Publications by authors named "James Hamilton"

312 Publications

Modelling Sand Fly Attraction to Host Odour: Synthetic Sex-Aggregation Pheromone Dominates the Response.

Microorganisms 2021 Mar 15;9(3). Epub 2021 Mar 15.

The Zeeman Institute for Systems Biology and Infectious Disease Epidemiology Research (SBIDER), The University of Warwick, Coventry CV4 7AL, UK.

Zoontic visceral leishmaniasis (ZVL) due to is a potentially fatal protozoan parasitic disease of humans and dogs. In the Americas, dogs are the reservoir and the sand fly, the principal vector. A synthetic version of the male sand fly produced sex-aggregation pheromone attracts both female and male conspecifics to co-located insecticide, reducing both reservoir infection and vector abundance. However the effect of the synthetic pheromone on the vector's "choice" of host (human, animal reservoir, or dead-end host) for blood feeding in the presence of the pheromone is less well understood. In this study, we developed a modelling framework to allow us to predict the relative attractiveness of the synthetic pheromone and potential alterations in host choice. Our analysis indicates that the synthetic pheromone can attract 53% (95% CIs: 39%-86%) of host-seeking female and thus it out-competes competing host odours. Importantly, the results suggest that the synthetic pheromone can lure vectors away from humans and dogs, such that when co-located with insecticide, it provides protection against transmission leading to human and canine ZVL.
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http://dx.doi.org/10.3390/microorganisms9030602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999287PMC
March 2021

Odour of domestic dogs infected with Leishmania infantum is attractive to female but not male sand flies: Evidence for parasite manipulation.

PLoS Pathog 2021 Mar 18;17(3):e1009354. Epub 2021 Mar 18.

Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancashire, United Kingdom.

Globally visceral leishmaniasis (VL) causes thousands of human deaths every year. In South America, the etiologic agent, Leishmania infantum, is transmitted from an infected canine reservoir to human hosts by the bite of the sand fly vector; predominantly Lutzomyia longipalpis. Previous evidence from model rodent systems have suggested that the odour of infected hosts is altered by the parasite making them more attractive to the vector leading to an increased biting rate and improved transmission prospects for the pathogen. However, there has been no assessment of the effect of Le infantum infection on the attractiveness of dogs, which are the natural reservoirs for human infection. Hair collected from infected and uninfected dogs residing in a VL endemic city in Brazil was entrained to collect the volatile chemical odours present in the headspace. Female and male Lu. longipalpis sand flies were offered a choice of odour entrained from infected and uninfected dogs in a series of behavioural experiments. Odour of uninfected dogs was equally attractive to male or female Lu. longipalpis when compared to a solvent control. Female Lu. longipalpis were significantly more attracted to infected dog odour than uninfected dog odour in all 15 experimental replicates (average 45.7±0.87 females attracted to infected odour; 23.9±0.82 to uninfected odour; paired T-test, P = 0.000). Male Lu. longipalpis did not significantly prefer either infected or uninfected odour (average 36.1±0.4 males to infected odour; 35.7±0.6 to uninfected odour; paired T-test, P = 0.722). A significantly greater proportion of females chose the infected dog odour compared to the males (paired T-test, P = 0.000). The results showed that the odour of dogs infected with Le. infantum was significantly more attractive to blood-seeking female sand flies than it was to male sand flies. This is strong evidence for parasite manipulation of the host odour in a natural transmission system and indicates that infected dogs may have a disproportionate significance in maintaining infection in the canine and human population.
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http://dx.doi.org/10.1371/journal.ppat.1009354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971543PMC
March 2021

Long-term serological, virological and histological responses to RNA inhibition by ARC-520 in Chinese chronic hepatitis B patients on entecavir treatment.

Gut 2021 Mar 12. Epub 2021 Mar 12.

Arrowhead Pharmaceuticals, Pasadena, California, USA.

Objective: We examined the serological, virological (in serum and liver) and histological profiles in chronic hepatitis B virus (HBV) patients during and after completion of multiple dose (MD) ARC-520.

Design: The present phase 1b study was a multidose, open-label extension cohort of patients that had received single dose ARC-520 in our previous study. Eight patients received 4-9 4 weekly doses of MD ARC-520 and entecavir. Liver biopsies were performed in six patients. Intrahepatic and serum HBV DNA, HBV RNA and viral antigens were measured.

Results: All patients had 28.9-30.4 months of follow-up after the last MD. All three hepatitis B e antigen (HBeAg)-positive patients had profound reductions in hepatitis B surface antigen (HBsAg), HBeAg, hepatitis B core-related antigen and HBV RNA with two undergoing HBeAg seroconversion. One further achieved HBsAg seroconversion (anti-HBs level of 25.1 IU/L) and the remaining two had HBsAg reductions of -1.7 and -3.5 log IU/mL >30 months after MD. Among the five HBeAg-negative patients, four had modest HBsAg reduction >29 months after completion of MD and one achieved HBsAg seroconversion (anti-HBs level of 152.5 IU/L) and was negative for liver HBsAg staining. Entecavir was successfully stopped in this patient 12 months after HBsAg seroconversion. Temporally related alanine aminotransferase elevations preceded by HBsAg reductions were observed in three patients suggesting immune activation. HBcAg staining was negative in all six biopsied patients. Two patients with 10% HBsAg positive staining of hepatocytes had correspondingly low serum HBsAg levels of 1.5 and 11.5 IU/mL.

Conclusions: MD ARC-520 therapy achieved sustained and profound reductions of viral antigens and HBV RNA. HBsAg seroclearance was achievable.

Trial Registration Number: NCT02065336.
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http://dx.doi.org/10.1136/gutjnl-2020-323445DOI Listing
March 2021

Systemic deletion of Atp7b modifies the hepatocytes' response to copper overload in the mouse models of Wilson disease.

Sci Rep 2021 Mar 11;11(1):5659. Epub 2021 Mar 11.

Department of Physiology, Johns Hopkins Medical Institutes, 725 N Wolfe street, Baltimore, MD, 21205, USA.

