Publications by authors named "Robert Scott"

470 Publications

Exploring the structure of atom-precise silver-palladium bimetallic clusters prepared via improved single-pot co-reduction synthesis protocol.

J Chem Phys 2021 Aug;155(8):084301

Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan S7N 5C9, Canada.

Designing atom-precise bimetallic clusters with a relatively cost-effective and more abundant metal than Au (i.e., Ag) is desirable for the development of heterogeneous bimetallic cluster catalysts for industrial applications. Atom-precise Ag-based bimetallic clusters, which are analogs of the well-studied Au based clusters, are yet to be fully explored as catalysts. Establishing the Pd loading limit and the position of the Pd dopant in AgPd bimetallic clusters will further give an insight into the structure-activity relationships for these atom-precise AgPd heterogeneous catalysts. In this study, an improved single-pot co-reduction strategy was employed to prepare the bimetallic clusters, which were then characterized by mass spectrometry, x-ray photoelectron spectroscopy (XPS), and x-ray absorption spectroscopy (XAS) to identify the loading and position of the dopant metal. Our results show that only a single dopant Pd atom can be incorporated, and in comparison with monometallic Ag clusters, the absorption peaks of AgPd(SPhMe) bimetallic clusters are blue shifted due to the incorporation of Pd. The XPS and XAS results show that the AgPd(SPhMe) bimetallic clusters have multivalent Ag(0) and Ag(I) atoms and surprisingly show Pd(II) species with significant Pd-S bonding, despite the prevailing wisdom that the Pd dopant should be in the center of the cluster. The XAS results show that the singly doped Pd atom predominantly occupies the staple position, albeit we cannot unambiguously rule out the Pd atom in an icosahedral surface position in some clusters. We discuss the ramifications of these results in terms of possible kinetically vs thermodynamically controlled cluster formation.
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http://dx.doi.org/10.1063/5.0060248DOI Listing
August 2021

Testing a global standard for quantifying species recovery and assessing conservation impact.

Conserv Biol 2021 Jul 21. Epub 2021 Jul 21.

Wildlife Institute of India, Dehradun, India.

Recognizing the imperative to evaluate species recovery and conservation impact, in 2012 the International Union for Conservation of Nature (IUCN) called for development of a "Green List of Species" (now the IUCN Green Status of Species). A draft Green Status framework for assessing species' progress toward recovery, published in 2018, proposed 2 separate but interlinked components: a standardized method (i.e., measurement against benchmarks of species' viability, functionality, and preimpact distribution) to determine current species recovery status (herein species recovery score) and application of that method to estimate past and potential future impacts of conservation based on 4 metrics (conservation legacy, conservation dependence, conservation gain, and recovery potential). We tested the framework with 181 species representing diverse taxa, life histories, biomes, and IUCN Red List categories (extinction risk). Based on the observed distribution of species' recovery scores, we propose the following species recovery categories: fully recovered, slightly depleted, moderately depleted, largely depleted, critically depleted, extinct in the wild, and indeterminate. Fifty-nine percent of tested species were considered largely or critically depleted. Although there was a negative relationship between extinction risk and species recovery score, variation was considerable. Some species in lower risk categories were assessed as farther from recovery than those at higher risk. This emphasizes that species recovery is conceptually different from extinction risk and reinforces the utility of the IUCN Green Status of Species to more fully understand species conservation status. Although extinction risk did not predict conservation legacy, conservation dependence, or conservation gain, it was positively correlated with recovery potential. Only 1.7% of tested species were categorized as zero across all 4 of these conservation impact metrics, indicating that conservation has, or will, play a role in improving or maintaining species status for the vast majority of these species. Based on our results, we devised an updated assessment framework that introduces the option of using a dynamic baseline to assess future impacts of conservation over the short term to avoid misleading results which were generated in a small number of cases, and redefines short term as 10 years to better align with conservation planning. These changes are reflected in the IUCN Green Status of Species Standard.
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http://dx.doi.org/10.1111/cobi.13756DOI Listing
July 2021

Pupal behavior emerges from unstructured muscle activity in response to neuromodulation in .

Elife 2021 07 8;10. Epub 2021 Jul 8.

National Institute of Mental Health, National Institutes of Health, Bethesda, United States.

