There is an urgent need for animal models to study SARS-CoV-2 pathogenicity. Here, we generate and characterize a novel mouse-adapted SARS-CoV-2 strain, MASCp36, that causes severe respiratory ...symptoms, and mortality. Our model exhibits age- and gender-related mortality akin to severe COVID-19. Deep sequencing identified three amino acid substitutions, N501Y, Q493H, and K417N, at the receptor binding domain (RBD) of MASCp36, during in vivo passaging. All three RBD mutations significantly enhance binding affinity to its endogenous receptor, ACE2. Cryo-electron microscopy analysis of human ACE2 (hACE2), or mouse ACE2 (mACE2), in complex with the RBD of MASCp36, at 3.1 to 3.7 Å resolution, reveals the molecular basis for the receptor-binding switch. N501Y and Q493H enhance the binding affinity to hACE2, whereas triple mutations at N501Y/Q493H/K417N decrease affinity and reduce infectivity of MASCp36. Our study provides a platform for studying SARS-CoV-2 pathogenesis, and unveils the molecular mechanism for its rapid adaptation and evolution.
Mitochondrial dysfunction in autism Giulivi, Cecilia; Zhang, Yi-Fan; Omanska-Klusek, Alicja ...
JAMA : the journal of the American Medical Association,
12/2010, Letnik:
304, Številka:
21
Journal Article
Recenzirano
Odprti dostop
Impaired mitochondrial function may influence processes highly dependent on energy, such as neurodevelopment, and contribute to autism. No studies have evaluated mitochondrial dysfunction and ...mitochondrial DNA (mtDNA) abnormalities in a well-defined population of children with autism.
To evaluate mitochondrial defects in children with autism.
Observational study using data collected from patients aged 2 to 5 years who were a subset of children participating in the Childhood Autism Risk From Genes and Environment study in California, which is a population-based, case-control investigation with confirmed autism cases and age-matched, genetically unrelated, typically developing controls, that was launched in 2003 and is still ongoing. Mitochondrial dysfunction and mtDNA abnormalities were evaluated in lymphocytes from 10 children with autism and 10 controls.
Oxidative phosphorylation capacity, mtDNA copy number and deletions, mitochondrial rate of hydrogen peroxide production, and plasma lactate and pyruvate.
The reduced nicotinamide adenine dinucleotide (NADH) oxidase activity (normalized to citrate synthase activity) in lymphocytic mitochondria from children with autism was significantly lower compared with controls (mean, 4.4 95% confidence interval {CI}, 2.8-6.0 vs 12 95% CI, 8-16, respectively; P = .001). The majority of children with autism (6 of 10) had complex I activity below control range values. Higher plasma pyruvate levels were found in children with autism compared with controls (0.23 mM 95% CI, 0.15-0.31 mM vs 0.08 mM 95% CI, 0.04-0.12 mM, respectively; P = .02). Eight of 10 cases had higher pyruvate levels but only 2 cases had higher lactate levels compared with controls. These results were consistent with the lower pyruvate dehydrogenase activity observed in children with autism compared with controls (1.0 95% CI, 0.6-1.4 nmol × min × mg protein(-1) vs 2.3 95% CI, 1.7-2.9 nmol × min × mg protein(-1), respectively; P = .01). Children with autism had higher mitochondrial rates of hydrogen peroxide production compared with controls (0.34 95% CI, 0.26-0.42 nmol × min × mg of protein(-1) vs 0.16 95% CI, 0.12-0.20 nmol × min × mg protein(-1) by complex III; P = .02). Mitochondrial DNA overreplication was found in 5 cases (mean ratio of mtDNA to nuclear DNA: 239 95% CI, 217-239 vs 179 95% CI, 165-193 in controls; P = 10(-4)). Deletions at the segment of cytochrome b were observed in 2 cases (ratio of cytochrome b to ND1: 0.80 95% CI, 0.68-0.92 vs 0.99 95% CI, 0.93-1.05 for controls; P = .01).
In this exploratory study, children with autism were more likely to have mitochondrial dysfunction, mtDNA overreplication, and mtDNA deletions than typically developing children.
Nitrate is one of the most common chemical contaminants of groundwater, and it is an important unqualified factor of rural groundwater in Yantai. In order to assess the risk of exposure to drinking ...water nitrate for adults and juveniles, in recent years, we monitored the nitrate concentrations in rural drinking water,a model was also used to assess the human health risk of nitrate pollution in groundwater.
