Neurotensin (Nts) is a neuropeptide implicated in the regulation of many facets of physiology, including cardiovascular tone, pain processing, ingestive behaviors, locomotor drive, sleep, addiction ...and social behaviors. Yet, there is incomplete understanding about how the various populations of Nts neurons distributed throughout the brain mediate such physiology. This knowledge gap largely stemmed from the inability to simultaneously identify Nts cell bodies and manipulate them in vivo. One means of overcoming this obstacle is to study NtsCre mice crossed onto a Cre-inducible green fluorescent reporter line (NtsCre;GFP mice), as these mice permit both visualization and in vivo modulation of specific populations of Nts neurons (using Cre-inducible viral and genetic tools) to reveal their function. Here we provide a comprehensive characterization of the distribution and relative densities of the Nts-GFP populations observed throughout the male NtsCre;GFP mouse brain, which will pave the way for future work to define their physiologic roles. We also compared the distribution of Nts-GFP neurons with Nts-In situ Hybridization (Nts-ISH) data from the adult mouse brain. By comparing these data sets we can distinguish Nts-GFP populations that may only transiently express Nts during development but not in the mature brain, and hence which populations may not be amenable to Cre-mediated manipulation in adult NtsCre;GFP mice. This atlas of Nts-GFP neurons will facilitate future studies using the NtsCre;GFP line to describe the physiological functions of individual Nts populations and how modulating them may be useful to treat disease.
•NtsCre;GFP mice identify many dense populations of Nts-GFP neurons in the brain.•Most regions of adult mouse brain with Nts-GFP neurons have comparable Nts-ISH.•Some mouse brain regions may only express Nts-GFP during development.•Nts neurons within brain regions may be molecularly heterogeneous.
Introduction
The randomized, placebo-controlled, double-blind MOVe-OUT trial demonstrated molnupiravir (800 mg every 12 h for 5 days) as safe and effective for outpatient treatment of ...mild-to-moderate COVID-19, significantly reducing the risk of hospitalization/death in high-risk adults. At the time of that report, virologic assessments from the trial were partially incomplete as a result of their time-intensive nature. Here we present final results from all prespecified virology endpoints in MOVe-OUT based on the full trial dataset.
Methods
Nasopharyngeal swabs were collected at baseline (day 1, prior to first dose) and days 3, 5 (end-of-treatment visit), 10, 15, and 29. From these samples, change from baseline in SARS-CoV-2 RNA titers (determined by quantitative PCR), detection of infectious SARS-CoV-2 (by plaque assay), and SARS-CoV-2 viral error induction (determined by whole genome next-generation sequencing) were assessed as exploratory endpoints.
Results
Molnupiravir was associated with greater mean reductions from baseline in SARS-CoV-2 RNA than placebo (including 50% relative reduction at end-of-treatment) through day 10. Among participants with infectious virus detected at baseline (
n
= 96 molnupiravir,
n
= 97 placebo) and evaluable post-baseline samples, no molnupiravir-treated participant had infectious SARS-CoV-2 by day 3, whereas infectious virus was recovered from 21% of placebo-arm participants on day 3 and 2% at end-of-treatment. Consistent with molnupiravir’s mechanism of action, sequence analysis demonstrated that molnupiravir was associated with an increased number of low-frequency transition errors randomly distributed across the SARS-CoV-2 RNA genome compared with placebo (median 143.5 molnupiravir, 15 placebo), while transversion errors were infrequent overall (median 2 in both arms). Outcomes were consistent regardless of baseline SARS-CoV-2 clade, presence of SARS-CoV-2-specific immune response, or viral load.
Conclusions
A 5-day course of orally administered molnupiravir demonstrated a consistently greater virologic effect than placebo, including rapidly eliminating infectious SARS-CoV-2, in high-risk outpatients with mild-to-moderate COVID-19.
Trial Registration
ClinicalTrials.gov, NCT04575597.
The “inactive” X chromosome (Xi) has been assumed to have little impact, in trans, on the “active” X (Xa). To test this, we quantified Xi and Xa gene expression in individuals with one Xa and zero to ...three Xis. Our linear modeling revealed modular Xi and Xa transcriptomes and significant Xi-driven expression changes for 38% (162/423) of expressed X chromosome genes. By integrating allele-specific analyses, we found that modulation of Xa transcript levels by Xi contributes to many of these Xi-driven changes (≥121 genes). By incorporating metrics of evolutionary constraint, we identified 10 X chromosome genes most likely to drive sex differences in common disease and sex chromosome aneuploidy syndromes. We conclude that human X chromosomes are regulated both in cis, through Xi-wide transcriptional attenuation, and in trans, through positive or negative modulation of individual Xa genes by Xi. The sum of these cis and trans effects differs widely among genes.
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•Analyzed gene expression in sex chromosome aneuploidy samples using linear models•Xi and Xa transcriptomes are modular•38% of X chromosome genes are affected by Xi copy number—in cis and in trans•10 X chromosome genes likely contribute to male-female differences in somatic tissues
Through RNA sequencing of individuals with sex chromosome aneuploidy, San Roman et al. identify modular “active” (Xa) and “inactive” (Xi) X chromosome transcriptomes. Looking beyond classical X inactivation, which acts in cis, they find that Xi modulates Xa transcript levels in trans. They identify 10 X chromosome genes most likely to contribute to male-female differences in common disease.
