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"Kelly, John M. H"
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The Statistics of Bulk Segregant Analysis Using Next Generation Sequencing
We describe a statistical framework for QTL mapping using bulk segregant analysis (BSA) based on high throughput, short-read sequencing. Our proposed approach is based on a smoothed version of the standard G statistic, and takes into account variation in allele frequency estimates due to sampling of segregants to form bulks as well as variation introduced during the sequencing of bulks. Using simulation, we explore the impact of key experimental variables such as bulk size and sequencing coverage on the ability to detect QTLs. Counterintuitively, we find that relatively large bulks maximize the power to detect QTLs even though this implies weaker selection and less extreme allele frequency differences. Our simulation studies suggest that with large bulks and sufficient sequencing depth, the methods we propose can be used to detect even weak effect QTLs and we demonstrate the utility of this framework by application to a BSA experiment in the budding yeast Saccharomyces cerevisiae.
Journal Article
Initial recommendations for performing, benchmarking and reporting single-cell proteomics experiments
Analyzing proteins from single cells by tandem mass spectrometry (MS) has recently become technically feasible. While such analysis has the potential to accurately quantify thousands of proteins across thousands of single cells, the accuracy and reproducibility of the results may be undermined by numerous factors affecting experimental design, sample preparation, data acquisition and data analysis. We expect that broadly accepted community guidelines and standardized metrics will enhance rigor, data quality and alignment between laboratories. Here we propose best practices, quality controls and data-reporting recommendations to assist in the broad adoption of reliable quantitative workflows for single-cell proteomics. Resources and discussion forums are available at
https://single-cell.net/guidelines
.
A community of researchers working in the emerging field of single-cell proteomics propose best-practice experimental and computational recommendations and reporting guidelines for studies analyzing proteins from single cells by mass spectrometry.
Journal Article
The broad footprint of climate change from genes to biomes to people
Anthropogenic climate change is now in full swing, our global average temperature already having increased by 1°C from preindustrial levels. Many studies have documented individual impacts of the changing climate that are particular to species or regions, but individual impacts are accumulating and being amplified more broadly. Scheffers et al. review the set of impacts that have been observed across genes, species, and ecosystems to reveal a world already undergoing substantial change. Understanding the causes, consequences, and potential mitigation of these changes will be essential as we move forward into a warming world. Science , this issue p. 10.1126/science.aaf7671 Most ecological processes now show responses to anthropogenic climate change. In terrestrial, freshwater, and marine ecosystems, species are changing genetically, physiologically, morphologically, and phenologically and are shifting their distributions, which affects food webs and results in new interactions. Disruptions scale from the gene to the ecosystem and have documented consequences for people, including unpredictable fisheries and crop yields, loss of genetic diversity in wild crop varieties, and increasing impacts of pests and diseases. In addition to the more easily observed changes, such as shifts in flowering phenology, we argue that many hidden dynamics, such as genetic changes, are also taking place. Understanding shifts in ecological processes can guide human adaptation strategies. In addition to reducing greenhouse gases, climate action and policy must therefore focus equally on strategies that safeguard biodiversity and ecosystems.
Journal Article
A whole-food, plant-based intensive lifestyle intervention improves glycaemic control and reduces medications in individuals with type 2 diabetes: a randomised controlled trial
Aims/hypothesis
We conducted the largest and longest clinical trial comparing a whole-food, plant-based intervention with standard medical care (SMC) in individuals with type 2 diabetes.
Methods
We randomised (parallel-arm; computerised 1:1 randomisation ratio) 169 adults aged 18–75 years with type 2 diabetes in the Marshall Islands to an intensive whole-food, plant-based intervention with moderate exercise (PB+Ex) or SMC for 24 weeks. The PB+Ex intervention included 12 weeks of meals, exercise sessions and group classes. Primary outcomes were glycaemic control (HbA
1c
, glucose, insulin and HOMA-IR) and glucose-lowering medication use. Secondary outcomes included lipids, blood pressure, heart rate and C-reactive protein. Only lab analysts were blinded.
Results
Compared with SMC (
n
=90 randomised;
n
=70 analysed), the PB+Ex (
n
=79 randomised;
n
=66 analysed) intervention decreased HbA
1c
by an additional 14 mmol/mol (1.3%) at week 12 (−22 vs −7 mmol/mol [−2.0% vs −0.7%];
p
<0.0001) and 8 mmol/mol (0.7%) at week 24 (−16 vs −8 mmol/mol [−1.4% vs −0.7%];
p
=0.01). Concomitantly, 63% of medicated PB+Ex participants reduced their glucose-lowering medications (vs 24%;
p
=0.006), and 23% of PB+Ex participants with a baseline HbA
1c
<75 mmol/mol (<9%) achieved remission. Additionally, the PB+Ex intervention reduced weight (−2.7 kg;
p
<0.0001), C-reactive protein (−11 nmol/l;
p
=0.005) and cardiovascular medication use compared with SMC. At intermediate timepoints, it improved glucose, insulin, HOMA-IR, cholesterol, triglycerides and heart rate, but not at week 24.
Conclusions/interpretation
A whole-food, plant-based lifestyle intervention was more effective for improving glycaemic control than SMC. It also reduced the need for diabetes and cardiovascular medications and induced diabetes remission in some participants. Therefore, it is an effective, evidence-based lifestyle option for individuals with type 2 diabetes.
