJ energy estimated per biological synapse, the proposed devices are powerful candidates for bio-interfaced online learning, bridging the gap between artificial and biological neural networks.
Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in China. The lower survival rate of ESCC is attributed to late diagnosis and poor therapeutic efficacy; therefore, the ...identification of tumor-associated proteins as biomarkers for early diagnosis, and the discovery of novel targets for therapeutic intervention, seems very important for increasing the survival rate of ESCC. To identify tumor-associated proteins as biomarkers in ESCC, we have analyzed ESCC tissues and adjacent normal tissues by two-dimensional electrophoresis (2DE) and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) analysis. The results showed that a total of 104 protein spots with different expression levels were found on 2DE, and 47 proteins were eventually identified by MALDI-TOF MS. Among these identified proteins, 33 proteins including keratin 17 (KRT17), biliverdin reductase B (BLVRB), proteasome activator subunit 1 (PSME1), manganese superoxide dismutase (MnSOD), high-mobility group box-1(HMGB1), heat shock protein 70 (HSP70), peroxiredoxin (PRDX1), keratin 13 (KRT13), and so on were overexpressed, and 14 proteins including cystatin B (CSTB), tropomyosin 2 (TPM2), annexin 1 (ANX1), transgelin (TAGLN), keratin 19 (KRT19), stratifin (SFN), and so on were down-expressed in ESCC. Biological functions of these proteins are associated with cell proliferation, cell motility, protein folding, oxidative stress, and signal transduction. In the subsequent study using immunoassay on ESCC serum samples and tissue-array slides, two representative proteins, HSP70 and HMGB1, were selected as examples for the purpose of validation. The results showed that both HSP70 and HMGB1 can induce autoantibody response in ESCC sera and have higher expression in ESCC tissues. Especially, the frequency of antibodies to HSP70 in ESCC sera was significantly higher than that in normal human sera. The preliminary results suggest that some of these identified proteins might contribute to esophageal cell differentiation and carcinogenesis, certain proteins could be used as tumor-associated antigen (TAA) biomarkers in cancer diagnosis, and further studies on these identified proteins should provide more evidence of how these proteins are involved in carcinogenesis of ESCC.
The objective of this study was to investigate the preventive effects of polysaccharides extracted from the roots of
(ALP) against acute lung injury (ALI) models induced by lipopolysaccharide (LPS). ...The polysaccharides were extracted and characterized, and their anti-inflammatory and antioxidant capacities were assessed. The findings demonstrated that ALP could mitigate the infiltration of inflammatory cells and reduce alveolar collapse in LPS-induced ALI in mice. The expression levels of the
-inflammatory factor TNF-α decreased, while the anti-inflammatory factor IL-10 increased. Furthermore, the administration of ALP improved the activities of lung antioxidant enzymes, including SOD, GSH, and CAT, and lowered MDA levels. These results suggest that ALP exhibits a preventive effect on ALI and has potential as an alternative treatment for lung injury.
The elimination of synapses during circuit remodeling is critical for brain maturation; however, the molecular mechanisms directing synapse elimination and its timing remain elusive. We show that the ...transcriptional regulator DVE-1, which shares homology with special AT-rich sequence-binding (SATB) family members previously implicated in human neurodevelopmental disorders, directs the elimination of juvenile synaptic inputs onto remodeling C. elegans GABAergic neurons. Juvenile acetylcholine receptor clusters and apposing presynaptic sites are eliminated during the maturation of wild-type GABAergic neurons but persist into adulthood in dve-1 mutants, producing heightened motor connectivity. DVE-1 localization to GABAergic nuclei is required for synapse elimination, consistent with DVE-1 regulation of transcription. Pathway analysis of putative DVE-1 target genes, proteasome inhibitor, and genetic experiments implicate the ubiquitin-proteasome system in synapse elimination. Together, our findings define a previously unappreciated role for a SATB family member in directing synapse elimination during circuit remodeling, likely through transcriptional regulation of protein degradation processes.
A commercial formulation of the insect growth regulator methoprene was applied to wheat stored in small bins either alone or in combination with controlled aeration of the bins, to lower grain ...temperature for insect pest management of stored wheat. Grain temperatures were monitored and modified by a computer-controlled thermocouple system that also activated the aeration system at programmed set-points to move cool ambient air through the grain mass to lower grain temperature. Results from sampling insect populations in experimental storage bins along with laboratory mortality bioassays of insects placed on wheat taken from the bins over the course of the storage period showed that methoprene was very effective in controlling infestation by the externally-feeding stored grain insects Plodia interpunctella (Hübner), the Indian meal moth Tribolium castaneum (Herbst), the red flour beetle, Cryptolestes ferrugineus (Stephens), the rusty grain beetle, and also for the internal-feeding pest Rhyzopertha dominica( Fauvel), the lesser grain borer. Methoprene did not give good control of the internal-feeding pest Sitophilus oryzae (L.), the rice weevil. Aeration alone was somewhat effective in suppressing insect population development, while methoprene alone or when combined with aeration greatly enhanced insect control. Commercial grain grading for industry quality standards at the end of the storage period confirmed the impact of insect suppression on maintaining high quality of the stored wheat. This field experiment shows that methoprene combined with aeration to cool grain can be effective for pest management of stored wheat in the southern plains of the United States of America.
Biallelic loss-of-function variants in the MUSK gene result in two allelic disorders: (1) congenital myasthenic syndrome (CMS; OMIM: 616325), a neuromuscular disorder that has a range of severity ...from severe neonatal-onset weakness to mild adult-onset weakness, and (2) fetal akinesia deformation sequence (OMIM: 208150), a form of pregnancy loss characterized by severe muscle weakness in the fetus. The MUSK gene codes for muscle-specific kinase (MuSK), a receptor tyrosine kinase involved in the development of the neuromuscular junction. Here, we report a case of neonatal-onset MUSK-related CMS in a patient harboring compound heterozygous deletions in the MUSK gene, including (1) a deletion of exons 2–3 leading to an in-frame MuSK protein lacking the immunoglobulin 1 (Ig1) domain and (2) a deletion of exons 7–11 leading to an out-of-frame, truncated MuSK protein. Individual domains of the MuSK protein have been elucidated structurally; however, a complete MuSK structure generated by machine learning algorithms has clear inaccuracies. We modify a predicted AlphaFold structure and integrate previously reported domain-specific structural data to suggest a MuSK protein that dimerizes in two locations (Ig1 and the transmembrane domain). We analyze known pathogenic variants in MUSK to discover domain-specific genotype-phenotype correlations; variants that lead to a loss of protein expression, disruption of the Ig1 domain, or Dok-7 binding are associated with the most severe phenotypes. A conceptual model is provided to explain the severe phenotypes seen in Ig1 variants and the poor response of our patient to pyridostigmine.
MUSK loss-of-function variants lead to highly variable clinical severity, from fetal loss to adult-onset weakness. Here we present a case of neonatal-onset congenital myasthenic syndrome due to loss of the Ig1 domain. We provide an improved AlphaFold structure and suggest a protein domain-based logic to the widely variable disease onset.
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