Wilson disease (WD) is caused by inactivation of the copper transporter Atp7b and copper overload in tissues. Mice with Atp7b deleted either globally (systemic inactivation) or only in hepatocyte recapitulate various aspects of human disease. However, their phenotypes vary, and neither the common response to copper overload nor factors contributing to variability are well defined. Using metabolic, histologic, and proteome analyses in three Atp7b-deficient mouse strains, we show that global inactivation of Atp7b enhances and specifically modifies the hepatocyte response to Cu overload. The loss of Atp7b only in hepatocytes dysregulates lipid and nucleic acid metabolisms and increases the abundance of respiratory chain components and redox balancing enzymes. In global knockouts, independently of their background, the metabolism of lipid, nucleic acid, and amino acids is inhibited, respiratory chain components are down-regulated, inflammatory response and regulation of chromosomal replication are enhanced. Decrease in glucokinase and lathosterol oxidase and elevation of mucin-13 and S100A10 are observed in all Atp7b mutant strains and reflect the extent of liver injury. The magnitude of proteomic changes in Atp7b animals inversely correlates with the metallothioneins levels rather than liver Cu content. These findings facilitate identification of WD-specific metabolic and proteomic changes for diagnostic and treatment.
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http://dx.doi.org/10.1038/s41598-021-84894-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952580PMC
March 2021

Community deployment of a synthetic pheromone of the sand fly Lutzomyia longipalpis co-located with insecticide reduces vector abundance in treated and neighbouring untreated houses: Implications for control of Leishmania infantum.

PLoS Negl Trop Dis 2021 Feb 3;15(2):e0009080. Epub 2021 Feb 3.

Zeeman Institute and School of Life Sciences, University of Warwick, Coventry, United Kingdom.

Background: The rising incidence of visceral leishmaniasis due to Leishmania infantum requires novel methods to control transmission by the sand fly vector. Indoor residual spraying of insecticide (IRS) against these largely exophilic / exophagic vectors may not be the most effective method. A synthetic copy of the male sex-aggregation pheromone of the key vector species Lutzomyia longipalpis in the Americas, was co-located with residual pyrethroid insecticide, and tested for its effects on vector abundance, hence potential transmission, in a Brazilian community study.

Methods: Houses within eight defined semi-urban blocks in an endemic municipality in Brazil were randomised to synthetic pheromone + insecticide or to placebo treatments. A similar number of houses located >100m from each block were placebo treated and considered as "True Controls" (thus, analysed as three trial arms). Insecticide was sprayed on a 2.6m2 surface area of the property boundary or outbuilding wall, co-located within one metre of 50mg synthetic pheromone in controlled-release dispensers. Vector numbers captured in nearby CDC light traps were recorded at monthly intervals over 3 months post intervention. Recruited sentinel houses under True Control and pheromone + insecticide treatments were similarly monitored at 7-9 day intervals. The intervention effects were estimated by mixed effects negative binomial models compared to the True Control group.

Results: Dose-response field assays using 50mg of the synthetic pheromone captured a mean 4.8 (95% C.L.: 3.91, 5.80) to 6.3 (95% C.L.: 3.24, 12.11) times more vectors (female Lu. longipalpis) than using 10mg of synthetic pheromone. The intervention reduced household female vector abundance by 59% (C.L.: 48.7, 66.7%) (IRR = 0.41) estimated by the cross-sectional community study, and by 70% (C.L.: 56.7%, 78.8%) estimated by the longitudinal sentinel study. Similar reductions in male Lu. longipalpis were observed. Beneficial spill-over intervention effects were also observed at nearby untreated households with a mean reduction of 24% (95% C.L.: 0.050%, 39.8%) in female vectors. The spill-over effect in untreated houses was 44% (95% C.L.: 29.7%, 56.1%) as effective as the intervention in pheromone-treated houses. Ownership of chickens increased the intervention effects in both treated and untreated houses, attributed to the suspected synergistic attraction of the synthetic pheromone and chicken kairomones. The variation in IRR between study blocks was not associated with inter-household distances, household densities, or coverage (proportion of total households treated).

Conclusions: The study confirms the entomological efficacy of the lure-and-kill method to reduce the abundance of this important sand fly vector in treated and untreated homesteads. The outcomes were achieved by low coverage and using only 1-2% of the quantity of insecticide as normally required for IRS, indicating the potential cost-effectiveness of this method. Implications for programmatic deployment of this vector control method are discussed.
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http://dx.doi.org/10.1371/journal.pntd.0009080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886189PMC
February 2021

The Impact of Dietary Patterns and Nutrition in Nonalcoholic Fatty Liver Disease.

Gastroenterol Clin North Am 2021 Mar;50(1):217-241

Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Nonalcoholic fatty liver disease (NAFLD) has become one of the most common causes of chronic liver disease worldwide. The prevalence of NAFLD has grown proportionally with the rise in obesity, sedentary lifestyle, unhealthy dietary patterns, and metabolic syndrome. Currently, in the absence of approved pharmacologic treatment, the keystone of treatment is lifestyle modification focused on achieving a weight loss of 7%-10%, cardiovascular exercise, and improving insulin sensitivity. The primary aim of this review is to outline the effect of different dietetic approaches against NAFLD and highlight the important micronutrient components in the management of NAFLD.
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http://dx.doi.org/10.1016/j.gtc.2020.10.013DOI Listing
March 2021

COVID-19: An overview and a clinical update.

World J Clin Cases 2021 Jan;9(1):8-23

Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, MD 21287, United States.

The outbreak of coronavirus disease-2019 (COVID-19, previously known as 2019 nCoV) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Wuhan City, China, has spread rapidly around the world. Most patients from the first cluster had an epidemiological connection to the Wuhan's Huanan Seafood Wholesale Market. Available evidence has shown that SARS-CoV-2 can be easily transmitted from person to person through close contact and respiratory droplets, posing a substantial challenge to public health. At present, the research on SARS-CoV-2 is still in the primary stages. However, dexa-methasone and remdesivir are appeared to be promising medical therapies. Still, there is no definite specific treatment, and the mainstay of treatment is still focused on supportive therapies. Currently, over 150 vaccines are under investigation. It is necessary to understand the nature of the virus and its clinical characteristics in order to find effectively manage the disease. The knowledge about this virus is rapidly evolving, and clinicians must update themselves regularly. The present review comprehensively summarizes the epidemiology, pathogenesis, clinical characteristics, and management of COVID-19 based on the current evidence.
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http://dx.doi.org/10.12998/wjcc.v9.i1.8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809683PMC
January 2021

Aging-induced microbleeds of the mouse thalamus compared to sensorimotor and memory defects.

Neurobiol Aging 2021 Apr 9;100:39-47. Epub 2020 Dec 9.

