There has been considerable debate, but little consensus regarding locus choice for DNA barcoding land plants. This is partly attributable to a shortage of comparable data from all proposed candidate ...loci on a common set of samples. In this study, we evaluated the seven main candidate plastid regions (rpoC1, rpoB, rbcL, matK, trnH-psbA, atpF-atpH, psbK-psbI) in three divergent groups of land plants Inga (angiosperm); Araucaria (gymnosperm); Asterella s.l. (liverwort). Across these groups, no single locus showed high levels of universality and resolvability. Interspecific sharing of sequences from individual loci was common. However, when multiple loci were combined, fewer barcodes were shared among species. Evaluation of the performance of previously published suggestions of particular multilocus barcode combinations showed broadly equivalent performance. Minor improvements on these were obtained by various new three-locus combinations involving rpoC1, rbcL, matK and trnH-psbA, but no single combination clearly outperformed all others. In terms of absolute discriminatory power, promising results occurred in liverworts (e.g. c. 90% species discrimination based on rbcL alone). However, Inga (rapid radiation) and Araucaria (slow rates of substitution) represent challenging groups for DNA barcoding, and their corresponding levels of species discrimination reflect this (upper estimate of species discrimination = 69% in Inga and only 32% in Araucaria; mean = 60% averaging all three groups).
Type 1 diabetes (T1D) is an autoimmune disease caused by loss of pancreatic β cells via apoptosis while neighboring α cells are preserved. Viral infections by coxsackieviruses (CVB) may contribute to ...trigger autoimmunity in T1D. Cellular permissiveness to viral infection is modulated by innate antiviral responses, which vary among different cell types. We presently describe that global gene expression is similar in cytokine-treated and virus-infected human islet cells, with up-regulation of gene networks involved in cell autonomous immune responses. Comparison between the responses of rat pancreatic α and β cells to infection by CVB5 and 4 indicate that α cells trigger a more efficient antiviral response than β cells, including higher basal and induced expression of STAT1-regulated genes, and are thus better able to clear viral infections than β cells. These differences may explain why pancreatic β cells, but not α cells, are targeted by an autoimmune response during T1D.
Male contraceptive options and infertility treatments are limited, and almost all innovation has been limited to updates to medically assisted reproduction protocols and methods. To accelerate the ...development of drugs that can either improve or inhibit fertility, we established a small molecule library as a toolbox for assay development and screening campaigns using human spermatozoa. We have profiled all compounds in the Sperm Toolbox in several automated high-throughput assays that measure stimulation or inhibition of sperm motility or the acrosome reaction. We have assayed motility under non-capacitating and capacitating conditions to distinguish between pathways operating under these different physiological states. We also assayed cell viability to ensure any effects on sperm function are specific. A key advantage of our studies is that all compounds are assayed together in the same experimental conditions, which allows quantitative comparisons of their effects in complementary functional assays. We have combined the resulting datasets to generate fingerprints of the Sperm Toolbox compounds on sperm function. The data are included in an on-line R-based app for convenient querying.
Oxidative phosphorylation (OXPHOS) defects caused by somatic mitochondrial DNA (mtDNA) mutations increase with age in human colorectal epithelium and are prevalent in colorectal tumours, but whether ...they actively contribute to tumorigenesis remains unknown. Here we demonstrate that mtDNA mutations causing OXPHOS defects are enriched during the human adenoma/carcinoma sequence, suggesting they may confer a metabolic advantage. To test this we deleted the tumour suppressor Apc in OXPHOS deficient intestinal stem cells in mice. The resulting tumours were larger than in control mice due to accelerated cell proliferation and reduced apoptosis. We show that both normal crypts and tumours undergo metabolic remodelling in response to OXPHOS deficiency by upregulating the
serine synthesis pathway (SSP). Moreover, normal human colonic crypts upregulate the SSP in response to OXPHOS deficiency prior to tumorigenesis. Our data show that age-associated OXPHOS deficiency causes metabolic remodelling that can functionally contribute to accelerated intestinal cancer development.
Abstract
BACKGROUND
Loss of control (LOC) is a pervasive feature of binge eating, which contributes significantly to the growing epidemic of obesity; approximately 80 million US adults are obese. ...Brain-responsive neurostimulation guided by the delta band was previously found to block binge-eating behavior in mice. Following novel preclinical work and a human case study demonstrating an association between the delta band and reward anticipation, the US Food and Drug Administration approved an Investigational Device Exemption for a first-in-human study.
OBJECTIVE
To assess feasibility, safety, and nonfutility of brain-responsive neurostimulation for LOC eating in treatment-refractory obesity.
METHODS
This is a single-site, early feasibility study with a randomized, single-blinded, staggered-onset design. Six subjects will undergo bilateral brain-responsive neurostimulation of the nucleus accumbens for LOC eating using the RNS® System (NeuroPace Inc). Eligible participants must have treatment-refractory obesity with body mass index ≥ 45 kg/m2. Electrophysiological signals of LOC will be characterized using real-time recording capabilities coupled with synchronized video monitoring. Effects on other eating disorder pathology, mood, neuropsychological profile, metabolic syndrome, and nutrition will also be assessed.
