The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat. The efficacy of several ...repurposed drugs has been evaluated in clinical trials. Among these drugs, a second-generation antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and Ad-ACE2-transduced mice. Tmprss2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cells, however, such antiviral efficacy was lacking in human lung cells and organoids. Accordingly, enzalutamide showed no antiviral activity due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 regulatory locus in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19 through reducing TMPRSS2 expression in lung cells.
MicroRNAs (miRNAs) have been regarded as promising biomarkers for the diagnosis and prognosis of early‐stage cancer as their expression levels are associated with different types of human cancers. ...However, it is a challenge to produce low‐cost miRNA sensors, as well as retain a high sensitivity, both of which are essential factors that must be considered in fabricating nanoscale biosensors and in future biomedical applications. To address such challenges, we develop a complementary metal oxide semiconductor (CMOS)‐compatible SiNW‐FET biosensor fabricated by an anisotropic wet etching technology with self‐limitation which provides a much lower manufacturing cost and an ultrahigh sensitivity. This nanosensor shows a rapid (< 1 minute) detection of miR‐21 and miR‐205, with a low limit of detection (LOD) of 1 zeptomole (ca. 600 copies), as well as an excellent discrimination for single‐nucleotide mismatched sequences of tumor‐associated miRNAs. To investigate its applicability in real settings, we have detected miRNAs in total RNA extracted from lung cancer cells as well as human serum samples using the nanosensors, which demonstrates their potential use in identifying clinical samples for early diagnosis of cancer.
miRNA sensors with an ultrahigh sensitivity in the zeptomolar region that are easy to fabricate at very low cost are demonstrated. The CMOS‐compatible SiNW‐FETbiosensors show a much improved selectivity and sensitivity for miRNA family members compared to conventional detection methods. These sensors will be crucial in the early diagnosis and prognosis of cancers.
We herein report the design of a novel semiconducting silicon nanowire field-effect transistor (SiNW-FET) biosensor array for ultrasensitive label-free and real-time detection of nucleic acids. ...Highly responsive SiNWs with narrow sizes and high surface-to-volume-ratios were “top-down” fabricated with a complementary metal oxide semiconductor compatible anisotropic self-stop etching technique. When SiNWs were covalently modified with DNA probes, the nanosensor showed highly sensitive concentration-dependent conductance change in response to specific target DNA sequences. This SiNW-FET nanosensor revealed ultrahigh sensitivity for rapid and reliable detection of 1 fM of target DNA and high specificity single-nucleotide polymorphism discrimination. As a proof-of-concept for multiplex detection with this small-size and mass producible sensor array, we demonstrated simultaneous selective detection of two pathogenic strain virus DNA sequences (H1N1 and H5N1) of avian influenza.
Programmed DNA recombination in mammalian cells occurs predominantly in a directional manner. While random DNA breaks are typically repaired both by deletion and by inversion at approximately equal ...proportions, V(D)J and class switch recombination (CSR) of immunoglobulin heavy chain gene overwhelmingly delete intervening sequences to yield productive rearrangement. What factors channel chromatin breaks to deletional CSR in lymphocytes is unknown. Integrating CRISPR knockout and chemical perturbation screening we here identify the Snf2-family helicase-like ERCC6L2 as one such factor. We show that ERCC6L2 promotes double-strand break end-joining and facilitates optimal CSR in mice. At the cellular levels, ERCC6L2 rapidly engages in DNA repair through its C-terminal domains. Mechanistically, ERCC6L2 interacts with other end-joining factors and plays a functionally redundant role with the XLF end-joining factor in V(D)J recombination. Strikingly, ERCC6L2 controls orientation-specific joining of broken ends during CSR, which relies on its helicase activity. Thus, ERCC6L2 facilitates programmed recombination through directional repair of distant breaks.
The targeting efficiency of knockin sequences via homologous recombination (HR) is generally low. Here we describe a method we call Tild-CRISPR (targeted integration with linearized dsDNA-CRISPR), a ...targeting strategy in which a PCR-amplified or precisely enzyme-cut transgene donor with 800-bp homology arms is injected with Cas9 mRNA and single guide RNA into mouse zygotes. Compared with existing targeting strategies, this method achieved much higher knockin efficiency in mouse embryos, as well as brain tissue. Importantly, the Tild-CRISPR method also yielded up to 12-fold higher knockin efficiency than HR-based methods in human embryos, making it suitable for studying gene functions in vivo and developing potential gene therapies.
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•Tild-CRISPR uses in vitro linearized transgene donor with 800-bp HA•Tild-CRISPR is a simple and efficient method for creating gene-modified mice•Tild-CRISPR shows robust DNA knockin efficiency in mouse brain and human embryos
Yao et al. describe Tild-CRISPR, a targeting strategy using PCR-amplified or precisely enzyme-cut transgene donor sequence. Tild-CRISPR yields robust knockin efficiency in mouse and human embryos, as well as mouse brain in vivo, suitable for studying gene functions in vivo and developing potential gene therapies.
