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CarD, an essential transcription regulator in Mycobacterium tuberculosis , directly interacts with the RNA polymerase (RNAP). We used a combination of in vivo and in vitro approaches to establish that CarD is a global regulator that stimulates the formation of RNAP-holoenzyme open promoter (RPo) complexes. We determined the X-ray crystal structure of Thermus thermophilus CarD, allowing us to generate a structural model of the CarD/RPo complex. On the basis of our structural and functional analyses, we propose that CarD functions by forming protein/protein and protein/DNA interactions that bridge the RNAP to the promoter DNA. CarD appears poised to interact with a DNA structure uniquely presented by the RPo: the splayed minor groove at the double-stranded/single-stranded DNA junction at the upstream edge of the transcription bubble. Thus, CarD uses an unusual mechanism for regulating transcription, sensing the DNA conformation where transcription bubble formation initiates.

The ability to regulate gene expression through transcription initiation underlies the adaptability and survival of all bacteria. Recent work has revealed that the transcription machinery in many bacteria diverges from the paradigm that has been established in Escherichia coli. Mycobacterium tuberculosis (Mtb) encodes the RNA polymerase (RNAP)-binding protein CarD, which is absent in E. coli but is required to form stable RNAP-promoter open complexes (RPₒ) and is essential for viability in Mtb. The stabilization of RPₒ by CarD has been proposed to result in activation of gene expression; however, CarD has only been examined on limited promoters that do not represent the typical promoter structure in Mtb. In this study, we investigate the outcome of CarD activity on gene expression from Mtb promoters genome-wide by performing RNA sequencing on a panel of mutants that differentially affect CarD’s ability to stabilize RPₒ. In all CarD mutants, the majority of Mtb protein encoding transcripts were differentially expressed, demonstrating that CarD had a global effect on gene expression. Contrary to the expected role of CarD as a transcriptional activator, mutation of CarD led to both up- and down-regulation of gene expression, suggesting that CarD can also act as a transcriptional repressor. Furthermore, we present evidence that stabilization of RPₒ by CarD could lead to transcriptional repression by inhibiting promoter escape, and the outcome of CarD activity is dependent on the intrinsic kinetic properties of a given promoter region. Collectively, our data support CarD’s genome-wide role of regulating diverse transcription outcomes.

Neuroimaging research requires purpose-built analysis software, which is challenging to install and may produce different results across computing environments. The community-oriented, open-source Neurodesk platform ( https://www.neurodesk.org/ ) harnesses a comprehensive and growing suite of neuroimaging software containers. Neurodesk includes a browser-accessible virtual desktop, command-line interface and computational notebook compatibility, allowing for accessible, flexible, portable and fully reproducible neuroimaging analysis on personal workstations, high-performance computers and the cloud. Neurodesk is a platform for analyzing human neuroimaging data, which provides numerous tools in a containerized form, thereby ensuring reproducibility and portability.

NP105–113-B*07:02-specific CD8+ T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP105–113-B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP105–113-B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP105–113-B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP105–113-B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design.Peng et al. find that immunodominant cytotoxic T lymphocytes (CTLs) specific for NP105–113-B*07:02 are associated with reduced COVID-19 severity. Mechanistically, NP105–113-B*07:02-specific CTLs show potent antiviral functionality and may represent rational T cell vaccine targets.

