Publications by authors named "Natalie Jones"

93 Publications

The correlation between social support and post-traumatic stress disorder in children and adolescents: A meta-analysis.

J Affect Disord 2021 Nov 16;294:543-557. Epub 2021 Jul 16.

Department of Clinical Psychology and Psychological Therapies, Norwich Medical School, University of East Anglia, UK.

Background: Risk factors exploring the link between trauma and Post-traumatic stress disorder (PTSD) have been extensively explored in adults, however, less is known about child and adolescent populations.

Methods: The current meta-analysis aimed to systematically evaluate and summarise the child focused literature to estimate the strength of the relationship between social support and PTSD symptoms following traumatic events.

Results: Fifty primary studies reporting an effect size for the relationship between total social support scale or a source of social support with PTSD were included. A small effect size was found for the relationship between social support and PTSD (r = -0.12, 95% CI -0.16 to -0.07, k = 41), with large heterogeneity (I = 90.3%). The effect sizes between peer support (r = -0.18, 95% CI -0.10 to -0.25, k = 12), family support (r = -0.16, 95% CI -0.09 to -0.24, k = 13) and teacher support (r = -0.20, 95% CI -0.15 to -0.24, k = 5) and PTSD were also small. Moderator analyses indicated that studies reporting on participants exposed to abuse (r = -0.25) and correlations based on univariate data (r = -0.14) had higher correlations and medium heterogeneity. The main effect size was robust to publication bias and study quality.

Limitations: The cross-sectional design of the studies limits the findings and future research using prospective and longitudinal design would help to explain the relationship between social support and PTSD further.

Conclusions: The current review suggests that social support may only play a small role in protecting against PTSD and future research may benefit from exploring the link between post-trauma cognitions and social support.
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http://dx.doi.org/10.1016/j.jad.2021.07.028DOI Listing
November 2021

Physical Activity Barriers and Assets in Rural Appalachian Kentucky: A Mixed-Methods Study.

Int J Environ Res Public Health 2021 07 19;18(14). Epub 2021 Jul 19.

Department of Health, Behavior & Society, College of Public Health, University of Kentucky, Lexington, KY 40504, USA.

Obesity is an increasing public health concern in the U.S. and a contributor to chronic illness, with trends revealing a rise in adult obesity and chronic disease rates among the most vulnerable and disadvantaged populations, including those in rural communities. A mixed-methods approach was used to examine perspectives on perceived physical activity barriers, resources, and level of community support. Researchers utilized the socioecological model to examine the multiple domains that support physical activity in rural Appalachia. The present study focuses on baseline data, including a cohort survey to assess physical activity, health status, and barriers to physical activity, and five focus groups with elected community leaders, community residents, members, and key stakeholders to assess perspectives on physical activity barriers and resources within the county. The cohort survey sample ( = 152) reported a median of 6 barriers (range 0-13) to participating in at least 30 min of physical activity daily. The qualitative analysis yielded three overarching themes related to physical activity participation: lack of motivation, physical environment, and cultural barriers. This mixed-methods study revealed the challenges and perceptions among rural residents across the socioecological model when assessing physical inactivity. Findings can be used to tailor future interventions focused on expanding social support, designing infrastructure, and creating policies that promote physical activity.
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http://dx.doi.org/10.3390/ijerph18147646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303275PMC
July 2021

Maternal effects and the outcome of interspecific competition.

Ecol Evol 2021 Jun 2;11(12):7544-7556. Epub 2021 May 2.

Zoology & Biodiversity Research Centre The University of British Columbia Vancouver BC Canada.

Maternal environmental effects create lagged population responses to past environments. Although they are ubiquitous and vary in expression across taxa, it remains unclear if and how their presence alters competitive interactions in ecological communities.Here, we use a discrete-time competition model to simulate how maternal effects alter competitive dynamics in fluctuating and constant environments. Further, we explore how omitting maternal effects alter estimates of known model parameters from observational time series data.Our simulations demonstrate that (i) maternal effects change competitive outcomes, regardless of whether competitors otherwise interact neutrally or exhibit non-neutral competitive differences, (ii) the consequences of maternal effects for competitive outcomes are mediated by the temporal structure of environmental variation, (iii) even in constant conditions, competitive outcomes are influenced by species' maternal effects strategies, and (iv) in observational time series data, omitting maternal effects reduces variation explained by models and biases parameter estimates, including competition coefficients.Our findings demonstrate that the ecological consequences of maternal effects hinge on the competitive environment. Evolutionary biologists have long recognized that maternal effects can be an important but often overlooked strategy buffering populations from environmental change. We suggest that maternal effects are similarly critical to ecology and call for research into maternal effects as drivers of dynamics in populations and communities.
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http://dx.doi.org/10.1002/ece3.7586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216948PMC
June 2021

A chemical genetics approach to examine the functions of AAA proteins.

Nat Struct Mol Biol 2021 04 29;28(4):388-397. Epub 2021 Mar 29.

Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY, USA.