Department of Health Sciences, Sargent College, Boston, MA, USA. Electronic address:

The aim of this study is to investigate the relationship between aging and brain vasculature health. Three groups of mice, 3, 17-18, and 24 months, comparable to young adult, middle age, and old human were studied. Prussian blue histology and fast imaging with steady precession T2∗-weighted magnetic resonance imaging were used to quantify structural changes in the brain across age groups. The novel object recognition test was used to assess behavioral changes associated with anatomical changes. This study is the first to show that the thalamus is the most vulnerable brain region in the mouse model for aging-induced vascular damage. Magnetic resonance imaging data document the timeline of accumulation of thalamic damage. Histological data reveal that the majority of vascular damage accumulates in the ventroposterior nucleus and mediodorsal thalamic nucleus. Functional studies indicate that aging-induced vascular damage in the thalamus is associated with memory and sensorimotor deficits. This study points to the possibility that aging-associated vascular disease is a factor in irreversible brain damage as early as middle age.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.11.017DOI Listing
April 2021

A narrative review of coronavirus disease 2019 (COVID-19): clinical, epidemiological characteristics, and systemic manifestations.

Intern Emerg Med 2021 Jan 16. Epub 2021 Jan 16.

Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 600 N. Wolfe St, Hal 407, Baltimore, MD, 21287, USA.

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease which has had a rapid surge in cases and deaths since it is first documented in Wuhan, China, in December 2019. COVID-19 is caused by the Betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 uses angiotensin-converting enzyme 2, which is highly expressed in the human lower respiratory tract but also in other tissues, as the cellular entry receptor. Thus, COVID-19 mainly affects the respiratory system but can cause damage to other body systems, including the cardiovascular, gastrointestinal, hepatobiliary, renal, and central nervous systems. We review the pathogenesis and clinical manifestations of the infection, focusing on our current understanding of the disease mechanisms and their translation to clinical outcomes, as well as adverse effects on different body systems. We also discuss the epidemiology pathogenesis, clinical, and multi-organ consequences, and highlight some of the research gaps regarding COVID-19.
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http://dx.doi.org/10.1007/s11739-020-02616-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811158PMC
January 2021

Global burden of disease: acute-on-chronic liver failure, a systematic review and meta-analysis.

Gut 2021 Jan 12. Epub 2021 Jan 12.

Gastroenterology and Hepatology, Depatment of Medicine, Baylor College of Medicine, Houston, Texas, USA

Background And Aims: Acute-on-chronic liver failure (ACLF) is characterised by acute decompensation of cirrhosis associated with organ failures. We systematically evaluated the geographical variations of ACLF across the world in terms of prevalence, mortality, aetiology of chronic liver disease (CLD), triggers and organ failures.

Methods: We searched EMBASE and PubMed from 3/1/2013 to 7/3/2020 using the ACLF-EASL-CLIF (European Association for the Study of the Liver-Chronic Liver Failure) criteria. Two investigators independently conducted the abstract selection/abstraction of the aetiology of CLD, triggers, organ failures and prevalence/mortality by presence/grade of ACLF. We grouped countries into Europe, East/South Asia and North/South America. We calculated the pooled proportions, evaluated the methodological quality using the Newcastle-Ottawa Scale and statistical heterogeneity, and performed sensitivity analyses.

Results: We identified 2369 studies; 30 cohort studies met our inclusion criteria (43 206 patients with ACLF and 140 835 without ACLF). The global prevalence of ACLF among patients admitted with decompensated cirrhosis was 35% (95% CI 33% to 38%), highest in South Asia at 65%. The global 90-day mortality was 58% (95% CI 51% to 64%), highest in South America at 73%. Alcohol was the most frequently reported aetiology of underlying CLD (45%, 95% CI 41 to 50). Infection was the most frequent trigger (35%) and kidney dysfunction the most common organ failure (49%). Sensitivity analyses showed regional estimates grossly unchanged for high-quality studies. Type of design, country health index, underlying CLD and triggers explained the variation in estimates.

Conclusions: The global prevalence and mortality of ACLF are high. Region-specific variations could be explained by the type of triggers/aetiology of CLD or grade. Health systems will need to tailor early recognition and treatment of ACLF based on region-specific data.
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http://dx.doi.org/10.1136/gutjnl-2020-322161DOI Listing
January 2021

Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis.

Proc Natl Acad Sci U S A 2020 12 14;117(52):33272-33281. Epub 2020 Dec 14.

Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach an der Riss, Germany;

As an alternative pathway of controlled cell death, necroptosis can be triggered by tumor necrosis factor via the kinases RIPK1/RIPK3 and the effector protein mixed-lineage kinase domain-like protein (MLKL). Upon activation, MLKL oligomerizes and integrates into the plasma membrane via its executioner domain. Here, we present the X-ray and NMR costructures of the human MLKL executioner domain covalently bound via Cys86 to a xanthine class inhibitor. The structures reveal that the compound stabilizes the interaction between the auto-inhibitory brace helix α6 and the four-helix bundle by stacking to Phe148. An NMR-based functional assay observing the conformation of this helix showed that the F148A mutant is unresponsive to the compound, providing further evidence for the importance of this interaction. Real-time and diffusion NMR studies demonstrate that xanthine derivatives inhibit MLKL oligomerization. Finally, we show that the other well-known MLKL inhibitor Necrosulfonamide, which also covalently modifies Cys86, must employ a different mode of action.
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http://dx.doi.org/10.1073/pnas.2017406117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7777204PMC
December 2020

Dynamic DNA methylation changes in early versus late adulthood suggest nondeterministic effects of childhood adversity: a meta-analysis.

J Dev Orig Health Dis 2020 Dec 14:1-12. Epub 2020 Dec 14.

CUIDA - Centro de Investigación del Abuso y la Adversidad Temprana, Pontificia Universidad Católica de Chile, Avenida Libertador Bernardo O'Higgins 340, Santiago, Chile.

Adverse childhood experiences (ACEs) are associated with a high risk of developing chronic diseases and decreased life expectancy, but no ACE epigenetic biomarkers have been identified until now. The latter may result from the interaction of multiple factors such as age, sex, degree of adversity, and lack of transcriptional effects of DNA methylation changes. We hypothesize that DNA methylation changes are related to childhood adversity levels and current age, and these markers evolve as aging proceeds. Two Gene Expression Omnibus datasets, regarding ACE, were selected (GSE72680 and GSE70603), considering raw- and meta-data availability, including validated ACE index (Childhood Trauma Questionnaire (CTQ) score). For DNA methylation, analyzed probes were restricted to those laying within promoters and first exons, and samples were grouped by CTQ scores terciles, to compare highly (ACE) with non-abused (control) cases. Comparison of control and ACE methylome profile did not retrieve differentially methylated CpG sites (DMCs) after correcting by false discovery rate < 0.05, and this was also observed when samples were separated by sex. In contrast, grouping by decade age ranges (i.e., the 20s, 30s, 40s, and 50s) showed a progressive increase in the number of DMCs and the intensity of changes, mainly related with hypomethylation. Comparison with transcriptome data for ACE subjects in the 40s, and 50s showed a similar age-dependent effect. This study provides evidence that epigenetic markers of ACE are age-dependent, but not defined in the long term. These differences among early, middle, and late adulthood epigenomic profiles suggest a window for interventions aimed to prevent the detrimental effects of ACE.
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http://dx.doi.org/10.1017/S2040174420001075DOI Listing
December 2020

Significant reduction in abundance of peridomestic mosquitoes (Culicidae) and Culicoides midges (Ceratopogonidae) after chemical intervention in western São Paulo, Brazil.