From the year 2015 to 2018, the drinking water in rural areas of Yantai was tested according to the "Sanitary Standard for Drinking Water" (GB5749-2006). The principal component analysis was used to analyze the relationship between groundwater chemicals and nitrate. The model was used to assess human health risks of groundwater nitrate through the drinking water and skin contact.
A total of 2348 samples were tested during the year 2015-2018.Nitrate and total dissolved solids, total hardness, chloride are all relevant, the above indicators may come from the same source of pollution; The median nitrate content (C
) was 17.8 mg / L; the risk of exposure in each group was ranked as: Juveniles > Adult female > Adult male;the median health risk (HQ
) for minors and adults exceed 1.
The concentrations of nitrate is stable and does not change over time. The high concentration of nitrate in rural areas of Yantai may be the result of the interaction of fertilizers and geological factors. The risk of exposure to nitrate in juveniles and adults is above the limit, so it is necessary to be on the alert for the high levels of nitrate.
•Proposing a simple model to shared parking platform.•Using a binary integer linear programming to maximize profit.•The profits under OA reach their maximum value earlier than first-book-first-serve ...case.
With increasing auto demands, efficient parking management is by no means less important than road traffic congestion control. This is due to shortages of parking spaces within the limited land areas of the city centers in many metropolises. The parking problem becomes an integrated part of traffic planning and management. On the other hand, it is a fact that many private parking spots are available during daytime in nearby residential compound because those residents drive their cars out to work. These temporarily vacant parking lots can be efficiently utilized to meet the parking demand of other drivers who are working at nearby locations or drivers who come for shopping or other activities. This paper proposes a framework and a simple model for embracing shared use of residential parking spaces between residents and public users. The proposed shared use is a winning strategy because it maximizes the use of private resources to benefit the community as a whole. It also creates a new business model enabled by the fast-growing mobile apps in our daily lives.
Parabacteroides distasonis (P. distasonis) plays an important role in human health, including diabetes, colorectal cancer and inflammatory bowel disease. Here, we show that P. distasonis is decreased ...in patients with hepatic fibrosis, and that administration of P. distasonis to male mice improves thioacetamide (TAA)- and methionine and choline-deficient (MCD) diet-induced hepatic fibrosis. Administration of P. distasonis also leads to increased bile salt hydrolase (BSH) activity, inhibition of intestinal farnesoid X receptor (FXR) signaling and decreased taurochenodeoxycholic acid (TCDCA) levels in liver. TCDCA produces toxicity in mouse primary hepatic cells (HSCs) and induces mitochondrial permeability transition (MPT) and Caspase-11 pyroptosis in mice. The decrease of TCDCA by P. distasonis improves activation of HSCs through decreasing MPT-Caspase-11 pyroptosis in hepatocytes. Celastrol, a compound reported to increase P. distasonis abundance in mice, promotes the growth of P. distasonis with concomitant enhancement of bile acid excretion and improvement of hepatic fibrosis in male mice. These data suggest that supplementation of P. distasonis may be a promising means to ameliorate hepatic fibrosis.
In this work, Fe3O4 and metal–organic framework MIL-101(Fe) composites (Fe3O4/MIL-101(Fe)) was demonstrated to possess excellent catalytic property to directly catalyze luminol chemiluminescence ...without extra oxidants. We utilized Fe3O4/MIL-101(Fe) to develop a ultra-sensitive quantitative analytical method for H2O2 and glucose. The possible mechanism of the chemiluminescence reaction had been investigated. Under optimal conditions, the relative chemiluminescence intensity was linearly proportional to the logarithm of H2O2 concentration in the range of 5–150nM with a limit of detection of 3.7nM (signal-to-noise ratio = 3), and glucose could be linearly detected in the range from 5 to 100nM and the detection limit was 4.9nM (signal-to-noise ratio = 3). Furthermore, the present approach was successfully applied to quantitative determination of H2O2 in medical disinfectant and glucose in human serum samples.
Fe3O4/MIL-101(Fe) could catalyze luminol chemiluminescence without extra oxidants and the chemiluminescence intensity of Fe3O4/MIL-101(Fe)-luminol system could be further improved by H2O2 and glucose, which were used to fabricate a ultra-sensitive quantitative analytical method for H2O2 and glucose. Display omitted
•Fe3O4/MIL-101(Fe) possessed more outstanding catalytic performance than individual Fe3O4 or MIL-101(Fe).•The composites ould catalyze luminol chemiluminescence without extra oxidants.•The nanomole of H2O2 and glucose could be detected by Fe3O4/MIL-101(Fe)-luminol chemiluminescence system.
