The fundamental goal of artificial intelligence (AI) is to mimic the core cognitive activities of human. Despite tremendous success in the AI research, most of existing methods have only ...single-cognitive ability. To overcome this limitation and take a solid step towards artificial general intelligence (AGI), we develop a foundation model pre-trained with huge multimodal data, which can be quickly adapted for various downstream cognitive tasks. To achieve this goal, we propose to pre-train our foundation model by self-supervised learning with weak semantic correlation data crawled from the Internet and show that promising results can be obtained on a wide range of downstream tasks. Particularly, with the developed model-interpretability tools, we demonstrate that strong imagination ability is now possessed by our foundation model. We believe that our work makes a transformative stride towards AGI, from our common practice of "weak or narrow AI" to that of "strong or generalized AI".
Carbon dots (CDs) are photoluminescent nanomaterials with wide-ranging applications. Despite their photoactivity, it remains unknown whether CDs degrade under illumination and whether such ...photodegradation poses any cytotoxic effects. Here, we show laboratory-synthesized CDs irradiated with light degrade into molecules that are toxic to both normal (HEK-293) and cancerous (HeLa and HepG2) human cells. Eight days of irradiation photolyzes 28.6-59.8% of the CDs to <3 kilo Dalton molecules, 1431 of which are detected by high-throughput, non-target high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Molecular network and community analysis further reveal 499 cytotoxicity-related molecules, 212 of which contain polyethylene glycol, glucose, or benzene-related structures. Photo-induced production of hydroxyl and alkyl radicals play important roles in CD degradation as affected by temperature, pH, light intensity and wavelength. Commercial CDs show similar photodegraded products and cytotoxicity profiles, demonstrating that photodegradation-induced cytotoxicity is likely common to CDs regardless of their chemical composition. Our results highlight the importance of light in cytocompatibility studies of CDs.
Transient receptor potential channel subfamily A member 1 (TRPA1) is a Ca2+-permeable cation channel that serves as one of the primary sensors of environmental irritants and noxious substances. Many ...TRPA1 agonists are electrophiles that are recognized by TRPA1 via covalent bond modifications of specific cysteine residues located in the cytoplasmic domains. However, a mechanistic understanding of electrophile sensing by TRPA1 has been limited due to a lack of high-resolution structural information. Here, we present the cryoelectron microscopy (cryo-EM) structures of nanodisc-reconstituted ligand-free TRPA1 and TRPA1 in complex with the covalent agonists JT010 and BITC at 2.8, 2.9, and 3.1 Å, respectively. Our structural and functional studies provide the molecular basis for electrophile recognition by the extraordinarily reactive C621 in TRPA1 and mechanistic insights into electrophile-dependent conformational changes in TRPA1. This work also provides a platform for future drug development targeting TRPA1.
•TRPA1 senses electrophiles via modification of the extraordinarily reactive C621•High-resolution cryo-EM structures explain the high reactivity of C621•C621 modification elicits conformational changes that are propagated to the channel•Structures provide a basis of promiscuous but rapid electrophile sensing by TRPA1
Here, Suo et al. unravel the molecular mechanism by which the “wasabi receptor” TRPA1 ion channel senses noxious chemicals. TRPA1 contains a highly sophisticated binding site for electrophile agents that undergoes a conformational change following covalent agonist binding, triggering TRPA1 activation.
Taiwan experienced two waves of imported infections with Coronavirus Disease 2019 (COVID-19). This study aimed at investigating the genomic variation of severe acute respiratory syndrome coronavirus ...2 (SARS-CoV-2) in Taiwan and compared their evolutionary trajectories with the global strains. We performed culture and full-genome sequencing of SARS-CoV-2 strains followed by phylogenetic analysis. A 382-nucleotides deletion in open reading frame 8 (ORF8) was found in a Taiwanese strain isolated from a patient on February 4, 2020 who had a travel history to Wuhan. Patients in the first wave also included several sporadic, local transmission cases. Genomes of 5 strains sequenced from clustered infections were classified into a new clade with ORF1ab-V378I mutation, in addition to 3 dominant clades ORF8-L84S, ORF3a-G251V and S-D614G. This highlighted clade also included some strains isolated from patients who had a travel history to Turkey and Iran. The second wave mostly resulted from patients who had a travel history to Europe and Americas. All Taiwanese viruses were classified into various clades. Genomic surveillance of SARS-CoV-2 in Taiwan revealed a new ORF8-deletion mutant and a virus clade that may be associated with infections in the Middle East, which contributed to a better understanding of the global SARS-CoV-2 transmission dynamics.