Identifying neural substrates of behavior requires defining actions in terms that map onto brain activity. Brain and muscle activity naturally correlate via the output of motor neurons, but apart from simple movements it has been difficult to define behavior in terms of muscle contractions. By mapping the musculature of the pupal fruit fly and comprehensively imaging muscle activation at single-cell resolution, we here describe a multiphasic behavioral sequence in . Our characterization identifies a previously undescribed behavioral phase and permits extraction of major movements by a convolutional neural network. We deconstruct movements into a syllabary of co-active muscles and identify specific syllables that are sensitive to neuromodulatory manipulations. We find that muscle activity shows considerable variability, with sequential increases in stereotypy dependent upon neuromodulation. Our work provides a platform for studying whole-animal behavior, quantifying its variability across multiple spatiotemporal scales, and analyzing its neuromodulatory regulation at cellular resolution.
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http://dx.doi.org/10.7554/eLife.68656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8331185PMC
July 2021

Historical Analysis of the Risk of Hepatitis E and Its Complications in Pregnant Women in Nepal, 1996-1998.

Am J Trop Med Hyg 2021 Jun 14. Epub 2021 Jun 14.

6Department of Virus Diseases, Walter Reed Army Institute of Research, Silver Spring, Maryland.

Hepatitis E (HE) during pregnancy can be fatal; there are no prospective risk estimates for HE and its complications during pregnancy. We followed 2,404 pregnant women for HE and pregnancy outcomes from 1996 to 1998. Subjects from Nepal were enrolled at an antenatal clinic with pregnancy of ≤ 24 weeks. Most women (65.1%) were anti-HE virus negative. There were 16 cases of HE (6.7 per 1,000); three mothers died (18.8%) having had intrauterine fetal death (IUFD). Thirteen mothers survived: five preterm and seven full-term deliveries, one IUFD. HE among seronegative women was the sole cause of maternal death and increased the risk of IUFD (relative risk [RR]: 10.6; 95% confidence interval [CI]: 4.29-26.3) and preterm delivery (RR: 17.1, 95% CI 7.56-38.5). HE vaccination of females in at-risk regions before or as they attain reproductive age would reduce their risk for preterm delivery, IUFD, and maternal death.
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http://dx.doi.org/10.4269/ajtmh.20-1007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437178PMC
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Delirious Mania: An Approach to Diagnosis and Treatment.

Prim Care Companion CNS Disord 2021 02 18;23(1). Epub 2021 Feb 18.

Department of Psychiatry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry.
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http://dx.doi.org/10.4088/PCC.20f02744DOI Listing
February 2021

Pleiotropic associations of heterozygosity for the Z allele in the UK Biobank.

ERJ Open Res 2021 Apr 10;7(2). Epub 2021 May 10.

Division of Respiratory Medicine, University of Nottingham, and NIHR Nottingham BRC, NUH NHS Trust, Nottingham, UK.

Homozygosity for the Z allele causes α-antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on nonrespiratory phenotypes, and on lung function in the general population, remain unclear. We conducted a large, population-based study to determine Z allele effects on >2400 phenotypes in the UK Biobank (N=303 353). Z allele heterozygosity was strongly associated with increased height (β=1.02 cm, p=3.91×10), and with other nonrespiratory phenotypes including increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function. Heterozygosity was associated with higher height-adjusted forced expiratory volume in 1 s (FEV) (β=19.36 mL, p=9.21×10) and FEV/forced vital capacity (β=0.0031, p=1.22×10) in nonsmokers, whereas in smokers, this protective effect was abolished. Furthermore, we show for the first time that sex modifies the association of the Z allele on lung function. We conclude that Z allele heterozygosity and homozygosity exhibit opposing effects on lung function in the UK population, and that these associations are modified by smoking and sex. In exploratory analyses, heterozygosity for the Z allele also showed pleiotropic associations with nonrespiratory health-related traits and disease risk.
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http://dx.doi.org/10.1183/23120541.00049-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107350PMC
April 2021

Virus shedding kinetics and unconventional virulence tradeoffs.

PLoS Pathog 2021 05 10;17(5):e1009528. Epub 2021 May 10.

Department of Biology, University of Washington, Seattle, Washington, United States of America.

