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Increasing evidence has shown that thirdhand smoke (THS) exposure is likely to induce adverse health effects. An important knowledge gap remains in our understanding of THS exposure related to cancer risk in the human population. Population-based animal models are useful and powerful in investigating the interplay between host genetics and THS exposure on cancer risk. Here, we used the Collaborative Cross (CC) mouse population-based model system, which recapitulates the genetic and phenotypic diversity observed in the human population, to assess cancer risk after a short period of exposure, between 4 and 9 weeks of age. Eight CC strains (CC001, CC019, CC026, CC036, CC037, CC041, CC042 and CC051) were included in our study. We quantified pan-tumor incidence, tumor burden per mouse, organ tumor spectrum and tumor-free survival until 18 months of age. At the population level, we observed a significantly increased pan-tumor incidence and tumor burden per mouse in THS-treated mice as compared to the control (p = 3.04E-06). Lung and liver tissues exhibited the largest risk of undergoing tumorigenesis after THS exposure. Tumor-free survival was significantly reduced in THS-treated mice compared to control (p = 0.044). At the individual strain level, we observed a large variation in tumor incidence across the 8 CC strains. CC036 and CC041 exhibited a significant increase in pan-tumor incidence (p = 0.0084 and p = 0.000066, respectively) after THS exposure compared to control. We conclude that early-life THS exposure increases tumor development in CC mice and that host genetic background plays an important role in individual susceptibility to THS-induced tumorigenesis. Genetic background is an important factor that should be taken into account when determining human cancer risk of THS exposure.

SARS coronavirus 2 (SARS-CoV-2) has caused an ongoing global pandemic with significant mortality and morbidity. At this time, the only FDA-approved therapeutic for COVID-19 is remdesivir, a broad-spectrum antiviral nucleoside analog. Efficacy is only moderate, and improved treatment strategies are urgently needed. To accomplish this goal, we devised a strategy to identify compounds that act synergistically with remdesivir in preventing SARS-CoV-2 replication. We conducted combinatorial high-throughput screening in the presence of submaximal remdesivir concentrations, using a human lung epithelial cell line infected with a clinical isolate of SARS-CoV-2. This identified 20 approved drugs that act synergistically with remdesivir, many with favorable pharmacokinetic and safety profiles. Strongest effects were observed with established antivirals, Hepatitis C virus nonstructural protein 5A (HCV NS5A) inhibitors velpatasvir and elbasvir. Combination with their partner drugs sofosbuvir and grazoprevir further increased efficacy, increasing remdesivir's apparent potency > 25-fold. We report that HCV NS5A inhibitors act on the SARS-CoV-2 exonuclease proofreader, providing a possible explanation for the synergy observed with nucleoside analog remdesivir. FDA-approved Hepatitis C therapeutics Epclusa® (velpatasvir/sofosbuvir) and Zepatier® (elbasvir/grazoprevir) could be further optimized to achieve potency and pharmacokinetic properties that support clinical evaluation in combination with remdesivir.

Severe COVID-19 is associated with epithelial and endothelial barrier dysfunction within the lung as well as in distal organs. While it is appreciated that an exaggerated inflammatory response is associated with barrier dysfunction, the triggers of vascular leak are unclear. Here, we report that cell-intrinsic interactions between the Spike (S) glycoprotein of SARS-CoV-2 and epithelial/endothelial cells are sufficient to induce barrier dysfunction in vitro and vascular leak in vivo, independently of viral replication and the ACE2 receptor. We identify an S-triggered transcriptional response associated with extracellular matrix reorganization and TGF-β signaling. Using genetic knockouts and specific inhibitors, we demonstrate that glycosaminoglycans, integrins, and the TGF-β signaling axis are required for S-mediated barrier dysfunction. Notably, we show that SARS-CoV-2 infection caused leak in vivo, which was reduced by inhibiting integrins. Our findings offer mechanistic insight into SARS-CoV-2-triggered vascular leak, providing a starting point for development of therapies targeting COVID-19.

The COVID-19 pandemic is exacting an increasing toll worldwide, with new SARS-CoV-2 variants emerging that exhibit higher infectivity rates and that may partially evade vaccine and antibody immunity. Rapid deployment of non-invasive therapeutic avenues capable of preventing infection by all SARS-CoV-2 variants could complement current vaccination efforts and help turn the tide on the COVID-19 pandemic. Here, we describe a novel therapeutic strategy targeting the SARS-CoV-2 RNA using locked nucleic acid antisense oligonucleotides (LNA ASOs). We identify an LNA ASO binding to the 5' leader sequence of SARS-CoV-2 that disrupts a highly conserved stem-loop structure with nanomolar efficacy in preventing viral replication in human cells. Daily intranasal administration of this LNA ASO in the COVID-19 mouse model potently suppresses viral replication (>80-fold) in the lungs of infected mice. We find that the LNA ASO is efficacious in countering all SARS-CoV-2 "variants of concern" tested both in vitro and in vivo. Hence, inhaled LNA ASOs targeting SARS-CoV-2 represents a promising therapeutic approach to reduce or prevent transmission and decrease severity of COVID-19 in infected individuals. LNA ASOs are chemically stable and can be flexibly modified to target different viral RNA sequences and could be stockpiled for future coronavirus pandemics.

