In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ...∼6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds; we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and three-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, a category B anthelmintic drug approved by the US Food and Drug Administration, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.
Automatic surface detection for quality control has largely employed image processing techniques, for example in steel and fabric defect inspection. There are rising demands in the quality control ...industry for defective image analysis to fulfill its vital role in visual inspection. In this paper, we introduce an unsupervised method using a low-rank representation based on texture prior for detection of defects on natural surfaces and formulate the detection process as a novel weighted low-rank reconstruction model. The first step of the proposed method estimates the texture prior to a given image by constructing a texture prior map where higher values indicate a higher probability of abnormality. The second step of the proposed method detects the defect via low-rank decomposition with the help of the texture prior. Experiments on synthetic and real images show that the proposed method is superior in terms of detection accuracy and competitive in computational efficiency with respect to the state-of-the-art methods in surface defect detection research. This contribution is of particular interest for manufacturers (e.g., steel and fabric) for which defect detection largely relies on manual inspection.
The world’s climate has changed dramatically in recent years due to the development of the industry. Climate change can significantly affect hydropower plants. One of the negative effects of climate ...change is the reduction of hydropower generation. Therefore, to better management of power supply and demand, the climate change effect on hydropower plants should be examined. The main purpose of this study is the prediction of future hydropower generation (2021–2050) in terms of climate change. One of the factors sensitive to climate change in hydropower plants is the amount of input flow to the reservoir. In this study, a method has been used that can increase the accuracy of flow estimation. This innovation is the use of the ANN model under the new version of the Developed Crow Search Algorithm (DCSA). This algorithm increases the accuracy of prediction by solving optimization disadvantages such as getting stuck in the optimal location, the imbalance between exploitation and exploration at different levels The results showed that the DCSA algorithm with minimum error (MSE = 1.06) and maximum correlation (R2 = 0.88) compared to other algorithms has the best performance. The results of the prediction of climate change under RCPs scenarios showed that the average annual power generation will decrease under RCP2.6 and RCP4.5 and RCP8.5 about 10.74% and% 16.38 and 22.25% respectively. Also, the average annual power generation under scenarios RCP2.6, RCP4.5, and RCP8.5 by 2050 are 740.33 MW, 603.12 MW, and 585.77 MW, respectively.
Long noncoding RNA (lncRNA) FOXC2-AS1 has been reported to act as an oncogene in multiple human cancers. However, the clinical significance, functional role and underlying mechanism of FOXC2-AS1 in ...gastric cancer (GC) remains largely unknown. Here, we found that FOXC2-AS1 expression was significantly elevated in GC tissues and cells, and overexpression of FOXC2-AS1 indicated advanced TNM stage and shorter overall survival in GC patients. Functionally, knockdown of FOXC2-AS1 attenuated the proliferation, migration and invasion of GC cells, whereas overexpression of FOXC2-AS1 showed the opposite effects. Further investigation revealed that FOXC2-AS1 interacted with FOXC2 mRNA and repressed its degradation. FOXC2-AS1 recruited RNA methyltransferase NSUN2 to FOXC2 mRNA, increasing its m
5
C level and association with YBX1. Taken together, our findings suggested that FOXC2-AS1 acted as an oncogenic lncRNA by stabilizing FOXC2 mRNA in an m
5
C-dependent manner, which may provide a novel therapeutic target for GC.
The clinical development of drug combinations is typically achieved through trial-and-error or via insight gained through a detailed molecular understanding of dysregulated signaling pathways in a ...specific cancer type. Unbiased small-molecule combination (matrix) screening represents a high-throughput means to explore hundreds and even thousands of drug–drug pairs for potential investigation and translation. Here, we describe a high-throughput screening platform capable of testing compounds in pairwise matrix blocks for the rapid and systematic identification of synergistic, additive, and antagonistic drug combinations. We use this platform to define potential therapeutic combinations for the activated B-cell–like subtype (ABC) of diffuse large B-cell lymphoma (DLBCL). We identify drugs with synergy, additivity, and antagonism with the Bruton’s tyrosine kinase inhibitor ibrutinib, which targets the chronic active B-cell receptor signaling that characterizes ABC DLBCL. Ibrutinib interacted favorably with a wide range of compounds, including inhibitors of the PI3K-AKT-mammalian target of rapamycin signaling cascade, other B-cell receptor pathway inhibitors, Bcl-2 family inhibitors, and several components of chemotherapy that is the standard of care for DLBCL.
Smart healthcare management is one of the frontier research directions. It is vital to achieve life assistance through data science, innovative technology, and wearable devices for residents who age ...at home. This paper analyzes 42 aids of intelligent communities in residents’ physical, psychological, and medical aspects to understand the demand factors for health-assisted public products and services. The results show that: (1) the importance of intelligent assistance technology is significant; (2) the demand for medical monitoring is the highest, especially for an emergency button, fall detection, sleep drop detection, electronic fence, and medication management; (3) remote nursing and telemedicine has the most significant direct and indirect effect on the need for elderly assistance respectively; and (4) health monitoring affects the need for aging assistance by affecting emergency assistance and psychological assistance. Finally, this paper proposes construction strategies for the space design and the elderly care system of communities.