Tradeoff theory, which postulates that virulence provides both transmission costs and benefits for pathogens, has become widely adopted by the scientific community. Although theoretical literature exploring virulence-tradeoffs is vast, empirical studies validating various assumptions still remain sparse. In particular, truncation of transmission duration as a cost of virulence has been difficult to quantify with robust controlled in vivo studies. We sought to fill this knowledge gap by investigating how transmission rate and duration were associated with virulence for infectious hematopoietic necrosis virus (IHNV) in rainbow trout (Oncorhynchus mykiss). Using host mortality to quantify virulence and viral shedding to quantify transmission, we found that IHNV did not conform to classical tradeoff theory. More virulent genotypes of the virus were found to have longer transmission durations due to lower recovery rates of infected hosts, but the relationship was not saturating as assumed by tradeoff theory. Furthermore, the impact of host mortality on limiting transmission duration was minimal and greatly outweighed by recovery. Transmission rate differences between high and low virulence genotypes were also small and inconsistent. Ultimately, more virulent genotypes were found to have the overall fitness advantage, and there was no apparent constraint on the evolution of increased virulence for IHNV. However, using a mathematical model parameterized with experimental data, it was found that host culling resurrected the virulence tradeoff and provided low virulence genotypes with the advantage. Human-induced or natural culling, as well as host population fragmentation, may be some of the mechanisms by which virulence diversity is maintained in nature. This work highlights the importance of considering non-classical virulence tradeoffs.
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http://dx.doi.org/10.1371/journal.ppat.1009528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109835PMC
May 2021

Mendelian randomization for studying the effects of perturbing drug targets.

Wellcome Open Res 2021 10;6:16. Epub 2021 Feb 10.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Drugs whose targets have genetic evidence to support efficacy and safety are more likely to be approved after clinical development. In this paper, we provide an overview of how natural sequence variation in the genes that encode drug targets can be used in Mendelian randomization analyses to offer insight into mechanism-based efficacy and adverse effects. Large databases of summary level genetic association data are increasingly available and can be leveraged to identify and validate variants that serve as proxies for drug target perturbation. As with all empirical research, Mendelian randomization has limitations including genetic confounding, its consideration of lifelong effects, and issues related to heterogeneity across different tissues and populations. When appropriately applied, Mendelian randomization provides a useful empirical framework for using population level data to improve the success rates of the drug development pipeline.
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http://dx.doi.org/10.12688/wellcomeopenres.16544.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903200PMC
February 2021

Probing the Thermal Stability of (3-Mercaptopropyl)-trimethoxysilane-Protected Au Clusters by In Situ Transmission Electron Microscopy.

Small 2021 Jul 28;17(27):e2004539. Epub 2021 Jan 28.

Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, S7N 5C9, Canada.

High-surface-area gold catalysts are promising catalysts for a number of selective oxidation and reduction reactions but typically suffer catalyst deactivation at higher temperatures. The major reason for catalyst deactivation is sintering, which can be triggered via two mechanisms: particle migration and coalescence, and Ostwald ripening. Herein, a direct method to synthesize Au clusters stabilized with 3-mercaptopropyltrimethoxysilane (MPTS) ligands is discussed. The sintering of Au (MPTS) clusters on mesoporous silica (SBA-15) is monitored by using an environmental in situ transmission electron microscopy (TEM) technique. Results show that agglomeration of smaller particles is accelerated by increased mobility of particles during heat treatment, while growth of immobile particles occurs via diffusion of atomic species from smaller particles. The mobility of the Au clusters can be alleviated by fabricating overlayers of silica around the clusters. The resulting materials show tremendous sinter-resistance at temperatures up to 650 °C as shown by in situ TEM and extended X-ray absorption fine structure analysis.
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http://dx.doi.org/10.1002/smll.202004539DOI Listing
July 2021

Exploring the Applicability of Robot-Assisted UV Disinfection in Radiology.

Front Robot AI 2020 6;7:590306. Epub 2021 Jan 6.

Department of Microbiology, Trinity College Dublin, Dublin, Ireland.