Urban street dusts were collected in commercial area (CA), traffic area (TA), educational area (EA), residential area (RA) and parks area (PA) of Chengdu, China, to investigate the concentrations of ...heavy metals (Pb, Zn, Cu, Ni, Cd and Cr), and analyzed to evaluated possible sources and health risk assessment. The average concentrations (mg/kg) of Pb (82.3), Zn (296), Cu (100), Cd (1.66) and Cr (84.3) in urban street dusts were all higher than the local soil background values. The concentrations of heavy metals in each functional area could be classified as follows: CA>TA>RA>EA>PA. Principal component analysis and Cluster analysis showed mainly derived from the mixed sources of nature and traffic (51.7%). The results of health risk assessment showed no non-carcinogenic and carcinogenic risks of the metals for inhabitants. However, higher concentrations and oral bioaccessibility of the heavy metals in the dusts from CA and TA, indicating there was more health risks to the inhabitants in than that in other functional areas.
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•Heavy metal concentrations in street dust collected from 5 functional areas•Health risks were evaluated for the metals combined with oral bioaccessibility.•The highest total metal concentrations were found in commercial area.•Pb, Zn, Cu, Cd and Cr mainly originate from anthropogenic sources.
•Heavy metal concentrations in household dust collected from 6 urban districts.•Health risks were evaluated for the metals combined with oral bioaccessibility.•There was negative correlation between ...the metals concentrations and floor levels.
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To investigate the characteristics of heavy metals (Cr, Cd, Pb, Zn, Cu and Ni) in household dust in urban household environment of Chengdu, China, 90 household dust samples were collected from 6 districts of the city. The information of houses and residents were also recorded during dust sampling to identify the correlations between heavy metals in household dust and the house attributes. And also the principal component analysis and cluster analysis for sources and impactor factors. The concentrations of Pb (123mg·kg−1), Zn (675mg·kg−1), Cu (190mg·kg−1), Cr (82.7mg·kg−1), Cd (2.37mg·kg−1) and Ni (52.6mg·kg−1) in household dust are in low or moderate levels when compare with that from other counties or areas. The heavy metals of household dust samples from Chengdu is higher concentrations than that in the street dust from Chengdu, except for Cr. Statistical analysis result showed traffic sources and corrosion of alloys are important factors contributing to the rise concentrations of heavy metals in household dust. In addition, there is negative correlation (p<0.05) between the heavy metals concentrations and floor levels. The ingestion is the important pathway for Pb, Zn, Cu and Ni via household dust exposure to the residents, and the dermal contact was identified as a main route for Cr and Cd in household dust exposure to the residents. There are minor non-carcinogenic and carcinogenic risks from the heavy metals in household dust for the residents in Chengdu.
The objective of this study was to characterize the lipid class and fatty acid composition of four kinds of marine oils including Phaeodactylum tricornutum oil (PO), Laminaria japonica oil (LO), ...krill oil (KO) and fish oil (FO), and evaluate their antioxidant capacities in vitro. The results indicated that compared to other three oils, PO showed the highest contents of total lipids and fucoxanthin (194.70 and 7.48 mg/g dry weight, respectively), the relatively higher content of long-chain polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (30.94 % in total fatty acids), and total phenolic content (675.88 mg gallic acid equivalent /100 g lipids), thereby contribute to great advantages in scavenging free radicals such as 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2-azino-bis (3-ethylbenzthiazoline)-6-sulfonic acid (ABTS), peroxyl radical, as well as reducing FRAP value. In conclusion, PO should be considered as a potential ingredient for dietary supplement with antioxidant capacity.