Parasit Vectors 2020 Nov 7;13(1):549. Epub 2020 Nov 7.

Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Bailrigg, LA1 4YG, Lancashire, UK.

Background: We assessed the impact of two sand fly insecticide interventions (insecticide spraying and insecticide-impregnated dog collars) on the peridomestic abundance and distribution of mosquitoes (Culicidae) and biting midges (Ceratopogonidae) in western São Paulo (Brazil) in a long-term (42-month) evaluation. Both of these dipteran groups are vectors of diseases of medical and veterinary relevance to humans and domestic animals in Brazil.

Methods: The interventions in the 3-arm stratified randomised control trial were: pheromone + insecticide (PI) (chicken roosts were sprayed with microencapsulated lambda-cyhalothrin; pheromone lure has no effect on the Diptera pests studied here); dog-collars (DC) (dogs fitted with deltamethrin-impregnated collars); and control (C) (unexposed to pyrethroids) were extended by 12 months. During that time, adult mosquitoes and midges were sampled along 280 households at three household locations (inside human dwellings, dog sleeping sites and chicken roosts).

Results: We collected 3145 culicids (9 genera, 87.6% Culex spp.) distributed relatively uniformly across all 3 arms: 41.9% at chicken roosts; 37.7% inside houses; and 20.3% at dog sleeping sites. We collected 11,464 Culicoides (15 species) found mostly at chicken roosting sites (84.7%) compared with dog sleeping sites (12.9%) or houses (2.4%). Mosquitoes and Culicoides were most abundant during the hot and rainy season. Increased daytime temperature was marginally associated with increased mosquito abundance (Z = 1.97, P = 0.049) and Culicoides abundance (Z = 1.71, P = 0.087). There was no significant association with daily average rainfall for either group. Household-level mosquito and midge numbers were both significantly reduced by the PI intervention 56% [incidence rate ratio, IRR = 0.54 (95% CI: 0.30-0.97), P ≤ 0.05] and 53% [IRR = 0.47 (95% CI: 0.26-0.85), P ≤ 0.05], respectively, compared to the control intervention. The abundance of both dipteran groups at dog sleeping sites was largely unaffected by the PI and DC interventions. The PI intervention significantly reduced abundance of mosquitoes inside houses (41%) and at chicken roosting sites (48%) and reduced midge abundance by 51% in chicken roosting sites.

Conclusions: Sprayed insecticide at chicken roosting sites reduced the abundance of mosquitoes and midges at the peridomestic level while dog collars had no effect on numbers for any group.
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http://dx.doi.org/10.1186/s13071-020-04427-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648319PMC
November 2020

Allosterically Coupled Multisite Binding of Testosterone to Human Serum Albumin.

Endocrinology 2021 02;162(2)

Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Human serum albumin (HSA) acts as a carrier for testosterone, other sex hormones, fatty acids, and drugs. However, the dynamics of testosterone's binding to HSA and the structure of its binding sites remain incompletely understood. Here, we characterize the dynamics of testosterone's binding to HSA and the stoichiometry and structural location of the binding sites using 2-dimensional nuclear magnetic resonance (2D NMR), fluorescence spectroscopy, 4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid dipotassium salt partitioning, and equilibrium dialysis, complemented by molecular modeling. 2D NMR studies showed that testosterone competitively displaced 18-[13C]-oleic acid from at least 3 known fatty acid binding sites on HSA that also bind many drugs. Binding isotherms of testosterone's binding to HSA generated using fluorescence spectroscopy and equilibrium dialysis were nonlinear and the apparent dissociation constant varied with different concentrations of testosterone and HSA. The binding isotherms neither conformed to a linear binding model with 1:1 stoichiometry nor to 2 independent binding sites; the binding isotherms were most consistent with 2 or more allosterically coupled binding sites. Molecular dynamics studies revealed that testosterone's binding to fatty acid binding site 3 on HSA was associated with conformational changes at site 6, indicating that residues in in these 2 distinct binding sites are allosterically coupled. There are multiple, allosterically coupled binding sites for testosterone on HSA. Testosterone shares these binding sites on HSA with free fatty acids, which could displace testosterone from HSA under various physiological states or disease conditions, affecting its bioavailability.
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http://dx.doi.org/10.1210/endocr/bqaa199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774055PMC
February 2021

Synthetic sex-aggregation pheromone of Lutzomyia longipalpis, the South American sand fly vector of Leishmania infantum, attracts males and females over long-distance.

PLoS Negl Trop Dis 2020 10 20;14(10):e0008798. Epub 2020 Oct 20.

Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Bailrigg, Lancashire, United Kingdom.

Background: In South America the sand fly Lutzomyia longipalpis is the predominant vector of Leishmania infantum, the parasite that causes canine and human visceral leishmaniasis. Co-location of synthetic male sex-aggregation pheromone with an insecticide provided protection against canine seroconversion, parasite infection, reduced tissue parasite loads, and female sand fly densities at households. Optimising the sex-aggregation pheromone + insecticide intervention requires information on the distance over which female and male Lu. longipalpis would be attracted to the synthetic pheromone in the field.

Methodology/principal Findings: Wild Lu. longipalpis were collected at two peridomestic study sites in Governador Valadares (Minas Gerais, Brazil). Sand flies were marked with coloured fluorescent powder using an improved protocol and then released into an existing domestic chicken shed at two independent sites, followed by recapture at synthetic-pheromone host-odour baited traps placed up to 30 metres distant from the release point. In total 1704 wild-caught Lu. longipalpis were released into the two chicken sheds. Overall 4.3% of the marked flies were recaptured in the pheromone baited experimental chicken sheds compared to no marked flies recaptured in the control sheds. At the first site, 14 specimens (10.4% of the marked and released specimens) were recaptured at 10m, 36 (14.8%) at 20m, and 15 (3.4%) at 30m. At the second site, lower recapture rates were recorded; 8 marked specimens (1.3%) were recaptured at 5 and 10m and no marked specimens were recaptured at 15m. Approximately 7x more marked males than females were recaptured although males were only 2x as common as females in the released population. 52% of the marked Lu. longipalpis were collected during the first night of sampling, 32% on the second night, and 16% on the third night.