E-cigarettes (electronic cigarettes) have been the most used tobacco product among US youth since 2014, reaching a plateau during the COVID-19 pandemic. Youth e-cigarette use is associated with negative health consequences such as impaired cognitive functioning. For many, the COVID-19 pandemic altered social interactions, harm perceptions, and product availability. This changed the frequency and locations in which youth use e-cigarettes. To better understand youth e-cigarette use, we need more information on factors that can alter e-cigarette use, specifically, how the pandemic changed e-cigarette use among youth. In 2020-2021, we conducted online, individual interviews with 19 youth (aged 13-17) e-cigarette users living in the US to explore how COVID-19 impacted their e-cigarette use. Youth described a progression of e-cigarette use from initial experimentation, regular social use, and ultimately to nicotine addiction demonstrated by individual use in isolation. Many youth initiated e-cigarette use due to influences by friends or family members. Youth discussed progression to social use, with social interactions as an important reason for use and an avenue for expanding one’s knowledge of e-cigarettes. After a period of time, youth began to recognize that the social interactions mattered less, suggesting to them that they had become addicted. This realization became more apparent during COVID-19, which changed how youth used e-cigarettes, especially around where use was occurring, health concerns, and use behavior and frequency. In our interviews, youth trajectory began with an initiation with family and friends, progressed to social use, and eventually developed to addiction, at which point social use was no longer the primary motivation for e-cigarette use. Understanding the trajectory of e-cigarette use will allow for effective interventions that reduce harm to youth from e-cigarette use.

Abstract BackgroundTo estimate the infectious period of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older adults with underlying conditions, we assessed duration of coronavirus disease 2019 (COVID-19) symptoms, reverse-transcription polymerase chain reaction (RT-PCR) positivity, and culture positivity among nursing home residents. MethodsWe enrolled residents within 15 days of their first positive SARS-CoV-2 test (diagnosis) at an Arkansas facility from July 7 to 15, 2020 and instead them for 42 days. Every 3 days for 21 days and then weekly, we assessed COVID-19 symptoms, collected specimens (oropharyngeal, anterior nares, and saliva), and reviewed medical charts. Blood for serology was collected on days 0, 6, 12, 21, and 42. Infectivity was defined by positive culture. Duration of culture positivity was compared with duration of COVID-19 symptoms and RT-PCR positivity. Data were summarized using measures of central tendency, frequencies, and proportions. ResultsWe enrolled 17 of 39 (44%) eligible residents. Median participant age was 82 years (range, 58–97 years). All had ≥3 underlying conditions. Median duration of RT-PCR positivity was 22 days (interquartile range [IQR], 8–31 days) from diagnosis; median duration of symptoms was 42 days (IQR, 28–49 days). Of 9 (53%) participants with any culture-positive specimens, 1 (11%) severely immunocompromised participant remained culture-positive 19 days from diagnosis; 8 of 9 (89%) were culture-positive ≤8 days from diagnosis. Seroconversion occurred in 12 of 12 (100%) surviving participants with ≥1 blood specimen; all participants were culture-negative before seroconversion. ConclusionsDuration of infectivity was considerably shorter than duration of symptoms and RT-PCR positivity. Severe immunocompromise may prolong SARS-CoV-2 infectivity. Seroconversion indicated noninfectivity in this cohort. Among 17 nursing home residents with laboratory-confirmed COVID-19, replication-competent virus was isolated >8 days from diagnosis in only 1 severely immunocompromised resident, despite longer median symptom duration and RT-PCR positivity. Seroconversion, assessed in 12 residents, occurred after culture negativity.

Neuroimaging data analysis often requires purpose-built software, which can be difficult to install and may produce different results across computing environments. Beyond being a roadblock to neuroscientists, these issues of accessibility and portability can hamper the reproducibility of neuroimaging data analysis pipelines. Here, we introduce the Neurodesk platform, which offers a sustainable, flexible solution; harnessing software containers to support a comprehensive and growing suite of neuroimaging software (https://www.neurodesk.org/). Neurodesk includes both a browser-accessible virtual desktop environment and a command line interface, mediating access to containerised neuroimaging software libraries from multiple systems; including personal computers, cloud computing, high-performance computers, and Jupyter notebooks. This community-driven, open-source platform represents a paradigm shift for neuroimaging data analysis, allowing for accessible, fully reproducible and portable data analysis pipelines, which can be redeployed in perpetuity, in any computing environment, with ease.Competing Interest StatementThe authors have declared no competing interest.Footnotes* https://www.neurodesk.org/* https://github.com/NeuroDesk