The potential of the diverse chemistries present in natural products (NP) for biotechnology and medicine remains untapped because NP databases are not searchable with raw data and the NP community has no way to share data other than in published papers. Although mass spectrometry techniques are well-suited to high-throughput characterization of natural products, there is a pressing need for an infrastructure to enable sharing and curation of data. We present Global Natural Products Social molecular networking (GNPS, http://gnps.ucsd.edu), an open-access knowledge base for community wide organization and sharing of raw, processed or identified tandem mass (MS/MS) spectrometry data. In GNPS crowdsourced curation of freely available community-wide reference MS libraries will underpin improved annotations. Data-driven social-networking should facilitate identification of spectra and foster collaborations. We also introduce the concept of ‘living data’ through continuous reanalysis of deposited data.
Neutralizing antibodies could be antivirals against COVID-19 pandemics. Here, we report isolation of four human-origin monoclonal antibodies from a convalescent patient, all of which display neutralization abilities. B38 and H4 block the binding between virus S-protein RBD and cellular receptor ACE2. A competition assay indicates their different epitopes on the RBD, making them a potential virus-targeting MAb-pair to avoid immune escape in future clinical applications. Moreover, a therapeutic study in a mouse model validated that these antibodies can reduce virus titers in infected lungs. The RBD-B38 complex structure revealed that most residues on the epitope overlap with the RBD-ACE2 binding interface, explaining the blocking effect and neutralizing capacity. Our results highlight the promise of antibodybased therapeutics and provide a structural basis for rational vaccine design.
Nanoscale robots have potential as intelligent drug delivery systems that respond to molecular triggers. Using DNA origami we constructed an autonomous DNA robot programmed to transport payloads and present them specifically in tumors. Our nanorobot is functionalized on the outside with a DNA aptamer that binds nucleolin, a protein specifically expressed on tumor-associated endothelial cells, and the blood coagulation protease thrombin within its inner cavity. The nucleolin-targeting aptamer serves both as a targeting domain and as a molecular trigger for the mechanical opening of the DNA nanorobot. The thrombin inside is thus exposed and activates coagulation at the tumor site. Using tumor-bearing mouse models, we demonstrate that intravenously injected DNA nanorobots deliver thrombin specifically to tumor-associated blood vessels and induce intravascular thrombosis, resulting in tumor necrosis and inhibition of tumor growth. The nanorobot proved safe and immunologically inert in mice and Bama miniature pigs. Our data show that DNA nanorobots represent a promising strategy for precise drug delivery in cancer therapy.
BACKGROUND: On January 20, 2020, a new coronavirus epidemic with human-to-human transmission was officially declared by the Chinese government, which caused significant public panic in China. In light of the coronavirus disease 2019 outbreak, pregnant women may be particularly vulnerable and in special need for preventive mental health strategies. Thus far, no reports exist to investigate the mental health response of pregnant women to the coronavirus disease 2019 outbreak. OBJECTIVE: This study aimed to examine the impact of coronavirus disease 2019 outbreak on the prevalence of depressive and anxiety symptoms and the corresponding risk factors among pregnant women across China. STUDY DESIGN: A multicenter, cross-sectional study was initiated in early December 2019 to identify mental health concerns in pregnancy using the Edinburgh Postnatal Depression Scale. This study provided a unique opportunity to compare the mental status of pregnant women before and after the declaration of the coronavirus disease 2019 epidemic. A total of 4124 pregnant women during their third trimester from 25 hospitals in 10 provinces across China were examined in this crosssectional study from January 1, 2020, to February 9, 2020. Of these women, 1285 were assessed after January 20, 2020, when the coronavirus epidemic was publicly declared and 2839 were assessed before this pivotal time point. The internationally recommended Edinburgh Postnatal Depression Scale was used to assess maternal depression and anxiety symptoms. Prevalence rates and risk factors were compared between the pre-and poststudy groups. RESULTS: Pregnant women assessed after the declaration of coronavirus disease 2019 epidemic had significantly higher rates of depressive symptoms (26.0% vs 29.6%, P¼.02) than women assessed before the epidemic declaration. These women were also more likely to have thoughts of self-harm (P¼.005). The depressive rates were positively associated with the number of newly confirmed cases of coronavirus disease 2019 (P¼.003), suspected infections (P¼.004), and deaths per day (P¼.001). Pregnant women who were underweight before pregnancy, primiparous, younger than 35 years, employed full time, in middle income category, and had appropriate living space were at increased risk for developing depressive and anxiety symptoms during the outbreak. CONCLUSION: Major life-threatening public health events such as the coronavirus disease 2019 outbreak may increase the risk for mental illness among pregnant women, including thoughts of self-harm. Strategies targeting maternal stress and isolation such as effective risk communication and the provision of psychological first aid may be particularly useful to prevent negative outcomes for women and their fetuses.