Conclusions/significance: The study established that both male and female sand flies can be attracted to the synthetic sex-aggregation pheromone in the presence of host odour over distances up to at least 30m in the field depending on local environmental and meterological conditions.
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http://dx.doi.org/10.1371/journal.pntd.0008798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598924PMC
October 2020

Ultrasound speckle tracking to detect vascular distensibility changes from angioplasty and branch ligation in a radio-cephalic fistula: Use of novel open source software.

J Vasc Access 2020 Sep 26:1129729820959910. Epub 2020 Sep 26.

VA Ann Arbor Healthcare System, Ann Arbor, MI, USA.

We used novel open source software, based on an ultrasound speckle tracking algorithm, to examine the distensibility of the vessel wall of the inflow artery, anastomosis, and outflow vein before and after two procedures. An 83-year-old white man with a poorly maturing radio-cephalic fistula received an angioplasty at the anastomosis followed by branch ligation 28 days later. Duplex Doppler measurements corroborated the blood flow related changes anticipated from the interventions. The experimental distensibility results showed that it is technically feasible to measure subtle vessel wall motion changes with high resolution (sub-millimeter) using standard Digital Imaging and Communications in Medicine (DICOM) ultrasound data, which are readily available on conventional ultrasound scanners. While this methodology was originally developed using high resolution radiofrequency from ultrasound data, the goal of this study was to use DICOM data, which makes this technology accessible to a wide range of users.
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http://dx.doi.org/10.1177/1129729820959910DOI Listing
September 2020

The Formosalides: Structure Determination by Total Synthesis.

Angew Chem Int Ed Engl 2021 01 3;60(1):446-454. Epub 2020 Nov 3.

Max-Planck-Institut für Kohlenforschung, 45470, Mülheim/Ruhr, Germany.

Total synthesis allowed the constitution of the cytotoxic marine macrolides of the formosalide family to be confirmed and their previously unknown stereostructure to be assigned with confidence. The underlying blueprint was inherently modular to ensure that each conceivable isomer could be reached. This flexibility derived from the use of strictly catalyst controlled transformations to set the stereocenters, except for the anomeric position, which is under thermodynamic control; as an extra safety measure, all stereogenic centers were set prior to ring closure to preclude any interference of the conformation adopted by the macrolactone rings of the different diastereomers. Late-stage macrocyclization by ring-closing alkyne metathesis was followed by a platinum-catalyzed transannular 6-exo-dig hydroalkoxylation/ketalization to craft the polycyclic frame. The side chain featuring a very labile unsaturation pattern was finally attached to the core by Stille coupling.
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http://dx.doi.org/10.1002/anie.202011472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821135PMC
January 2021

Mutant huntingtin does not cross the mitochondrial outer membrane.

Hum Mol Genet 2020 Oct;29(17):2962-2975

Department of Pharmacology and Toxicology.

Mutant huntingtin (mHTT) is associated with mitochondria, but the exact mitochondrial location of mHTT has not been definitively established. Recently, it was reported that mHTT is present in the intermembrane space and inhibits mitochondrial protein import by interacting with TIM23, a major component of mitochondrial protein import machinery, but evidence for functional ramifications were not provided. We assessed mHTT location using synaptic and nonsynaptic mitochondria isolated from brains of YAC128 mice and subjected to alkali treatment or limited trypsin digestion. Mitochondria were purified either with discontinuous Percoll gradient or with anti-TOM22-conjugated iron microbeads. We also used mitochondria isolated from postmortem brain tissues of unaffected individuals and HD patients. Our results demonstrate that mHTT is located on the cytosolic side of the mitochondrial outer membrane (MOM) but does not cross it. This refutes the hypothesis that mHTT may interact with TIM23 and inhibit mitochondrial protein import. The levels of expression of nuclear-encoded, TIM23-transported mitochondrial proteins ACO2, TUFM, IDH3A, CLPP and mitochondrially encoded and synthesized protein mtCO1 were similar in mitochondria from YAC128 mice and their wild-type littermates as well as in mitochondria from postmortem brain tissues of unaffected individuals and HD patients, supporting the lack of deficit in mitochondrial protein import. Regardless of purification technique, mitochondria from YAC128 and WT mice had similar respiratory activities and mitochondrial membrane potentials. Thus, our data argue against mHTT crossing the MOM and entering into the mitochondrial intermembrane space, making it highly unlikely that mHTT interacts with TIM23 and inhibits protein import in intact mitochondria.
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http://dx.doi.org/10.1093/hmg/ddaa185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566381PMC
October 2020

Management of Post-Traumatic Maxillofacial Pseudoaneurysms: Review of the Literature and Suggested Algorithm.

J Oral Maxillofac Surg 2020 Nov 15;78(11):2008.e1-2008.e9. Epub 2020 Jul 15.

Associate Professor, Oral and Maxillofacial Surgery and Pediatrics, Emory University, School of Medicine, Chief of Oral and Maxillofacial Surgery, Children's Healthcare of Atlanta, Atlanta, GA.

A pseudoaneurysm (PA) is a collection of blood caused by an incomplete tear in the vessel wall. PA can be arterial or venous in origin. In the maxillofacial region, arterial PA can result from surgical interventions. Venous PAs in the maxillofacial region have never been described. A standardized protocol for management of post-traumatic PAs in the maxillofacial region would help clinicians make treatment decisions. On the basis of the available literature and our institutional experience, we present an algorithm for management of post-traumatic maxillofacial PAs. We also present patients from our institution who illustrate some of the management options in the algorithm.
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http://dx.doi.org/10.1016/j.joms.2020.07.007DOI Listing
November 2020

Epigenetic mechanisms activated by childhood adversity.

Epigenomics 2020 07 24;12(14):1239-1255. Epub 2020 Jul 24.

CUIDA - Centro de Investigación del Abuso y la Adversidad Temprana, Pontificia Universidad Católica de Chile, Avenida Libertador Bernardo O'Higgins 340, Santiago, Chile.