The upgrade of D-xylose, the most abundant pentose, to value-added biochemicals is economically important to next-generation biorefineries. myo-Inositol, as vitamin B8, has a six-carbon carbon-carbon ...ring. Here we designed an in vitro artificial NAD(P)-free 12-enzyme pathway that can effectively convert the five-carbon xylose to inositol involving xylose phosphorylation, carbon-carbon (C-C) rearrangement, C-C bond circulation, and dephosphorylation. The reaction conditions catalyzed by all thermostable enzymes from hyperthermophilic microorganisms Thermus thermophiles, Thermotoga maritima, and Archaeoglobus fulgidus were optimized in reaction temperature, buffer type and concentration, enzyme composition, Mg2+ concentration, and fed-batch addition of ATP. The 11-enzyme cocktail, whereas a fructose 1,6-bisphosphatase from T. maritima has another function of inositol monophosphatase, converted 20 mM xylose to 16.1 mM inositol with a conversion efficiency of 96.6% at 70 °C. Polyphosphate was found to replace ATP for xylulose phosphorylation due to broad substrate promiscuity of the T. maritima xylulokinase. The Tris-HCl buffer effectively mitigated the Maillard reaction at 70 °C or higher temperature. The co-production of value-added biochemicals, such as inositol, from wood sugar could greatly improve economics of new biorefineries, similar to oil refineries that make value-added plastic precursors to subsidize gasoline/diesel production.
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•An artificial 12-enzyme pathway was validated to convert xylose to inositol.•Eleven hypthermophilic enzymes were used to implement high-yield conversion.•The Maillard reaction was mitigated by optimization of reaction conditions.•The coproduction of inositol from wood sugar improves economics of biorefineries.
Pharmacological studies have shown that some traditional Chinese medicines (TCMs) have applications in the treatment of Alzheimer’s disease (AD).
Morinda officinalis
How. (MO) is a TCM with a long ...history and is widely used to tonify kidney Yang.
In vitro
and
in vivo
experiments have suggested that MO contains various effective pharmaceutical components and chemicals, including oligosaccharides, anthraquinones, iridoids, flavonoids, amino acids, and trace elements, conferring MO with anti-inflammatory and antioxidant properties. Neuroinflammation and oxidative stress are undoubtedly hallmarks of neurodegeneration, contributing to AD progression. In this mini-review, we summarize the molecular mechanisms, structure-activity relationships, and potential synergistic and antagonistic effects of active components in MO. This discussion highlights the roles of these active components, such as oligosaccharides, anthraquinones, and iridoid glycosides, in the treatment of AD
via
anti-inflammatory and antioxidant mechanisms, providing a scientific basis for further utilization of MO.
Histone methylation has important roles in regulating transcription, genome integrity and epigenetic inheritance. Historically, methylated histone arginine and lysine residues have been considered ...static modifications because of the low levels of methyl-group turnover in chromatin. The recent identification of enzymes that antagonize or remove histone methylation has changed this view and now the dynamic nature of these modifications is being appreciated. Here, we examine the enzymatic and structural basis for the mechanisms that these enzymes use to counteract histone methylation and provide insights into their substrate specificity and biological function.
Anti-IgLON5 disease is a recently defined autoimmune disorder of the nervous system associated with autoantibodies against IgLON5. Given its broad clinical spectrum and extremely complex ...pathogenesis, as well as difficulties in its early diagnosis and treatment, anti-IgLON5 disease has become the subject of considerable research attention in the field of neuroimmunology. Anti-IgLON5 disease has characteristics of both autoimmunity and neurodegeneration due to the unique activity of the anti-IgLON5 antibody. Neuropathologic examination revealed the presence of a tauopathy preferentially affecting the hypothalamus and brainstem tegmentum, potentially broadening our understanding of tauopathies. In contrast to that seen with other autoimmune encephalitis-related antibodies, basic studies have demonstrated that IgLON5 antibody-induced neuronal damage and degeneration are irreversible, indicative of a potential link between autoimmunity and neurodegeneration in anti-IgLON5 disease. Herein, we comprehensively review and discuss basic and clinical studies relating to anti-IgLON5 disease to better understand this complicated disorder.
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