EXPECTED OUTCOMES
Safety/feasibility of brain-responsive neurostimulation of the nucleus accumbens will be examined. The primary success criterion is a decrease of ≥1 LOC eating episode/week based on a 28-d average in ≥50% of subjects after 6 mo of responsive neurostimulation.
DISCUSSION
This study is the first to use brain-responsive neurostimulation for obesity; this approach represents a paradigm shift for intractable mental health disorders.
Opioid use disorder (OUD) affects approximately 5.6 million people in the United States annually, yet rates of the use of effective medication for OUD (MOUD) treatment are low. We conducted an ...observational cohort study from August 2017 through May 2021, the MOUD Study, to better understand treatment engagement and factors that may influence treatment experiences and outcomes. In this article, we describe the study design, data collected, and treatment outcomes.
We recruited adult patients receiving OUD treatment at US outpatient facilities for the MOUD Study. We collected patient-level data at 5 time points (baseline to 18 months) via self-administered questionnaires and health record data. We collected facility-level data via questionnaires administered to facility directors at 2 time points. Across 16 states, 62 OUD treatment facilities participated, and 1974 patients enrolled in the study. We summarized descriptive data on the characteristics of patients and OUD treatment facilities and selected treatment outcomes.
Approximately half of the 62 facilities were private, nonprofit organizations; 62% focused primarily on substance use treatment; and 20% also offered mental health services. Most participants were receiving methadone (61%) or buprenorphine (32%) and were predominately non-Hispanic White (68%), aged 25-44 years (62%), and female (54%). Compared with patient-reported estimates at baseline, 18-month estimates suggested that rates of abstinence increased (55% to 77%), and rates of opioid-related overdoses (7% to 2%), emergency department visits (9% to 4%), and arrests (15% to 7%) decreased.
Our results demonstrated the benefits of treatment retention not only on abstinence from opioid use but also on other quality-of-life metrics, with data collected during an extended period. The MOUD Study produced rich, multilevel data that can lay the foundation for an evidence base to inform OUD treatment and support improvement of care and patient outcomes.
This review highlights examples of the translation of the Diabetes Prevention Program (DPP) to underserved populations. Here, underserved populations are defined as groups whose members are at ...greater risk for health conditions such as diabetes but often face barriers accessing treatment. Strategies to develop and evaluate future DPP translations are discussed.
Neutrophils play fundamental roles in innate immune response, shape adaptive immunity, and are a potentially causal cell type underpinning genetic associations with immune system traits and diseases. ...Here, we profile the binding of myeloid master regulator PU.1 in primary neutrophils across nearly a hundred volunteers. We show that variants associated with differential PU.1 binding underlie genetically-driven differences in cell count and susceptibility to autoimmune and inflammatory diseases. We integrate these results with other multi-individual genomic readouts, revealing coordinated effects of PU.1 binding variants on the local chromatin state, enhancer-promoter contacts and downstream gene expression, and providing a functional interpretation for 27 genes underlying immune traits. Collectively, these results demonstrate the functional role of PU.1 and its target enhancers in neutrophil transcriptional control and immune disease susceptibility.
To determine clinic-level and individual-level correlates of viral suppression among HIV-positive adolescents and young adult (AYA) aged 10-24 years receiving antiretroviral treatment (ART).
...Multilevel cross-sectional analysis using viral load data and facility surveys from HIV treatment programs throughout Kenya.
We abstracted medical records of AYA in HIV care, analyzed the subset on ART for more than 6 months between January 2016 and December 2017, and collected information on services at each clinic. Multilevel logistic regression models were used to determine correlates of viral suppression at most recent assessment.
In 99 HIV clinics, among 10 096 AYA on ART more than 6 months, 2683 (27%) had unsuppressed viral load at last test. Among 16% of clinics, more than 80% of AYA were virally suppressed. Clinic-level correlates of individual viral suppression included designated adolescent spaces aOR: 1.32, 95% CI (1.07-1.63) and faster viral load turnaround time aOR: 1.06 (95% CI 1.03-1.09). Adjusting for clinic-level factors, AYA aged 10-14 and 15-19 years had lower odds of viral suppression compared with AYA aged 20-24 years aOR: 0.61 (0.54-0.69) and 0.59 (0.52-0.67, respectively. Compared with female patients, male patients had lower odds of viral suppression aOR: 0.69 (0.62-0.77). Compared with ART duration of 6-12 months, ART for 2-5, above 5-10 or more than 10 years was associated with poor viral suppression (P < 0.001).
Dedicated adolescent space, rapid viral load turnaround time, and tailored approaches for male individuals and perinatally infected AYA may improve viral suppression. Routine summarization of viral load suppression in clinics could provide benchmarking to motivate innovations in clinic-AYA and individual-AYA care strategies.
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