A visible‐light‐mediated radical heteroarylation of 2‐mercaptothiazolinium salts with N‐heteroarenes is reported, furnishing the corresponding functionalized N‐heteroarenes in good to high yields. Various alkyl bromides were converted conveniently into redox‐active thiazolinium salts and subsequently into alkyl radicals by reaction with an excited‐state photocatalyst. This mild protocol permits efficient functionalization of various N‐heteroarenes with a wild range of cyclic and acyclic primary and secondary alkyl groups. [ABSTRACT FROM AUTHOR]

In vitro cultures of primary cortical neurons are widely used to investigate neuronal function. However, it has yet to be fully investigated whether there are significant differences in development and function between cultured rodent and primate cortical neurons, and whether these differences influence the utilization of cultured cortical neurons to model pathological conditions. Using in vitro culture techniques combined with immunofluorescence and electrophysiological methods, our study found that the development and maturation of primary cerebral cortical neurons from cynomolgus monkeys were slower than those from mice. We used a microelectrode array technique to compare the electrophysiological differences in cortical neurons, and found that primary cortical neurons from the mouse brain began to show electrical activity earlier than those from the cynomolgus monkey. Although cultured monkey cortical neurons developed slowly in vitro, they exhibited typical pathological features-revealed by immunofluorescent staining-when infected with adeno-associated viral vectors expressing mutant huntingtin (HTT), the Huntington's disease protein. A quantitative analysis of the cultured monkey cortical neurons also confirmed that mutant HTT significantly reduced the length of neurites. Therefore, compared with the primary cortical neurons of mice, cultured monkey cortical neurons have longer developmental and survival times and greater sustained physiological activity, such as electrophysiological activity. Our findings also suggest that primary cynomolgus monkey neurons cultured in vitro can simulate a cell model of human neurodegenerative disease, and may be useful for investigating time-dependent neuronal death as well as treatment via neuronal regeneration. All mouse experiments and protocols were approved by the Animal Care and Use Committee of Jinan University of China (IACUC Approval No. 20200512-04) on May 12, 2020. All monkey experiments were approved by the IACUC protocol (IACUC Approval No. LDACU 20190820-01) on August 23, 2019 for animal management and use.

Up to now, numerous electric-powered wheelchairs (EPWs) have been developed for the disabled and the elderly. Among these EPWs, the traditional attendant-propelled power-assist wheelchairs (APAWs) usually run at a preset speed and greatly reduce the attendant's burden. Since the attendant's operating feeling is essential for the widespread use of the APAWs, many control approaches have been studied and developed. In the power-assist of our developed APAW, the speed of the wheelchair is controlled by the attendant's force to keep an appropriate burden with a natural operational feeling. In this study, we clarify the fact that the handle velocity of the APAW inevitably changes when passing through a slope, which causes the attendant to have an uncomfortable feeling. This phenomenon and its result in the uncomfortable feeling have not been reported yet. Consequently, in order to reduce or eliminate such uncomfortable feelings, we construct an APAW model on the slope and propose a velocity compensation method. From simulations and experiments, the validity of the proposed velocity compensation control is verified. [ABSTRACT FROM AUTHOR]

In order to improve the teaching level of engineering thermodynamics experiments and deepen students' understanding of the temperature and pressure characteristics of saturated gases and the concept of supercritical fluids, this article develops an experimental teaching equipment for saturated steam pressure temperature characteristics and supercritical phenomena. This equipment consists of a steam generation system and a data acquisition system, equipped with a large window with a diameter of 60 mm and an automatic control program, which has good visibility, safety, and operability. During the teaching process, four different refrigerants with different properties are used as research objects and teaching projects such as "Research on pressure temperature characteristics of saturated steam" and "Demonstration of critical ophthalmic phenomenon" are established. Through this experimental course, students can enhance their understanding of the micro meanings of pressure and temperature, as well as the concepts of gas-liquid equilibrium in saturated states. They can master common methods and characteristics of pressure and temperature measurement and understand commonly used data processing and error analysis methods. At the same time, students can deepen their understanding of material phases by observing the mutual transformation process between subcritical and supercritical fluids. [ABSTRACT FROM AUTHOR]

In this paper, we consider the existence and uniqueness of random periodic solutions of the SDEs with coefficients satisfying the one-sided Lipschitz condition. By using the tamed Euler-Maruyama (EM) method we give a numerical approximation for the random periodic solution and reveal that the numerical approximation converges to the exact solution with an order a ∈ (0,1/2) in the mean square sense. Examples are given to verify the theoretical result. [ABSTRACT FROM AUTHOR]