The importance of infection control procedures in hospital radiology departments has become increasingly apparent in recent months as the impact of COVID-19 has spread across the world. Existing disinfectant procedures that rely on the manual application of chemical-based disinfectants are time consuming, resource intensive and prone to high degrees of human error. Alternative non-touch disinfection methods, such as Ultraviolet Germicidal Irradiation (UVGI), have the potential to overcome many of the limitations of existing approaches while significantly improving workflow and equipment utilization. The aim of this research was to investigate the germicidal effectiveness and the practical feasibility of using a robotic UVGI device for disinfecting surfaces in a radiology setting. We present the design of a robotic UVGI platform that can be deployed alongside human workers and can operate autonomously within cramped rooms, thereby addressing two important requirements necessary for integrating the technology within radiology settings. In one hospital, we conducted experiments in a CT and X-ray room. In a second hospital, we investigated the germicidal performance of the robot when deployed to disinfect a CT room in <15 minutes, a period which is estimated to be 2-4 times faster than current practice for disinfecting rooms after infectious (or potentially infectious) patients. Findings from both test sites show that UVGI successfully inactivated all of measurable microbial load on 22 out of 24 surfaces. On the remaining two surfaces, UVGI reduced the microbial load by 84 and 95%, respectively. The study also exposes some of the challenges of manually disinfecting radiology suites, revealing high concentrations of microbial load in hard-to-reach places. Our findings provide compelling evidence that UVGI can effectively inactivate microbes on commonly touched surfaces in radiology suites, even if they were only exposed to relatively short bursts of irradiation. Despite the short irradiation period, we demonstrated the ability to inactivate microbes with more complex cell structures and requiring higher UV inactivation energies than SARS-CoV-2, thus indicating high likelihood of effectiveness against coronavirus.
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http://dx.doi.org/10.3389/frobt.2020.590306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815819PMC
January 2021

A cross-platform approach identifies genetic regulators of human metabolism and health.

Nat Genet 2021 01 7;53(1):54-64. Epub 2021 Jan 7.

Metabolic Research Laboratories, University of Cambridge, Cambridge, UK.

In cross-platform analyses of 174 metabolites, we identify 499 associations (P < 4.9 × 10) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with β-arrestin signaling as the underlying mechanism. Genetically higher serine levels are shown to reduce the likelihood (by 95%) and predict development of macular telangiectasia type 2, a rare degenerative retinal disease. Integration of genomic and small molecule data across platforms enables the discovery of regulators of human metabolism and translation into clinical insights.
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http://dx.doi.org/10.1038/s41588-020-00751-5DOI Listing
January 2021

Longitudinal Examination of COVID-19 Public Health Measures on Mental Health for Rural Patients With Serious Mental Illness.

Mil Med 2021 08;186(9-10):e956-e961

Department of Psychiatry, Geisel School of Medicine at Dartmouth College, Hanover, NH 03755, USA.

Introduction: There is emerging evidence to support that the COVID-19 pandemic and related public health measures may be associated with negative mental health sequelae. Rural populations in particular may fair worse because they share many unique characteristics that may put them at higher risk for adverse outcomes with the pandemic. Yet, rural populations may also be more resilient due to increased sense of community. Little is known about the impact of the pandemic on the mental health and well-being of a rural population pre- and post-pandemic, especially those with serious mental illness.

Material And Methods: We conducted a longitudinal, mixed-methods study with assessments preceding the pandemic (between October 2019 and March 2020) and during the stay-at-home orders (between April 23, 2020, and May 4, 2020). Changes in hopelessness, suicidal ideation, connectedness, and treatment engagement were assessed using a repeated-measures ANOVA or Friedman test.

Results: Among 17 eligible participants, 11 people were interviewed. Overall, there were no notable changes in any symptom scale in the first 3-5 months before the pandemic or during the stay-at-home orders. The few patients who reported worse symptoms were significantly older (mean age: 71.7 years, SD: 4.0). Most patients denied disruptions to treatment, and some perceived telepsychiatry as beneficial.

Conclusions: Rural patients with serious mental illness may be fairly resilient in the face of the COVID-19 pandemic when they have access to treatment and supports. Longer-term outcomes are needed in rural patients with serious mental illness to better understand the impact of the pandemic on this population.
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http://dx.doi.org/10.1093/milmed/usaa559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798823PMC
August 2021

MR Measures of Small Bowel Wall T2 Are Associated With Increased Permeability.

J Magn Reson Imaging 2021 05 16;53(5):1422-1431. Epub 2020 Dec 16.

National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.

Background: Increased small bowel permeability leads to bacterial translocation, associated with significant morbidity and mortality. Biomarkers are needed to evaluate these changes in vivo, stratify an individual's risk, and evaluate the efficacy of interventions. MRI is an established biomarker of small bowel inflammation.

