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  1. Free, publicly-accessible full text available August 1, 2024
  2. Rapid and ultrasensitive point-of-care RNA detection plays a critical role in the diagnosis and management of various infectious diseases. The gold-standard detection method of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is ultrasensitive and accurate yet limited by the lengthy turnaround time (1-2 days). On the other hand, antigen test offers rapid at-home detection (15-20 min) but suffers from low sensitivity and high false-negative rates. An ideal point-of-care diagnostic device would combine the merits of PCR-level sensitivity and rapid sample-to-result workflow comparable to antigen testing. However, the existing RNA detection platform typically possesses superior sensitivity or rapid sample-to-result time, but not both. This paper reports a point-of-care microfluidic device that offers ultrasensitive yet rapid detection of viral RNA from clinical samples. The device consists of a microfluidic chip for precisely manipulating small volumes of samples, a miniaturized heater for viral lysis and ribonuclease (RNase) inactivation, a CRISPR Cas13a- electrochemical sensor for target preamplification-free and ultrasensitive RNA detection, and a smartphone-compatible potentiostat for data acquisition. As demonstrations, the devices achieve the detection of heat-inactivated SARS-CoV-2 samples with a limit of detection (LOD) down to 10 aM within 25 minutes, which is comparable to the sensitivity of RT-PCR and rapidness of antigen test. The platform also successfully distinguishes all nine positive unprocessed clinical SARS-CoV-2 nasopharyngeal swab samples from four negative samples within 25 minutes of sample-to-result time. Together, this device provides a point-of-care solution that can be deployed in diverse settings beyond laboratory environments for rapid and accurate detection of RNA from clinical samples. The device can potentially be expandable to detect other viral targets, such as human immunodeficiency virus (HIV) self-testing and Zika virus, where rapid and ultrasensitive point-of-care detection is required. 
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    Free, publicly-accessible full text available July 26, 2024
  3. Abstract

    DNA base editors use deaminases fused to a programmable DNA-binding protein for targeted nucleotide conversion. However, the most widely used TadA deaminases lack post-translational control in living cells. Here, we present a split adenine base editor (sABE) that utilizes chemically induced dimerization (CID) to control the catalytic activity of the deoxyadenosine deaminase TadA-8e. sABE shows high on-target editing activity comparable to the original ABE with TadA-8e (ABE8e) upon rapamycin induction while maintaining low background activity without induction. Importantly, sABE exhibits a narrower activity window on DNA and higher precision than ABE8e, with an improved single-to-double ratio of adenine editing and reduced genomic and transcriptomic off-target effects. sABE can achieve gene knockout through multiplex splice donor disruption in human cells. Furthermore, when delivered via dual adeno-associated virus vectors, sABE can efficiently convert a single A•T base pair to a G•C base pair on thePCSK9gene in mouse liver, demonstrating in vivo CID-controlled DNA base editing. Thus, sABE enables precise control of base editing, which will have broad implications for basic research and in vivo therapeutic applications.

     
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  4. Free, publicly-accessible full text available April 28, 2024
  5. Sustainable development requires an accelerated transition toward renewable energy. In particular, substantially scaling up solar photovoltaics (PV) adoption is a crucial component of reducing the impacts of climate change and promoting sustainable development. However, it is challenging to convince local governments to take action. This study uses a combination of propensity score matching (PSM) and difference-in-differences (DID) models to assess the effectiveness of a voluntary environmental program (VEP) called SolSmart that targets local governments to engage in solar-friendly practices to promote the local solar PV market in the United States. Via specific designation requirements and technical assistance, SolSmart simplifies the process of acting on interest in being solar friendly, has a wide coverage of basic solar-friendly actions with flexible implementation, and motivates completion with multiple levels of designation. We find that a local government’s participation in SolSmart is associated with an increased installed capacity of 18 to 19%/mo or with less statistical significance, an increased number of installations of 17%/mo in its jurisdiction. However, SolSmart has not shown a statistically significant impact on soft cost reductions to date. In evaluating the impact of the SolSmart program, this study improves our understanding of the causation between a VEP that encourages solar-friendly local government practices and multiple solar market outcomes. VEPs may be able to promote shifts toward sustainable development at the local level. Our findings have several implications for the design of VEPs that promote local sustainability. 
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  6. Abstract

    Base editors (BEs) hold great potential for medical applications of gene therapy. However, high precision base editing requires BEs that can discriminate between the target base and multiple bystander bases within a narrow active window (4 – 10 nucleotides). Here, to assist in the design of these optimized editors, we propose a discrete-state stochastic approach to build an analytical model that explicitly evaluates the probabilities of editing the target base and bystanders. Combined with all-atom molecular dynamic simulations, our model reproduces the experimental data of A3A-BE3 and its variants for targeting the “TC” motif and bystander editing. Analyzing this approach, we propose several general principles that can guide the design of BEs with a reduced bystander effect. These principles are then applied to design a series of point mutations at T218 position of A3G-BEs to further reduce its bystander editing. We verify experimentally that the new mutations provide different levels of stringency on reducing the bystander editing at different genomic loci, which is consistent with our theoretical model. Thus, our study provides a computational-aided platform to assist in the scientifically-based design of BEs with reduced bystander effects.

     
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