We studied molecular sieving properties of zeolitic imidazolate framework-8 (ZIF-8) by estimating the thermodynamically corrected diffusivities of probe molecules at 35 °C. From helium (2.6 Å) to iso-C4H10 (5.0 Å), the corrected diffusivity drops 14 orders of magnitude. Our results further suggest that the effective aperture size of ZIF-8 for molecular sieving is in the range of 4.0 to 4.2 Å, which is significantly larger than the XRD-derived value (3.4 Å) and between the well-known aperture size of zeolite 4A (3.8 Å) and 5A (4.3 Å). Interestingly, because of aperture flexibility, the studied C4 hydrocarbon molecules that are larger than this effective aperture size still adsorb in the micropores of ZIF-8 with kinetic selectivities for iso-C4H8/iso-C4H10 of 180 and n-C4H10/iso-C4H10 of 2.5 × 10(6). These unexpected molecular sieving properties open up new opportunities for ZIF materials for separations that cannot be economically achieved by traditional microporous adsorbents such as synthetic zeolites.
Metallic glasses and cancer theranostics are emerging fields that do not seem to be related to each other. Herein, we report the facile synthesis of amorphous iron nanoparticles (AFeNPs) and their superior physicochemical properties compared to their crystalline counterpart, iron nanocrystals (FeNCs). The AFeNPs can be used for cancer theranostics by inducing a Fenton reaction in the tumor by taking advantage of the mild acidity and the overproduced H2 O2 in a tumor microenvironment: Ionization of the AFeNPs enables on-demand ferrous ion release in the tumor, and subsequent H2 O2 disproportionation leads to efficient (.)OH generation. The endogenous stimuli-responsive (.)OH generation in the presence AFeNPs enables a highly specific cancer therapy without the need for external energy input.
Parkinson's disease (PD) is characterized by the selective vulnerability of the nigrostriatal dopaminergic circuit. Recently, loss-offunction mutations in the PTEN-induced kinase 1 (PINK1) gene have been linked to early-onset PD. How PINK1 deficiency causes dopaminergic dysfunction and degeneration in PD patients is unknown. Here, we investigate the physiological role of PINK1 in the nigrostriatal dopaminergic circuit through the generation and multidisciplinary analysis of PINK1 ؊/؊ mutant mice. We found that numbers of dopaminergic neurons and levels of striatal dopamine (DA) and DA receptors are unchanged in PINK1 ؊/؊ mice. Amperometric recordings, however, revealed decreases in evoked DA release in striatal slices and reductions in the quantal size and release frequency of catecholamine in dissociated chromaffin cells. Intracellular recordings of striatal medium spiny neurons, the major dopaminergic target, showed specific impairments of corticostriatal long-term potentiation and long-term depression in PINK1 ؊/؊ mice. Consistent with a decrease in evoked DA release, these striatal plasticity impairments could be rescued by either DA receptor agonists or agents that increase DA release, such as amphetamine or L-dopa. These results reveal a critical role for PINK1 in DA release and striatal synaptic plasticity in the nigrostriatal circuit and suggest that altered dopaminergic physiology may be a pathogenic precursor to nigrostriatal degeneration.neurodegeneration ͉ Parkinson's disease ͉ substantia nigra P arkinson's disease (PD) is the most common movement disorder and is characterized by bradykinesia, rigidity, resting tremor, and postural instability. These clinical features are thought to result from reduced dopaminergic input to the striatum and the loss of dopaminergic neurons in the pars compacta of the substantia nigra (SNpc). Although the occurrence of PD is largely sporadic, mutations in five distinct genes have been linked to clinical syndromes that are often indistinguishable from sporadic PD. Of these, mutations in the parkin, DJ-1, and PINK1 (PTEN induced kinase 1) genes are recessively inherited and include large exonic deletions or frame-shift truncations, suggesting a loss-of-function pathogenic mechanism (1-3).PINK1 was originally identified as a gene whose transcription was activated by the tumor suppressor PTEN in carcinoma cell lines (4). The PINK1 gene has eight exons spanning 1.8 kb and encodes 581 aa residues. The deduced amino acid sequence indicates that PINK1 contains a mitochondrial targeting motif (amino acids 1-34) and a kinase domain (amino acids 156-509) that is highly homologous to Ca 2ϩ /calmodulin-dependent kinases. Since the first report linking recessively inherited nonsense (W437X) and missense (G309D) mutations in PINK1 to familial PARK6 cases (3), large numbers (Ͼ30) of additional truncation and missense mutations have been identified in early-onset PD cases with or without family history (5-11). Genetic analysis revealed that homozygous and compound heterozygous mutatio...
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