Adverse childhood experiences (ACE) impair health and life expectancy and may result in an epigenetic signature that drives increased morbidity primed during early stages of life. This literature review focuses on the current evidence for epigenetic-mediated programming of brain and immune function resulting from ACE. To address this aim, a total of 88 articles indexed in PubMed before August 2019 concerning ACE and epigenetics were surveyed. Current evidence partially supports epigenetic programming of the hypothalamic-pituitary-adrenal axis, but convincingly shows that ACE impairs immune function. Additionally, the needs and challenges that face this area are discussed in order to provide a framework that may help to clarify the role of epigenetics in the long-lasting effects of ACE.
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http://dx.doi.org/10.2217/epi-2020-0042DOI Listing
July 2020

Surgical, Economic, and Psychological Impacts of SARS-COV-2 on a Kansas Community Hospital System.

Authors:
James J Hamilton

Am Surg 2020 Jun;86(6):599-601

Department of Surgery, University of Kansas School of Medicine, Kansas City, KS, USA.

The chief of surgery of a 264-bed acute care facility and clinic system in Topeka, KS, USA, gives a chronology that illustrates the rapid and profound clinical, economic, and emotional impact of the SARS-CoV-2 outbreak on his hospital and community. In his view, the pandemic has laid bare the weaknesses of several factors basic to the modern US health care system and the resulting economic crisis: just-in-time supply chain technology; foreign sourcing of masks, gowns, and critical equipment, all at critical shortages during the crisis; rural hospital closings; lack of excess capacity through maximization of utilization for efficiency; and an overreliance on high revenue elective procedures and tests. His team was tested by an emergency operation for bowel obstruction that put all the isolation protocols into action. Despite their readiness and the success of the operation and the potential for telemedicine as an alternative to in-person evaluations and outpatient visits, the forced cancellation of all elective operations have led to the loss of revenue for both hospital system and providers, furlough and termination of workers, and financial hardship and uncertainty.
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http://dx.doi.org/10.1177/0003134820924394DOI Listing
June 2020

The brains of aged mice are characterized by altered tissue diffusion properties and cerebral microbleeds.

J Transl Med 2020 07 8;18(1):277. Epub 2020 Jul 8.

Department of Physiology & Biophysics, Boston University School of Medicine, Boston, MA, USA.

Background: Brain aging is a major risk factor in the progression of cognitive diseases including Alzheimer's disease (AD) and vascular dementia. We investigated a mouse model of brain aging up to 24 months old (mo).

Methods: A high field (11.7T) MRI protocol was developed to characterize specific features of brain aging including the presence of cerebral microbleeds (CMBs), morphology of grey and white matter, and tissue diffusion properties. Mice were selected from age categories of either young (3 mo), middle-aged (18 mo), or old (24 mo) and fed normal chow over the duration of the study. Mice were imaged in vivo with multimodal MRI, including conventional T2-weighted (T2W) and T2*-weighted (T2*W) imaging, followed by ex vivo diffusion-weighted imaging (DWI) and T2*W MR-microscopy to enhance the detection of microstructural features.

Results: Structural changes observed in the mouse brain with aging included reduced cortical grey matter volume and enlargement of the brain ventricles. A remarkable age-related change in the brains was the development of CMBs found starting at 18 mo and increasing in total volume at 24 mo, primarily in the thalamus. CMBs presence was confirmed with high resolution ex vivo MRI and histology. DWI detected further brain tissue changes in the aged mice including reduced fractional anisotropy, increased radial diffusion, increased mean diffusion, and changes in the white matter fibers visualized by color-coded tractography, including around a large cortical CMB.

Conclusions: The mouse is a valuable model of age-related vascular contributions to cognitive impairment and dementia (VCID). In composite, these methods and results reveal brain aging in older mice as a multifactorial process including CMBs and tissue diffusion alterations that can be well characterized by high field MRI.
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http://dx.doi.org/10.1186/s12967-020-02441-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346388PMC
July 2020

Effect of phyB and phyC loss-of-function mutations on the wheat transcriptome under short and long day photoperiods.

BMC Plant Biol 2020 Jun 29;20(1):297. Epub 2020 Jun 29.

Department of Soil and Crop Sciences, Colorado State University, Fort Collins, CO, 80523, USA.

Background: Photoperiod signals provide important cues by which plants regulate their growth and development in response to predictable seasonal changes. Phytochromes, a family of red and far-red light receptors, play critical roles in regulating flowering time in response to changing photoperiods. A previous study showed that loss-of-function mutations in either PHYB or PHYC result in large delays in heading time and in the differential regulation of a large number of genes in wheat plants grown in an inductive long day (LD) photoperiod.

Results: We found that under non-inductive short-day (SD) photoperiods, phyB-null and phyC-null mutants were taller, had a reduced number of tillers, longer and wider leaves, and headed later than wild-type (WT) plants. The delay in heading between WT and phy mutants was greater in LD than in SD, confirming the importance of PHYB and PHYC in accelerating heading date in LDs. Both mutants flowered earlier in SD than LD, the inverse response to that of WT plants. In both SD and LD photoperiods, PHYB regulated more genes than PHYC. We identified subsets of differentially expressed and alternatively spliced genes that were specifically regulated by PHYB and PHYC in either SD or LD photoperiods, and a smaller set of genes that were regulated in both photoperiods. We found that photoperiod had a contrasting effect on transcript levels of the flowering promoting genes VRN-A1 and PPD-B1 in phyB and phyC mutants compared to the WT.

Conclusions: Our study confirms the major role of both PHYB and PHYC in flowering promotion in LD conditions. Transcriptome characterization revealed an unexpected reversion of the wheat LD plants into SD plants in the phyB-null and phyC-null mutants and identified flowering genes showing significant interactions between phytochromes and photoperiod that may be involved in this phenomenon. Our RNA-seq data provides insight into light signaling pathways in inductive and non-inductive photoperiods and a set of candidate genes to dissect the underlying developmental regulatory networks in wheat.
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http://dx.doi.org/10.1186/s12870-020-02506-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325275PMC
June 2020

Narrowband Imaging for p16+ Unknown Primary Squamous Cell Carcinoma Prior to Transoral Robotic Surgery.

Otolaryngol Head Neck Surg 2020 12 23;163(6):1198-1201. Epub 2020 Jun 23.

Department of Otolaryngology-Head and Neck Surgery, Emory University, Atlanta, Georgia, USA.