Trial registration
ClinicalTrials.gov NCT03862963
Funding
This research was funded by the Department of the Army (W81XWH-05-1-0547). CJH received support through a National Institutes of Health Predoctoral T32 Obesity Fellowship (T32 HL105349).
Graphical Abstract
Journal Article
Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial
Neuroprotection with NA-1 (Tat-NR2B9c), an inhibitor of postsynaptic density-95 protein, has been shown in a primate model of stroke. We assessed whether NA-1 could reduce ischaemic brain damage in human beings.
For this double-blind, randomised, controlled study, we enrolled patients aged 18 years or older who had a ruptured or unruptured intracranial aneurysm amenable to endovascular repair from 14 hospitals in Canada and the USA. We used a computer-generated randomisation sequence to allocate patients to receive an intravenous infusion of either NA-1 or saline control at the end of their endovascular procedure (1:1; stratified by site, age, and aneurysm status). Both patients and investigators were masked to treatment allocation. The primary outcome was safety and primary clinical outcomes were the number and volume of new ischaemic strokes defined by MRI at 12–95 h after infusion. We used a modified intention-to-treat (mITT) analysis. This trial is registered with ClinicalTrials.gov, number NCT00728182.
Between Sept 16, 2008, and March 30, 2011, we randomly allocated 197 patients to treatment—12 individuals did not receive treatment because they were found to be ineligible after randomisation, so the mITT population consisted of 185 individuals, 92 in the NA-1 group and 93 in the placebo group. Two minor adverse events were adjudged to be associated with NA-1; no serious adverse events were attributable to NA-1. We recorded no difference between groups in the volume of lesions by either diffusion-weighted MRI (adjusted p value=0·120) or fluid-attenuated inversion recovery MRI (adjusted p value=0·236). Patients in the NA-1 group sustained fewer ischaemic infarcts than did patients in the placebo group, as gauged by diffusion-weighted MRI (adjusted incidence rate ratio 0·53, 95% CI 0·38–0·74) and fluid-attenuated inversion recovery MRI (0·59, 0·42–0·83).
Our findings suggest that neuroprotection in human ischaemic stroke is possible and that it should be investigated in larger trials.
NoNO Inc and Arbor Vita Corp.
Journal Article
Placental methylome reveals a 22q13.33 brain regulatory gene locus associated with autism
Background
Autism spectrum disorder (ASD) involves complex genetics interacting with the perinatal environment, complicating the discovery of common genetic risk. The epigenetic layer of DNA methylation shows dynamic developmental changes and molecular memory of in utero experiences, particularly in placenta, a fetal tissue discarded at birth. However, current array-based methods to identify novel ASD risk genes lack coverage of the most structurally and epigenetically variable regions of the human genome.
Results
We use whole genome bisulfite sequencing in placenta samples from prospective ASD studies to discover a previously uncharacterized ASD risk gene,
LOC105373085
, renamed
NHIP
. Out of 134 differentially methylated regions associated with ASD in placental samples, a cluster at 22q13.33 corresponds to a 118-kb hypomethylated block that replicates in two additional cohorts. Within this locus,
NHIP
is functionally characterized as a nuclear peptide-encoding transcript with high expression in brain, and increased expression following neuronal differentiation or hypoxia, but decreased expression in ASD placenta and brain.
NHIP
overexpression increases cellular proliferation and alters expression of genes regulating synapses and neurogenesis, overlapping significantly with known ASD risk genes and
NHIP
-associated genes in ASD brain. A common structural variant disrupting the proximity of
NHIP
to a fetal brain enhancer is associated with
NHIP
expression and methylation levels and ASD risk, demonstrating a common genetic influence.
Conclusions
Together, these results identify and initially characterize a novel environmentally responsive ASD risk gene relevant to brain development in a hitherto under-characterized region of the human genome.
Journal Article
Goserelin for Ovarian Protection during Breast-Cancer Adjuvant Chemotherapy
Women with hormone-receptor–negative breast cancer who received goserelin with adjuvant chemotherapy had less amenorrhea and better fertility at 2 years after treatment, and better rates of disease-free and overall survival, than did those who received chemotherapy alone.
Early ovarian failure is an important and potentially devastating long-term toxic effect of chemotherapy. Manifestations include menopausal symptoms, osteoporosis, and infertility. Concerns about fertility may influence treatment choices for young women with breast cancer
1
,
2
despite the known survival benefit of adjuvant chemotherapy.
Trials of the coadministration of a gonadotropin-releasing hormone (GnRH) agonist with adjuvant chemotherapy for the purpose of protecting ovarian function have shown mixed results.
3
A large randomized trial addressing this issue suggested that coadministration of a GnRH agonist with chemotherapy had an ovarian protective effect in a cohort of patients in which 86% had estrogen-receptor–positive breast cancer, . . .
Journal Article
Committing to ecological restoration
Efforts around the globe need legal and policy clarification At the September 2014 United Nations Climate Summit, governments rallied around an international agreement—the New York Declaration on Forests—that underscored restoration of degraded ecosystems as an auspicious solution to climate change. Ethiopia committed to restore more than one-sixth of its land. Uganda, the Democratic Republic of Congo, Guatemala, and Colombia pledged to restore huge areas within their borders. In total, parties committed to restore a staggering 350 million hectares by 2030.
Journal Article