Purpose: To characterize changes in the small bowel with quantitative MRI measures associated with increased permeability induced by indomethacin.

Study Type: Prospective single-center, double-blind, two-way crossover provocation study.

Subjects: A provocation cohort (22 healthy volunteers) and intrasubject reproducibility cohort (8 healthy volunteers).

Field Strength/sequence: 2D balanced turbo field echo sequences to measure small bowel wall thickness, T , and motility acquired at 3T.

Assessment: Participants were randomized to receive indomethacin or placebo prior to assessment. After a minimum 2-week washout, measures were repeated with the alternative allocation. MR measures (wall thickness, T , motility) at each study visit were compared to the reference standard 2-hour lactulose/mannitol urinary excretion ratio (LMR) test performed by a lab technician. All analyses were performed blind.

Statistical Tests: Normality was tested (Shapiro-Wilk's test). Paired testing (Student's t-test or Wilcoxon) determined the significance of paired differences with indomethacin provocation. Pearson's correlation coefficient compared significant measures with indomethacin provocation to LMR. Intrasubject (intraclass correlation) and interrater variability (Bland-Altman) were assessed.

Results: Indomethacin provocation induced a significant increase in LMR compared to placebo (P < 0.05) and a significant increase in small bowel T (0.12 seconds compared to placebo 0.07 seconds, P < 0.05). Small bowel wall thickness (P = 0.17) and motility (P = 0.149) showed no significant change. T and LMR were positively correlated (r = 0.68, P < 0.05). T measurements were robust to interobserver (intraclass correlation 0.89) and intrasubject variability (Bland-Altman bias of 0.005 seconds, 95% confidence interval [CI] -0.04 to +0.05 seconds, and 0.0006 seconds, 95% CI -0.05 to +0.06 seconds).

Data Conclusion: MR measures of small bowel wall T were significantly increased following indomethacin provocation and correlated with 2-hour LMR test results.

Level Of Evidence: 1 TECHNICAL EFFICACY STAGE: 2.
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http://dx.doi.org/10.1002/jmri.27463DOI Listing
May 2021

Ingestive behaviors in bearded capuchins (Sapajus libidinosus).

Sci Rep 2020 11 30;10(1):20850. Epub 2020 Nov 30.

Department of Biomedical Sciences, University of Missouri Kansas City School of Medicine, 2411 Holmes Street, Kansas City, MO, 64108, USA.

The biomechanical and adaptive significance of variation in craniodental and mandibular morphology in fossil hominins is not always clear, at least in part because of a poor understanding of how different feeding behaviors impact feeding system design (form-function relationships). While laboratory studies suggest that ingestive behaviors produce variable loading, stress, and strain regimes in the cranium and mandible, understanding the relative importance of these behaviors for feeding system design requires data on their use in wild populations. Here we assess the frequencies and durations of manual, ingestive, and masticatory behaviors from more than 1400 observations of feeding behaviors video-recorded in a wild population of bearded capuchins (Sapajus libidinosus) at Fazenda Boa Vista in Piauí, Brazil. Our results suggest that ingestive behaviors in wild Sapajus libidinosus were used for a range of food material properties and typically performed using the anterior dentition. Coupled with previous laboratory work indicating that ingestive behaviors are associated with higher mandibular strain magnitudes than mastication, these results suggest that ingestive behaviors may play an important role in craniodental and mandibular design in capuchins and may be reflected in robust adaptations in fossil hominins.
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http://dx.doi.org/10.1038/s41598-020-77797-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705727PMC
November 2020

The Split Gal4 System for Neural Circuit Mapping.

Front Neural Circuits 2020 9;14:603397. Epub 2020 Nov 9.

Laboratory of Molecular Biology, National Institute of Mental Health, NIH, Bethesda, MD, United States.