Our purpose was to assess the potential utility of narrowband imaging (NBI) as a tool in diagnosing and treating unknown primary oropharyngeal squamous cell carcinoma (OPSCC) in patients prior to diagnostic resection with transoral robotic surgery (TORS). Between 2016 and March 2019, 29 patients with carcinoma of unknown primary meeting inclusion criteria were identified and treated with TORS. NBI was used preoperatively in 9 of 29 patients. A suspected tumor site was delineated by NBI in 8 of 9 patients (89%). Of the patients imaged with NBI, 8 of 9 (89%) patients had a pathologically confirmed tumor following TORS, corresponding to the same 8 suspected tumor sites identified with NBI. In contrast, a primary tumor was localized following TORS in 15 of 20 (75%) patients not evaluated with NBI. Thus, we see NBI as a potentially useful tool for the diagnosis and management of p16+ carcinoma of unknown primary.: IIb.
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http://dx.doi.org/10.1177/0194599820933204DOI Listing
December 2020

Development of an RNAi therapeutic for alpha-1-antitrypsin liver disease.

JCI Insight 2020 06 18;5(12). Epub 2020 Jun 18.

Departments of Pediatrics and Biochemistry, St. Louis University School of Medicine, Cardinal Glennon Children's Hospital, St. Louis, Missouri, USA.

The autosomal codominant genetic disorder alpha-1 antitrypsin (AAT) deficiency (AATD) causes pulmonary and liver disease. Individuals homozygous for the mutant Z allele accumulate polymers of Z-AAT protein in hepatocytes, where AAT is primarily produced. This accumulation causes endoplasmic reticulum (ER) stress, oxidative stress, damage to mitochondria, and inflammation, leading to fibrosis, cirrhosis, and hepatocellular carcinoma. The magnitude of AAT reduction and duration of response from first-generation intravenously administered RNA interference (RNAi) therapeutic ARC-AAT and then with next-generation subcutaneously administered ARO-AAT were assessed by measuring AAT protein in serum of the PiZ transgenic mouse model and human volunteers. The impact of Z-AAT reduction by RNAi on liver disease phenotypes was evaluated in PiZ mice by measuring polymeric Z-AAT in the liver; expression of genes associated with fibrosis, autophagy, apoptosis, and redox regulation; inflammation; Z-AAT globule parameters; and tumor formation. Ultrastructure of the ER, mitochondria, and autophagosomes in hepatocytes was evaluated by electron microscopy. In mice, sustained RNAi treatment reduced hepatic Z-AAT polymer, restored ER and mitochondrial health, normalized expression of disease-associated genes, reduced inflammation, and prevented tumor formation. RNAi therapy holds promise for the treatment of patients with AATD-associated liver disease. ARO-AAT is currently in phase II/III clinical trials.
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http://dx.doi.org/10.1172/jci.insight.135348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406265PMC
June 2020

Characterization of copulatory courtship song in the Old World sand fly species Phlebotomus argentipes.

Sci Rep 2020 03 20;10(1):5116. Epub 2020 Mar 20.

Universidade Federal do Rio de Janeiro, Instituto de Biologia. Avenida Carlos Chagas Filho, 373, Block A/A2-075.Cidade Universitária/CCS - Centro de Ciências da Saúde, 21941902, Rio de Janeiro, Brazil.

Acoustic communication in the form of courtship and mating songs are often involved in reproductive isolation between species of Diptera, such as Drosophila, mosquitoes and sand flies. The patterns of courtship songs in New World sand fly species evolve quickly under sexual selection; and therefore, represent an important trait that can be used as a marker to study the evolution of species complexes and may aid identification of sibling species with a complex. The ability to identify vector species within species complexes is of critical importance for effective and efficient vector control programs. Species-specific song patterns seems to contribute to reproductive isolation in New World sand fly species, suggesting that auditory communication signals may be widespread among these important vectors of leishmaniasis. The main goal of the present study was to characterize the copulatory courtship song of Phlebotomus argentipes, an important vector of visceral leishmaniasis in the Old World. Ph. argentipes males produce acoustic signals during copulation and two types of songs were observed. The one we called primary song is a 'pulse song' with similar length and amplitude to the previously observed 'P1' pattern recorded in Brazilian populations of Lu. longipalpis s.l. The secondary song has 'sine song' characteristics and is quite different from any song produced by New World species. The discovery of this copulation courtship songs in Ph. argentipes supports the possibility that acoustic communication in sandflies might be more widespread than previously thought, including Old World species. Our results highlight the importance of further research on acoustic communication in the Ph. argentipes species complex and other Old World vectors of leishmaniasis.
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http://dx.doi.org/10.1038/s41598-020-61867-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083918PMC
March 2020

SSO and other putative inhibitors of FA transport across membranes by CD36 disrupt intracellular metabolism, but do not affect FA translocation.

J Lipid Res 2020 05 26;61(5):790-807. Epub 2020 Feb 26.

Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118

Membrane-bound proteins have been proposed to mediate the transport of long-chain FA (LCFA) transport through the plasma membrane (PM). These proposals are based largely on reports that PM transport of LCFAs can be blocked by a number of enzymes and purported inhibitors of LCFA transport. Here, using the ratiometric pH indicator (2',7'-bis-(2-carboxyethyl)-5-(and-6-)-carboxyfluorescein and acrylodated intestinal FA-binding protein-based dual fluorescence assays, we investigated the effects of nine inhibitors of the putative FA transporter protein CD36 on the binding and transmembrane movement of LCFAs. We particularly focused on sulfosuccinimidyl oleate (SSO), reported to be a competitive inhibitor of CD36-mediated LCFA transport. Using these assays in adipocytes and inhibitor-treated protein-free lipid vesicles, we demonstrate that rapid LCFA transport across model and biological membranes remains unchanged in the presence of these purported inhibitors. We have previously shown in live cells that CD36 does not accelerate the transport of unesterified LCFAs across the PM. Our present experiments indicated disruption of LCFA metabolism inside the cell within minutes upon treatment with many of the "inhibitors" previously assumed to inhibit LCFA transport across the PM. Furthermore, using confocal microscopy and a specific anti-SSO antibody, we found that numerous intracellular and PM-bound proteins are SSO-modified in addition to CD36. Our results support the hypothesis that LCFAs diffuse rapidly across biological membranes and do not require an active protein transporter for their transmembrane movement.
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http://dx.doi.org/10.1194/jlr.RA120000648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193964PMC
May 2020

Role of angiopoietin-like protein 3 in sugar-induced dyslipidemia in rhesus macaques: suppression by fish oil or RNAi.

J Lipid Res 2020 03 9;61(3):376-386. Epub 2020 Jan 9.