Silicon nanowire (SiNW) field effect transistors (FETs) have emerged as powerful sensors for ultrasensitive, direct electrical readout, and label-free biological/chemical detection. The sensing ...mechanism of SiNW-FET can be understood in terms of the change in charge density at the SiNW surface after hybridization. So far, there have been limited systematic studies on fundamental factors related to device sensitivity to further make clear the overall effect on sensing sensitivity. Here, we present an analytical result for our triangle cross-section wire for predicting the sensitivity of nanowire surface-charge sensors. It was confirmed through sensing experiments that the back-gated SiNW-FET sensor had the highest percentage current response in the subthreshold regime and the sensor performance could be optimized in low buffer ionic strength and at moderate probe concentration. The optimized SiNW-FET nanosensor revealed ultrahigh sensitivity for rapid and reliable detection of target DNA with a detection limit of 0.1 fM and high specificity for single-nucleotide polymorphism discrimination. In our work, enhanced sensing of biological species by optimization of operating parameters and fundamental understanding for SiNW FET detection limit was obtained.
Walking impairment, a common health problem among older adults, has been linked to poor vision and mental health. This study aimed to investigate the associations of walking impairment with visual ...impairment, depression, and cognitive function in older adults.
A total of 1,489 adults aged 60 years and older who had participated in the National Health and Examination Survey (NHANES) 2013-2014 in the United States were included. Multivariate logistic regression models were used to examine the associations of walking impairment with visual impairment, depression, and four subdomains of cognitive function. Sample weights were used to ensure the generalizability of the results.
Among all the participants (median age = 68 years; 53.7% women), 17.5% reported walking impairment. Walking impairment was significantly associated with visual impairment (adjusted odds ratio aOR = 2.76; 95% CI: 1.47-5.20) and depression (aOR = 4.66; 95% CI: 3.11-6.99). Walking impairment was only associated with the Digit Symbol Substitution (DSST) subdomain of cognitive function in total participants (aOR = 0.97; 95% CI: 0.95-0.99) and in non-Hispanic white adults (aOR = 0.96; 95% CI: 0.94-0.98). Participants with two or three impairment indicators had a higher OR of walking impairment (aOR = 3.64, 95% CI = 2.46-5.38) than those with 0-1 (reference group) impairment indicator.
Walking impairment was associated with visual impairment, depression, and cognitive impairment in American older adults and also positively associated with the number of impairment indicators. The association between walking impairment and cognitive impairment varied according to race. Evaluations of vision, cognition, and depression should be conducted among older adults with walking impairment, and the needs of older adults should be provided in the evaluations alongside information on the biological aspects of their particular race.
This review article focuses on providing a full picture of preparing high quality metal halide perovskite films for realizing high performance perovskite solar cells, including the strategies of ...antisolvent, Lewis acid-base, additive engineering, scaleable fabrication, strain engineering and band gap adjustment.
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With the development of human society, the problems of environmental deterioration and energy shortage have become increasingly prominent. In order to solve these problems, metal halide perovskite solar cells (PSCs) stand out because of their excellent properties (i.e., high optical absorption coefficient, long carrier lifetime and carrier diffusion length, adjustable band gap) and have been widely studied. PSCs with low cost, high power conversion efficiency and high stability are the future development trend. The quality of perovskite film is essential for fabricating PSCs with high performance. To provide a full picture of realizing high performance PSCs, this review focuses on the strategies for preparing high quality perovskite films (including antisolvent, Lewis acid-base, additive engineering, scaleable fabrication, strain engineering and band gap adjustment), and therefore to fabricate high performance PSCs and to accelerate the commercialization.
The formation mechanism of passivation film and corrosion resistance of (40-x)Zr-30Ti-20Nb-10Al-xTa (x=0, 2, 4, atom fraction/%, the same below, referred to as Tax alloy) high entropy alloy in a ...0.3mol/L LiOH solution were investigated by potentiodynamic polarization, electrochemical impedance technique, Mott-Schottky analysis and potentiostatic polarization. The results show that the addition of appropriate amount of Ta (2%) helps to form a compact oxide film, which improves the corrosion resistance, while the excessive amount of Ta (4%) decreases the corrosion resistance due to the increase of oxygen vacancy concentration. The corrosion current density of the Ta2 alloy is 49.66 nA/cm2, which is less than the Ta0 and Ta4 alloys of 201.40, 70.16 nA/cm2. The concentration of oxygen vacancy point defect in the passivation film of the Ta2 alloy is 9.79×1018 cm-3, which is less than 2.13×1019, 2.05×1019 cm-3 in the Ta0 and Ta4 alloys, with the most compact passive film structure. The passivation film of the alloy
With the development of high-voltage and high-frequency switching circuits, GaN high-electron-mobility transistor (HEMT) devices with high bandwidth, high electron mobility, and high breakdown ...voltage have become an important research topic in this field. It has been found that GaN HEMT devices have a drift in threshold voltage under the conditions of temperature and gate stress changes. Under high-temperature conditions, the difference in gate contact also causes the threshold voltage to shift. The variation in the threshold voltage affects the stability of the device as well as the overall circuit performance. Therefore, in this paper, a review of previous work is presented. Temperature variation, gate stress variation, and gate contact variation are investigated to analyze the physical mechanisms that generate the threshold voltage (
) drift phenomenon in GaN HEMT devices. Finally, improvement methods suitable for GaN HEMT devices under high-temperature and high-voltage conditions are summarized.
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