The diversity and dense interconnectivity of cells in the nervous system present a huge challenge to understanding how brains work. Recent progress toward such understanding, however, has been fuelled by the development of techniques for selectively monitoring and manipulating the function of distinct cell types-and even individual neurons-in the brains of living animals. These sophisticated techniques are fundamentally genetic and have found their greatest application in genetic model organisms, such as the fruit fly . combines genetic tractability with a compact, but cell-type rich, nervous system and has been the incubator for a variety of methods of neuronal targeting. One such method, called Split Gal4, is playing an increasingly important role in mapping neural circuits in the fly. In conjunction with functional perturbations and behavioral screens, Split Gal4 has been used to characterize circuits governing such activities as grooming, aggression, and mating. It has also been leveraged to comprehensively map and functionally characterize cells composing important brain regions, such as the central complex, lateral horn, and the mushroom body-the latter being the insect seat of learning and memory. With connectomics data emerging for both the larval and adult brains of , Split Gal4 is also poised to play an important role in characterizing neurons of interest based on their connectivity. We summarize the history and current state of the Split Gal4 method and indicate promising areas for further development or future application.
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http://dx.doi.org/10.3389/fncir.2020.603397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680822PMC
November 2020

Exome sequencing and characterization of 49,960 individuals in the UK Biobank.

Nature 2020 10 21;586(7831):749-756. Epub 2020 Oct 21.

University of Michigan, Ann Arbor, MI, USA.

The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world. Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenic BRCA1 and BRCA2 variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.
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http://dx.doi.org/10.1038/s41586-020-2853-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759458PMC
October 2020

Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.

Diabetes 2020 12 11;69(12):2806-2818. Epub 2020 Sep 11.

Department of Biostatistics, Boston University School of Public Health, Boston, MA.

Leptin influences food intake by informing the brain about the status of body fat stores. Rare mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in , , , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry ( = 2 × 10, = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
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http://dx.doi.org/10.2337/db20-0070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679778PMC
December 2020

Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases.

Nat Genet 2020 10 7;52(10):1122-1131. Epub 2020 Sep 7.

MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Bristol, UK.

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( https://www.epigraphdb.org/pqtl/ ). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-0682-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610464PMC
October 2020

Inflammatory and Fibrogenic Factors in Proliferative Vitreoretinopathy Development.

Transl Vis Sci Technol 2020 02 21;9(3):23. Epub 2020 Feb 21.

Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.

Purpose: Proliferative vitreoretinopathy (PVR) occurs in 5%-10% of rhegmatogenous retinal detachment cases and is the principle cause for failure of retinal reattachment surgery. Although there are a number of surgical adjunctive agents available for preventing the development of PVR, all have limited efficacy. Discovering predictive molecular biomarkers to determine the probability of PVR development after retinal reattachment surgery will allow better patient stratification for more targeted drug evaluations.

Methods: Narrative literature review.

Results: We provide a summary of the inflammatory and fibrogenic factors found in ocular fluid samples during the development of retinal detachment and PVR and discuss their possible use as molecular PVR predictive biomarkers.

Conclusions: Studies monitoring the levels of the above factors have found that few if any have predictive biomarker value, suggesting that widening the phenotype of potential factors and a combinatorial approach are required to determine predictive biomarkers for PVR.

Translational Relevance: The identification of relevant biomarkers relies on an understanding of disease signaling pathways derived from basic science research. We discuss the extent to which those molecules identified as biomarkers and predictors of PVR relate to disease pathogenesis and could function as useful disease predictors. (http://www.umin.ac.jp/ctr/ number, UMIN000005604).
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http://dx.doi.org/10.1167/tvst.9.3.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357815PMC
February 2020

Evaluation of a Rapid Point-of-Care Multiplex Immunochromatographic Assay for the Diagnosis of Enteric Fever.

mSphere 2020 06 10;5(3). Epub 2020 Jun 10.

Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA

There is a critical need for an improved rapid diagnostic for enteric fever. We have previously demonstrated that serum IgA responses targeting serovar Typhi hemolysin E (HlyE) and lipopolysaccharide (LPS) are able to discriminate patients with acute typhoid from healthy controls in areas where enteric fever is endemic (healthy endemic controls) and from patients with other bacterial infections. We now have data demonstrating that IgA antibody responses against these antigens also work well for identifying patients with acute Paratyphi A infection. To develop a test for acute enteric fever detection, we have adapted a point-of-care immunochromatographic dual-path platform technology (DPP), which improves on the traditional lateral flow technology by using separate sample and conjugate paths and a compact, portable reader, resulting in diagnostics with higher sensitivity and multiplexing abilities. In this analysis, we have compared our standard enzyme-linked immunosorbent assay (ELISA) method to the DPP method in detecting acute phase plasma/serum anti-HlyE and anti-LPS IgA antibodies in a cohort of patients with culture-confirmed Typhi ( = 30) and Paratyphi A infection ( = 20), healthy endemic controls ( = 25), and febrile endemic controls ( = 25). We found that the DPP measurements highly correlated with ELISA results, and both antigens had an area under the curve (AUC) of 0.98 (sensitivity of 92%, specificity of 94%) with all controls and an AUC of 0.98 (sensitivity of 90%, specificity of 96%) with febrile endemic controls. Our results suggest that the point-of-care DPP Typhoid System has high diagnostic accuracy for the rapid detection of enteric fever and warrants further evaluation. Enteric fever remains a significant global problem, and control programs are significantly limited by the lack of an optimal assay for identifying individuals with acute infection. This is especially critical considering the recently released World Health Organization (WHO) position paper endorsing the role of the typhoid conjugate vaccine in communities where enteric fever is endemic. A reliable diagnostic test is needed to assess and evaluate typhoid intervention strategies and determine which high-burden areas may benefit most from a vaccine intervention. Our collaborative team has developed and evaluated a point-of-care serodiagnostic assay based on detection of anti-HlyE and LPS IgA. Our finding of the high diagnostic accuracy of the DPP Typhoid System for the rapid detection of enteric fever has the potential to have significant public health impact by allowing for improved surveillance and for control and prevention programs in areas with limited laboratory capacity.
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http://dx.doi.org/10.1128/mSphere.00253-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289704PMC
June 2020

Non-canonical Eclosion Hormone-Expressing Cells Regulate Drosophila Ecdysis.

iScience 2020 May 27;23(5):101108. Epub 2020 Apr 27.

Laboratory of Molecular Biology, National Institute of Mental Health, NIH, Bethesda, MD 20892, USA. Electronic address:

Eclosion hormone (EH) was originally identified as a brain-derived hormone capable of inducing the behavioral sequences required for molting across insect species. However, its role in this process (called ecdysis) has since been confounded by discrepancies in the effects of genetic and cellular manipulations of EH function in Drosophila. Although knock-out of the Eh gene results in severe ecdysis-associated deficits accompanied by nearly complete larval lethality, ablation of the only neurons known to express EH (i.e. V neurons) is only partially lethal and surviving adults emerge, albeit abnormally. Using new tools for sensitively detecting Eh gene expression, we show that EH is more widely expressed than previously thought, both within the nervous system and in somatic tissues, including trachea. Ablating all Eh-expressing cells has effects that closely match those of Eh gene knock-out; developmentally suppressing them severely disrupts eclosion. Our results thus clarify and extend the scope of EH action.
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http://dx.doi.org/10.1016/j.isci.2020.101108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225733PMC
May 2020

Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.

Am J Hum Genet 2020 03 27;106(3):389-404. Epub 2020 Feb 27.

Department of Cardiovascular Sciences, University of Leicester, LE3 9QP, United Kingdom; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, United Kingdom.

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
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http://dx.doi.org/10.1016/j.ajhg.2020.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058826PMC
March 2020

Preserving the Exposed Facets of PtSn Intermetallic Nanocubes During an Order to Disorder Transition Allows the Elucidation of the Effect of the Degree of Alloy Ordering on Electrocatalysis.

J Am Chem Soc 2020 02 28;142(6):3231-3239. Epub 2020 Jan 28.

Department of Chemistry , University of Saskatchewan , 110 Science Place , Saskatoon , Saskatchewan S7N 5C9 , Canada.

Controlling which facets are exposed in nanocrystals is crucial to understanding different activity between ordered and disordered alloy electrocatalysts. We modify the degree of ordering of PtSn nanocubes, while maintaining the shape and size, to enable a direct evaluation of the effect of the order on ORR catalytic activity. We demonstrate a 2.3-fold enhancement in specific activity by 60- and 30%-ordered PtSn nanocubes compared to 95%-ordered. This was shown to be likely due to surface vacancies in the less-ordered particles. The greater order, however, results in higher stability of the electrocatalyst, with the more disordered nanoparticles showing the dissolution of tin and platinum species during electrocatalysis.
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http://dx.doi.org/10.1021/jacs.9b13313DOI Listing
February 2020

Last appearance of Homo erectus at Ngandong, Java, 117,000-108,000 years ago.