Discovery of a minimal form of RNase P in Pyrobaculum Lai, Lien B.; Chan, Patricia P.; Cozen, Aaron E. ...
Proceedings of the National Academy of Sciences - PNAS,
12/2010, Letnik:
107, Številka:
52
Journal Article
Recenzirano
Odprti dostop
RNase P RNA is an ancient, nearly universal feature of life. As part of the ribonucleoprotein RNase P complex, the RNA component catalyzes essential removal of 5' leaders in pre-tRNAs. In 2004, Li ...and Altman computationally identified the RNase P RNA gene in all but three sequenced microbes: Nanoarchaeum equitans, Pyrobaculum aerophilum, and Aquifex aeolicus (all hyperthermophiles) Li Y, Altman S (2004) RNA 10:1533—1540. A recent study concluded that N. equitans does not have or require RNase P activity because it lacks 5' tRNA leaders. The "missing" RNase P RNAs in the other two species is perplexing given evidence or predictions that tRNAs are trimmed in both, prompting speculation that they may have developed novel alternatives to 5' pre-tRNA processing. Using comparative genomics and improved computational methods, we have now identified a radically minimized form of the RNase P RNA in five Pyrobaculum species and the related crenarchaea Caldivirga maquilingensis and Vulcanisaeta distributa, all retaining a conventional catalytic domain, but lacking a recognizable specificity domain. We confirmed 5' tRNA processing activity by high-through-put RNA sequencing and in vitro biochemical assays. The Pyrobaculum and Caldivirga RNase P RNAs are the smallest naturally occurring form yet discovered to function as trans-acting precursor tRNA-processing ribozymes. Loss of the specificity domain in these RNAs suggests altered substrate specificity and could be a useful model for finding other potential roles of RNase P. This study illustrates an effective combination of next-generation RNA sequencing, computational genomics, and biochemistry to identify a divergent, formerly undetectable variant of an essential noncoding RNA gene.
Background: High‐risk alcohol use among college students is associated with accidents, partner violence, unwanted sexual encounters, tobacco use, and performance issues. The identification and ...treatment of high‐risk drinking students is a priority for many college campuses and college health centers. The goal of this study was to test the psychometric properties of the Alcohol Use Disorders Identification Test (AUDIT) in college students.
Methods: A convenience sample of students coming into a college health clinic was asked to complete the 10‐question AUDIT and then participate in a research interview. The interview focused on assessing students for alcohol abuse and dependence by using the Composite International Diagnostic Interview Substance Abuse Module and timeline follow‐back procedures to assess a 28‐day drinking history.
Results: A total of 302 students met the eligibility criteria and agreed to participate in the study. The sample consisted of 185 females (61%) and 117 males (39%), with a mean age of 20.3 years. Forty students were abstinent, 88 were high‐risk drinkers, and 103 met criteria for a 12‐month history of dependence. Receiver operator curves demonstrated that the AUDIT had the highest area under the cure for detecting high‐risk alcohol use (0.872) and the lowest for identifying persons with a lifetime history of alcohol abuse or dependence (0.775). An AUDIT cutoff score of 6 or greater demonstrated a sensitivity of 91.0% and a specificity of 60.0% in the detection of high‐risk drinkers.
Conclusions: The AUDIT has reasonable psychometric properties in sample of college students using student health services. This study supports the use of the AUDIT in this population.
This study aims to determine the prevalence of neurodevelopmental impairments at age ten years among children born extremely preterm (less than 28 weeks gestational age) and to offer a framework for ...categorizing neurological limitations.
A multicenter, prospective cohort follow-up study recruited 889 ten-year-old children born from 2002 to 2004. We assessed prevalence of cognitive impairment, measured by intelligent quotient and tests of executive function, cerebral palsy (CP), autism spectrum disorder (ASD), and epilepsy singly and in combination. The three levels of impairment severity were: category I—no major neurodevelopmental impairment; category II—normal cognitive ability with CP, ASD, and/or epilepsy; and category III—children with cognitive impairment.
A total 214 of 873 children (25%) had cognitive impairment, 93 of 849 children (11%) had CP, 61 of 857 children (7%) had ASD, and 66 of 888 children (7%) had epilepsy. Further, 19% of all children had one diagnosis, 10% had two diagnoses, and 3% had three diagnoses. Decreasing gestational age was associated with increasing number of impairments (P < 0.001). Half the children with cognitive impairment and one third of children with CP, ASD, or epilepsy had a single impairment. Six hundred one (68% 95% CI, 64.5%-70.7%) children were in category I, 74 (8% 95% CI, 6.6%-10.3%) were in category II, and 214 (24% 95% CI 21.7%-27.4%) were in category III.
Three quarters of children had normal intellect at age ten years; nearly 70% were free of neurodevelopmental impairment. Forty percent of children with impairments had multiple diagnoses.