Incessant antigenic evolution enables the persistence and spread of influenza virus in the human population. As the principal target of the immune response, the hemagglutinin (HA) surface antigen on ...influenza viruses continuously acquires and replaces N-linked glycosylation sites to shield immunogenic protein epitopes using host-derived glycans. Anti-glycan antibodies, such as 2G12, target the HIV-1 envelope protein (Env), which is even more extensively glycosylated and contains under-processed oligomannose-type clusters on its dense glycan shield. Here, we illustrate that 2G12 can also neutralize human seasonal influenza A H3N2 viruses that have evolved to present similar oligomannose-type clusters on their HAs from around 20 years after the 1968 pandemic. Using structural biology and mass spectrometric approaches, we find that two N-glycosylation sites close to the receptor binding site (RBS) on influenza hemagglutinin represent the oligomannose cluster recognized by 2G12. One of these glycan sites is highly conserved in all human H3N2 strains and the other emerged during virus evolution. These two N-glycosylation sites have also become crucial for fitness of recent H3N2 strains. These findings shed light on the evolution of the glycan shield on influenza virus and suggest 2G12-like antibodies can potentially act as broad neutralizers to target human enveloped viruses.
Accumulating evidence suggests that activation of spinal microglia contributes to the development of inflammatory and neuropathic pain. However, the role of spinal microglia in the maintenance of ...chronic pain remains controversial. Bone cancer pain shares features of inflammatory and neuropathic pain, but the temporal activation of microglia and astrocytes in this model is not well defined. Here, we report an unconventional role of spinal microglia in the maintenance of advanced-phase bone cancer pain in a female rat model. Bone cancer elicited delayed and persistent microglial activation in the spinal dorsal horn on days 14 and 21, but not on day 7. In contrast, bone cancer induced rapid and persistent astrocytic activation on days 7-21. Spinal inhibition of microglia by minocycline at 14 d effectively reduced bone cancer-induced allodynia and hyperalgesia. However, pretreatment of minocycline in the first week did not affect the development of cancer pain. Bone cancer increased ATP levels in CSF, and upregulated P2X7 receptor, phosphorylated p38, and IL-18 in spinal microglia. Spinal inhibition of P2X7/p-38/IL-18 pathway reduced advanced-phase bone cancer pain and suppressed hyperactivity of spinal wide dynamic range (WDR) neurons. IL-18 induced allodynia and hyperalgesia after intrathecal injection, elicited mechanical hyperactivity of WDR neurons in vivo, and increased the frequency of mEPSCs in spinal lamina IIo nociceptive synapses in spinal cord slices. Together, our findings demonstrate a novel role of microglia in maintaining advanced phase cancer pain in females via producing the proinflammatory cytokine IL-18 to enhance synaptic transmission of spinal cord nociceptive neurons.
Large-scale pre-trained models (PTMs) such as BERT and GPT have recently achieved great success and become a milestone in the field of artificial intelligence (AI). Owing to sophisticated ...pre-training objectives and huge model parameters, large-scale PTMs can effectively capture knowledge from massive labeled and unlabeled data. By storing knowledge into huge parameters and fine-tuning on specific tasks, the rich knowledge implicitly encoded in huge parameters can benefit a variety of downstream tasks, which has been extensively demonstrated via experimental verification and empirical analysis. It is now the consensus of the AI community to adopt PTMs as backbone for downstream tasks rather than learning models from scratch. In this paper, we take a deep look into the history of pre-training, especially its special relation with transfer learning and self-supervised learning, to reveal the crucial position of PTMs in the AI development spectrum. Further, we comprehensively review the latest breakthroughs of PTMs. These breakthroughs are driven by the surge of computational power and the increasing availability of data, towards four important directions: designing effective architectures, utilizing rich contexts, improving computational efficiency, and conducting interpretation and theoretical analysis. Finally, we discuss a series of open problems and research directions of PTMs, and hope our view can inspire and advance the future study of PTMs.
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