Plain Language Summary
Smart healthcare management is one of the frontier research directions. It is vital to achieve life assistance through data science, innovative technology, and wearable devices for residents who age at home. This paper analyzes 42 aids of intelligent communities in residents’ physical, psychological, and medical aspects to understand the demand factors for health-assisted public products and services.
Control of parasite transmission is critical for the eradication of malaria. However, most antimalarial drugs are not active against P. falciparum gametocytes, responsible for the spread of malaria. ...Consequently, patients can remain infectious for weeks after the clearance of asexual parasites and clinical symptoms. Here we report the identification of 27 potent gametocytocidal compounds (IC50 < 1 μM) from screening 5,215 known drugs and compounds. All these compounds were active against three strains of gametocytes with different drug sensitivities and geographical origins, 3D7, HB3 and Dd2. Cheminformatic analysis revealed chemical signatures for P. falciparum sexual and asexual stages indicative of druggability and suggesting potential targets. Torin 2, a top lead compound (IC50 = 8 nM against gametocytes in vitro), completely blocked oocyst formation in a mouse model of transmission. These results provide critical new leads and potential targets to expand the repertoire of malaria transmission-blocking reagents.
SARS-CoV-2 infection causes spike-dependent fusion of infected cells with ACE2 positive neighboring cells, generating multi-nuclear syncytia that are often associated with severe COVID. To better ...elucidate the mechanism of spike-induced syncytium formation, we combine chemical genetics with 4D confocal imaging to establish the cell surface heparan sulfate (HS) as a critical stimulator for spike-induced cell-cell fusion. We show that HS binds spike and promotes spike-induced ACE2 clustering, forming synapse-like cell-cell contacts that facilitate fusion pore formation between ACE2-expresing and spike-transfected human cells. Chemical or genetic inhibition of HS mitigates ACE2 clustering, and thus, syncytium formation, whereas in a cell-free system comprising purified HS and lipid-anchored ACE2, HS stimulates ACE2 clustering directly in the presence of spike. Furthermore, HS-stimulated syncytium formation and receptor clustering require a conserved ACE2 linker distal from the spike-binding site. Importantly, the cell fusion-boosting function of HS can be targeted by an investigational HS-binding drug, which reduces syncytium formation in vitro and viral infection in mice. Thus, HS, as a host factor exploited by SARS-CoV-2 to facilitate receptor clustering and a stimulator of infection-associated syncytium formation, may be a promising therapeutic target for severe COVID.
Because the TSH receptor (TSHR) plays an important role in the pathogenesis of thyroid disease, a TSHR antagonist could be a novel treatment. We attempted to develop a small molecule, drug-like ...antagonist of TSHR signaling that is selective and active in vivo. We synthesized NCGC00242364 (ANTAG3) by chemical modification of a previously reported TSHR antagonist. We tested its potency, efficacy, and selectivity in a model cell system in vitro by measuring its activity to inhibit stimulation of cAMP production stimulated by TSH, LH, or FSH. We tested the in vivo activity of ANTAG3 by measuring its effects to lower serum free T4 and thyroid gene expression in female BALB/c mice continuously treated with ANTAG3 for 3 days and given low doses of TRH continuously or stimulated by a single administration of a monoclonal thyroid-stimulating antibody M22. ANTAG3 was selective for TSHR inhibition; half-maximal inhibitory doses were 2.1 μM for TSHR and greater than 30 μM for LH and FSH receptors. In mice treated with TRH, ANTAG3 lowered serum free T4 by 44% and lowered mRNAs for sodium-iodide cotransporter and thyroperoxidase by 75% and 83%, respectively. In mice given M22, ANTAG3 lowered serum free T4 by 38% and lowered mRNAs for sodium-iodide cotransporter and thyroperoxidase by 73% and 40%, respectively. In conclusion, we developed a selective TSHR antagonist that is effective in vivo in mice. This is the first report of a small-molecule TSHR antagonist active in vivo and may lead to a drug to treat Graves' disease.
Neuregulin 1 (NRG1) and ErbB4, critical neurodevelopmental genes, are implicated in schizophrenia, but the mediating mechanisms are unknown. Here we identify a genetically regulated, ...pharmacologically targetable, risk pathway associated with schizophrenia and with ErbB4 genetic variation involving increased expression of a PI3K-linked ErbB4 receptor (CYT-1) and the phosphoinositide 3-kinase subunit, p110δ (PIK3CD). In human lymphoblasts, NRG1-mediated phosphatidyl-inositol,3,4,5 triphosphate PI(3,4,5)P3 signaling is predicted by schizophrenia-associated ErbB4 genotype and PIK3CD levels and is impaired in patients with schizophrenia. In human brain, the same ErbB4 genotype again predicts increased PIK3CD expression. Pharmacological inhibition of p110δ using the small molecule inhibitor, IC87114, blocks the effects of amphetamine in a mouse pharmacological model of psychosis and reverses schizophrenia-related phenotypes in a rat neonatal ventral hippocampal lesion model. Consistent with these antipsychotic-like properties, IC87114 increases AKT phosphorylation in brains of treated mice, implicating a mechanism of action. Finally, in two family-based genetic studies, PIK3CD shows evidence of association with schizophrenia. Our data provide insight into a mechanism of ErbB4 association with schizophrenia; reveal a previously unidentified biological and disease link between NRG1-ErbB4, p110δ, and AKT; and suggest that p110δ is a previously undescribed therapeutic target for the treatment of psychiatric disorders.
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