A focus on intraindividual change and person-specific pathways is a necessary starting point for developmental science inquiries. However, research often relies on ergodicity-based assumptions about ...group averages and other variable-centered approaches. Using ideas associated with relational developmental systems metatheory, such as the Bornstein Specificity Principle, we re-examine the ergodicity assumption using Executive Functioning (EF) data from the Measures and Methods Across the Developmental Continuum Project. Participants from Grades 4 to 12 (M age = 14.60) completed three behavioral EF tasks (i.e., working memory, response inhibition, and cognitive flexibility). The final analytic sample included 64 participants who provided data on 30 measurement occasions. Intraindividual and interindividual EF latent constructs appeared to be different, and we identified a wide range of person-specific EF trajectories. These findings challenge the ergodicity assumption framing variable- and group-oriented approaches to individual development. This study demonstrates the feasibility of collecting intensive longitudinal data to understand youth development on an individual level as an alternative to immediate data aggregation and as means to illuminate the use of the specificity principle in understanding human development and in applications pertinent to enhancing the lives of diverse youth across specific times and places in their specific developmental pathways.
•Group-based findings may not apply equally well to all individuals in the group.•We found different within- and between-person executive functioning structures.•Children and adolescents demonstrated meaningful person-specific fluctuations.
The incidence of skin cancer is increasing and surgery is the mainstay of management. The James Lind Alliance (JLA) priority setting partnership (PSP) was designed to address research uncertainties ...in skin cancer surgery. We report the outcome and top ten research priorities from the JLA PSP in skin cancer surgery.
Background: Social-emotional risk for subsequent behavioral health problems can be identified at toddler age, a period where prevention has a heightened impact. This study aimed to meaningfully ...engage pediatric clinicians, given the emphasis on health promotion and broad reach of primary care, to prepare an Implementation Research Logic Model to guide the implementation of a screening and referral process for toddlers with elevated social-emotional risk. Method: Using an adaptation of a previously published community partner engagement method, six pediatricians from community health centers (CHCs) comprised a Clinical Partner Work Group. The group was engaged in identifying determinants (barriers/facilitators), selecting and specifying strategies, strategy-determinant matching, a modified Delphi approach for strategy prioritization, and user-centered design methods. The data gathered from individual interviews, two group sessions, and a follow-up survey resulted in a completed Implementation Research Logic Model. Results: The Clinical Partner Work Group identified 16 determinants, including barriers (e.g., patient access to electronic devices) and facilitators (e.g., clinician buy-in). They then selected and specified 14 strategies, which were prioritized based on ratings of feasibility, effectiveness, and priority. The highest-rated strategies (e.g., integration of the screener into the electronic health record) provided coverage of all identified barriers and comprised the primary implementation strategy "package" to be used and tested. Conclusions: Clinical partners provided important context and insights for implementation strategy selection and specification to support the implementation of social-emotional risk screening and referral in pediatric primary care. The methodology described herein can improve partner engagement in implementation efforts and increase the likelihood of success.
Public Significance StatementIdentification of risk for mental health problems as early as possible in the lifespan is critical to preventing negative health and societal impacts. This study provides a method for working with pediatric clinicians in identifying ways to implement evidence-based tools for mental health risk screening and referral to programs to support parents.
Abstract
To examine long-term effects of early intervention services (EIS) for first-episode psychosis, we compared Heinrichs-Carpenter Quality of Life (QLS) and Positive and Negative Syndrome Scale ...(PANSS) scores and inpatient hospitalization days over 5 years with data from the site-randomized RAISE-ETP trial that compared the EIS NAVIGATE (17 sites; 223 participants) and community care (CC) (17 sites; 181 participants). Inclusion criteria were: age 15–40 years; DSM-IV diagnoses of schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, or psychotic disorder not otherwise specified; first psychotic episode; antipsychotic medication taken for ≤6 months. NAVIGATE-randomized participants could receive NAVIGATE from their study entry date until NAVIGATE ended when the last-enrolled NAVIGATE participant completed 2 years of treatment. Assessments occurred every 6 months. 61% of participants had assessments conducted ≥2 years; 31% at 5 years. Median follow-up length was CC 30 months and NAVIGATE 38 months. Primary analyses assumed data were not-missing-at-random (NMAR); sensitivity analyses assumed data were missing-at-random (MAR). MAR analyses found no significant treatment-by-time interactions for QLS or PANSS. NMAR analyses revealed that NAVIGATE was associated with a 13.14 (95%CI:6.92,19.37) unit QLS and 7.73 (95%CI:2.98,12.47) unit PANSS better improvement and 2.53 (95%CI:0.59,4.47) fewer inpatient days than CC (all comparisons significant). QLS and PANSS effect sizes were 0.856 and 0.70. NAVIGATE opportunity length (mean 33.8 (SD = 5.1) months) was not associated (P = .72) with QLS outcome; duration of untreated psychosis did not moderate (P = .32) differential QLS outcome. While conclusions are limited by the low rate of five-year follow-up, the data support long-term benefit of NAVIGATE compared to community care.
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