Single-cell RNA sequencing algorithms underestimate changes in transcriptional noise compared to single-molecule RNA imaging.

Stochastic fluctuations (noise) in transcription generate substantial cell-to-cell variability. However, how best to quantify genome-wide noise remains unclear. Here, we utilize a small-molecule perturbation (5'-iodo-2'-deoxyuridine [IdU]) to amplify noise and assess noise quantification from numerous single-cell RNA sequencing (scRNA-seq) algorithms on human and mouse datasets and then compare it to noise quantification from single-molecule RNA fluorescence in situ hybridization (smFISH) for a panel of representative genes.

Quantitative comparison of single-cell RNA sequencing versus single-molecule RNA imaging for quantifying transcriptional noise.

Stochastic fluctuations (noise) in transcription generate substantial cell-to-cell variability. However, how best to quantify genome-wide noise, remains unclear. Here we utilize a small-molecule perturbation (IdU) to amplify noise and assess noise quantification from numerous scRNA-seq algorithms on human and mouse datasets, and then compare to noise quantification from single-molecule RNA FISH (smFISH) for a panel of representative genes.

Engineered deletions of HIV replicate conditionally to reduce disease in nonhuman primates.

Antiviral therapies with reduced frequencies of administration and high barriers to resistance remain a major goal. For HIV, theories have proposed that viral-deletion variants, which conditionally replicate with a basic reproductive ratio [R] > 1 (termed "therapeutic interfering particles" or "TIPs"), could parasitize wild-type virus to constitute single-administration, escape-resistant antiviral therapies. We report the engineering of a TIP that, in rhesus macaques, reduces viremia of a highly pathogenic model of HIV by >3log following a single intravenous injection.

Evidence for Behavioral Autorepression in Covid-19 Epidemiological Dynamics.

Unlabelled: It has long been hypothesized that behavioral reactions to epidemic severity autoregulate infection dynamics, for example when susceptible individuals self-sequester based on perceived levels of circulating disease. However, evidence for such 'behavioral autorepression' has remained elusive, and its presence could significantly affect epidemic forecasting and interventions. Here, we analyzed early COVID-19 dynamics at 708 locations over three epidemiological scales (96 countries, 50 US states, and 562 US counties).

HER2 and HLA-A*02 dual CAR-T cells utilize LOH in a NOT logic gate to address on-target off-tumor toxicity.

Background: One of the major challenges in chimeric antigen receptor (CAR)-T cell therapy for solid tumors is the potential for on-target off-tumor toxicity due to the expression of CAR tumor antigens in essential tissues and organs. Here, we describe a dual CAR NOT gate incorporating an inhibitory CAR (iCAR) recognizing HLA-A*02 ("A2") that enables effective treatment with a potent HER2 activating CAR (aCAR) in the context of A2 loss of heterozygosity (LOH).

Methods: A CAR-T cell screen was conducted to identify inhibitory domains derived from natural immune receptors (iDomains) to be used in a NOT gate, to kill A2 HER2 lung cancer cell lines but spare A2 HER2 lung cancer cell-lines with high specificity.