Nature 2020 01 18;577(7790):381-385. Epub 2019 Dec 18.

Department of Anthropology and Museum of Natural History, University of Iowa, Iowa City, IA, USA.

Homo erectus is the founding early hominin species of Island Southeast Asia, and reached Java (Indonesia) more than 1.5 million years ago. Twelve H. erectus calvaria (skull caps) and two tibiae (lower leg bones) were discovered from a bone bed located about 20 m above the Solo River at Ngandong (Central Java) between 1931 and 1933, and are of the youngest, most-advanced form of H. erectus. Despite the importance of the Ngandong fossils, the relationship between the fossils, terrace fill and ages have been heavily debated. Here, to resolve the age of the Ngandong evidence, we use Bayesian modelling of 52 radiometric age estimates to establish-to our knowledge-the first robust chronology at regional, valley and local scales. We used uranium-series dating of speleothems to constrain regional landscape evolution; luminescence, argon/argon (Ar/Ar) and uranium-series dating to constrain the sequence of terrace evolution; and applied uranium-series and uranium series-electron-spin resonance (US-ESR) dating to non-human fossils to directly date our re-excavation of Ngandong. We show that at least by 500 thousand years ago (ka) the Solo River was diverted into the Kendeng Hills, and that it formed the Solo terrace sequence between 316 and 31 ka and the Ngandong terrace between about 140 and 92 ka. Non-human fossils recovered during the re-excavation of Ngandong date to between 109 and 106 ka (uranium-series minimum) and 134 and 118 ka (US-ESR), with modelled ages of 117 to 108 thousand years (kyr) for the H. erectus bone bed, which accumulated during flood conditions. These results negate the extreme ages that have been proposed for the site and solidify Ngandong as the last known occurrence of this long-lived species.
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http://dx.doi.org/10.1038/s41586-019-1863-2DOI Listing
January 2020

Calcification Microstructure Reflects Breast Tissue Microenvironment.

J Mammary Gland Biol Neoplasia 2019 12 5;24(4):333-342. Epub 2019 Dec 5.

Cranfield Forensic Institute, Cranfield University, Shrivenham, UK.

Microcalcifications are important diagnostic indicators of disease in breast tissue. Tissue microenvironments differ in many aspects between normal and cancerous cells, notably extracellular pH and glycolytic respiration. Hydroxyapatite microcalcification microstructure is also found to differ between tissue pathologies, including differential ion substitutions and the presence of additional crystallographic phases. Distinguishing between tissue pathologies at an early stage is essential to improve patient experience and diagnostic accuracy, leading to better disease outcome. This study explores the hypothesis that microenvironment features may become immortalised within calcification crystallite characteristics thus becoming indicators of tissue pathology. In total, 55 breast calcifications incorporating 3 tissue pathologies (benign - B2, ductal carcinoma in-situ - B5a and invasive malignancy - B5b) from archive formalin-fixed paraffin-embedded core needle breast biopsies were analysed using X-ray diffraction. Crystallite size and strain were determined from 548 diffractograms using Williamson-Hall analysis. There was an increased crystallinity of hydroxyapatite with tissue malignancy compared to benign tissue. Coherence length was significantly correlated with pathology grade in all basis crystallographic directions (P < 0.01), with a greater difference between benign and in situ disease compared to in-situ disease and invasive malignancy. Crystallite size and non-uniform strain contributed to peak broadening in all three pathologies. Furthermore, crystallite size and non-uniform strain normal to the basal planes increased significantly with malignancy (P < 0.05). Our findings support the view that tissue microenvironments can influence differing formation mechanisms of hydroxyapatite through acidic precursors, leading to differential substitution of carbonate into the hydroxide and phosphate sites, causing significant changes in crystallite size and non-uniform strain.
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http://dx.doi.org/10.1007/s10911-019-09441-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908550PMC
December 2019

Genetic predisposition to mosaic Y chromosome loss in blood.

Nature 2019 11 20;575(7784):652-657. Epub 2019 Nov 20.

Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.
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http://dx.doi.org/10.1038/s41586-019-1765-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887549PMC
November 2019

Genetic predisposition to mosaic Y chromosome loss in blood.

Nature 2019 11 20;575(7784):652-657. Epub 2019 Nov 20.

Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.
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http://dx.doi.org/10.1038/s41586-019-1765-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887549PMC
November 2019
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