Department of Molecular Biosciences, University of California, Davis, Davis, CA

Angiopoietin-like protein 3 (ANGPTL3) inhibits lipid clearance and is a promising target for managing cardiovascular disease. Here we investigated the effects of a high-sugar (high-fructose) diet on circulating ANGPTL3 concentrations in rhesus macaques. Plasma ANGPTL3 concentrations increased ∼30% to 40% after 1 and 3 months of a high-fructose diet (both < 0.001 vs. baseline). During fructose-induced metabolic dysregulation, plasma ANGPTL3 concentrations were positively correlated with circulating indices of insulin resistance [assessed with fasting insulin and the homeostatic model assessment of insulin resistance (HOMA-IR)], hypertriglyceridemia, adiposity (assessed as leptin), and systemic inflammation [C-reactive peptide (CRP)] and negatively correlated with plasma levels of the insulin-sensitizing hormone adropin. Multiple regression analyses identified a strong association between circulating APOC3 and ANGPTL3 concentrations. Higher baseline plasma levels of both ANGPTL3 and APOC3 were associated with an increased risk for fructose-induced insulin resistance. Fish oil previously shown to prevent insulin resistance and hypertriglyceridemia in this model prevented increases of ANGPTL3 without affecting systemic inflammation (increased plasma CRP and interleukin-6 concentrations). RNAi lowered plasma concentrations of ANGPTL3, triglycerides (TGs), VLDL-C, APOC3, and APOE. These decreases were consistent with a reduced risk of atherosclerosis. In summary, dietary sugar-induced increases of circulating ANGPTL3 concentrations after metabolic dysregulation correlated positively with leptin levels, HOMA-IR, and dyslipidemia. Targeting ANGPTL3 expression with RNAi inhibited dyslipidemia by lowering plasma TGs, VLDL-C, APOC3, and APOE levels in rhesus macaques.
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http://dx.doi.org/10.1194/jlr.RA119000423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053838PMC
March 2020

RNA Interference Therapy With ARC-520 Results in Prolonged Hepatitis B Surface Antigen Response in Patients With Chronic Hepatitis B Infection.

Hepatology 2020 07 23;72(1):19-31. Epub 2020 Apr 23.

Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Stanford, CA.

Background And Aims: ARC-520, the first an RNA interference (RNAi) therapeutic, was designed to reduce all RNA transcripts derived from covalently closed circular DNA, leading to a reduction in viral antigens and hepatitis B virus (HBV) DNA.

Approach And Results: We aimed to evaluate the depth of hepatitis B surface antigen (HBsAg) decline in response to multiple doses of ARC-520 compared to placebo (PBO) in two randomized, multicenter studies in nucleoside/nucleotide analogue reverse-transcriptase inhibitor (NUC)-experienced patients with hepatitis B early antigen (HBeAg)-negative (E-neg) or HBeAg-positive (E-pos) disease. A total of 58 E-neg and 32 E-pos patients were enrolled and received four monthly doses of PBO (n = 20 E-neg, 11 E-pos), 1 mg/kg ARC-520 (n = 17 E-neg, 10 E-pos), or 2 mg/kg ARC-520 (n = 21 E-neg, 11 E-pos) concomitantly with NUC. HBsAg change from baseline to 30 days after the last ARC-520 dose were compared to PBO. Both E-neg and E-pos high-dose groups significantly reduced HBsAg compared to PBO, with mean reductions of 0.38 and 0.54 log IU/mL, respectively. HBsAg reductions persisted for approximately 85 days and >85 days after the last dose in E-neg and E-pos patients, respectively. The low-dose groups did not reach statistical significance in either study. E-pos patients showed a dose-dependent reduction in HBeAg from baseline. Mean maximum reduction was 0.23 and 0.69 log Paul Ehrlich IUs/mL in the low-dose and high dose ARC-520 groups respectively. ARC-520 was well tolerated, with only two serious adverse events of pyrexia possibly related to study drug observed.

Conclusions: ARC-520 was active in both E-neg and E-pos, NUC-experienced HBV patients; but absolute HBsAg reductions were moderate, possibly due to expression of HBsAg from integrated HBV DNA, indicating the need for RNAi therapeutics that can target viral transcripts regardless of origin.
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http://dx.doi.org/10.1002/hep.31008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496196PMC
July 2020

Sand fly synthetic sex-aggregation pheromone co-located with insecticide reduces the incidence of infection in the canine reservoir of visceral leishmaniasis: A stratified cluster randomised trial.

PLoS Negl Trop Dis 2019 10 25;13(10):e0007767. Epub 2019 Oct 25.

Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Bailrigg, Lancaster, Lancashire, United Kingdom.

Objective: To evaluate the efficacy of a synthetic sex-aggregation pheromone of the sand fly vector Lu. longipalpis, co-located with residual insecticide, to reduce the infection incidence of Leishmania infantum in the canine reservoir.

Methods: A stratified cluster randomised trial was designed to detect a 50% reduction in canine incident infection after 24 months in 42 recruited clusters, randomly assigned to one of three intervention arms (14 cluster each): synthetic pheromone + insecticide, insecticide-impregnated dog collars, or placebo control. Infection incidence was measured by seroconversion to anti-Leishmania serum antibody, Leishmania parasite detection and canine tissue parasite loads. Changes in relative Lu. longipalpis abundance within households were measured by setting three CDC light traps per household.

Results: A total 1,454 seronegative dogs were followed-up for a median 15.2 (95% C.I.s: 14.6, 16.2) months per cluster. The pheromone + insecticide intervention provided 13% (95% C.I. 0%, 44.0%) protection against anti-Leishmania antibody seroconversion, 52% (95% C.I. 6.2%, 74·9%) against parasite infection, reduced tissue parasite loads by 53% (95% C.I. 5.4%, 76.7%), and reduced household female sand fly abundance by 49% (95% C.I. 8.2%, 71.3%). Variation in the efficacy against seroconversion varied between trial strata. Equivalent protection attributed to the impregnated-collars were 36% (95% C.I. 14.4%, 51.8%), 23% (95% C.I. 0%, 57·5%), 48% (95% C.I. 0%, 73.4%) and 43% (95% C.I. 0%, 67.9%), respectively. Comparison of the two interventions showed no statistically consistent differences in their efficacies; however, the errors were broad for all outcomes. Reductions in sand fly numbers were predominant where insecticide was located (chicken and dog sleeping sites), with no evidence of insecticide-induced repellence onto humans or dogs.

Conclusion: The synthetic pheromone co-located with insecticide provides protection particularly against canine L. infantum parasite transmission and sand fly vector abundance. The effect estimates are not dissimilar to those of the insecticide-impregnated collars, which are documented to reduce canine infection incidence, human infection and clinical VL disease incidence, in different global regions. The trialled novel lure-and-kill approach is a low-cost potential vector control tool against ZVL in the Americas.
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http://dx.doi.org/10.1371/journal.pntd.0007767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834291PMC
October 2019