The structural conservation across the AAA (ATPases associated with diverse cellular activities) protein family makes designing selective chemical inhibitors challenging. Here, we identify a triazolopyridine-based fragment that binds the AAA domain of human katanin, a microtubule-severing protein. We have developed a model for compound binding and designed ASPIR-1 (allele-specific, proximity-induced reactivity-based inhibitor-1), a cell-permeable compound that selectively inhibits katanin with an engineered cysteine mutation. Only in cells expressing mutant katanin does ASPIR-1 treatment increase the accumulation of CAMSAP2 at microtubule minus ends, confirming specific on-target cellular activity. Importantly, ASPIR-1 also selectively inhibits engineered cysteine mutants of human VPS4B and FIGL1-AAA proteins, involved in organelle dynamics and genome stability, respectively. Structural studies confirm our model for compound binding at the AAA ATPase site and the proximity-induced reactivity-based inhibition. Together, our findings suggest a chemical genetics approach to decipher AAA protein functions across essential cellular processes and to test hypotheses for developing therapeutics.
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http://dx.doi.org/10.1038/s41594-021-00575-9DOI Listing
April 2021

Males and females differ in the regulation and engagement of, but not requirement for, protein degradation in the amygdala during fear memory formation.

Neurobiol Learn Mem 2021 04 18;180:107404. Epub 2021 Feb 18.

School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; Department of Animal and Poultry Science, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; Fralin Biomedical Research Institute, Translational Biology, Medicine and Health, Virginia Polytechnic Institute and State University, Roanoke, VA, USA. Electronic address:

Over the last decade, strong evidence has emerged that protein degradation mediated by the ubiquitin-proteasome system is critical for fear memory formation in the amygdala. However, this work has been done primarily in males, leaving unanswered questions about whether females also require protein degradation during fear memory formation. Here, we found that male and female rats differed in their engagement and regulation of, but not need for, protein degradation in the amygdala during fear memory formation. Male, but not female, rats had increased protein degradation in the nuclei of amygdala cells after fear conditioning. Conversely, females had elevated baseline levels of overall ubiquitin-proteasome activity in amygdala nuclei. Gene expression and DNA methylation analyses identified that females had increased baseline expression of the ubiquitin coding gene Uba52, which had increased DNA 5-hydroxymethylation (5hmc) in its promoter region, indicating a euchromatin state necessary for increased levels of ubiquitin in females. Consistent with this, persistent CRISPR-dCas9 mediated silencing of Uba52 and proteasome subunit Psmd14 in the amygdala reduced baseline protein degradation levels and impaired fear memory in male and female rats, while enhancing baseline protein degradation in the amygdala of both sexes promoted fear memory formation. These results suggest that while both males and females require protein degradation in the amygdala for fear memory formation, they differ in their baseline regulation and engagement of this process following learning. These results have important implications for understanding the etiology of sex-related differences in fear memory formation.
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http://dx.doi.org/10.1016/j.nlm.2021.107404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076082PMC
April 2021

"We're, Like, the Most Unhealthy People in the Country": Using an Equity Lens to Reduce Barriers to Healthy Food Access in Rural Appalachia.

Prev Chronic Dis 2020 12 24;17:E165. Epub 2020 Dec 24.

Department of Dietetics and Human Nutrition, University of Kentucky, Lexington, Kentucky.

Introduction: Obesity disproportionately affects rural communities, and Appalachia has some of the highest obesity rates in the nation. Successful policy, systems, and environmental (PSE) interventions to reduce obesity must reflect the circumstances of the population. We used a health equity lens to identify barriers and facilitators for healthy food access in Martin County, Kentucky, to design interventions responsive to social, cultural, and historical contexts.

Methods: We conducted 5 focus groups in Martin County, Kentucky, in fall 2019 to obtain perspectives on the local food system and gauge acceptability of PSE interventions. We used grounded theory to identify perceived barriers and facilitators for healthy eating.

Results: Thirty-four adults (27 women; median age, 46 years) participated in 5 groups. One prominent theme was declining interest in farming; many participants believed this decline was generational. One participant noted, "Most of my adult male relatives worked in the coal mines, and they worked 6 days a week. . . . My grandpa had the garden, but then my dad's generation is the one quit gardening." Another shared, "You would probably have to have someone to teach [gardening]." Instead of enhancing farmers markets, participants suggested building community capacity for home gardens to increase vegetable consumption.

Conclusion: Our findings demonstrate the importance of obtaining community input on the development of PSE interventions to mitigate inequities in obesity. Although farmers market interventions were deemed not feasible, other solutions to enhance access to produce were identified. Developers of community-responsive PSE interventions to improve healthy eating in rural, food-insecure locations should consider using an equity-oriented prevention framework to ensure acceptable interventions.
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http://dx.doi.org/10.5888/pcd17.200340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784552PMC
December 2020

The role of titles in enhancing data visualization.

Eval Program Plann 2021 02 28;84:101896. Epub 2020 Nov 28.

Department of Psychology, University of Wisconsin-Stout, 721 3rd St E, Harvey Hall 473, Menomonie, WI, 54751, United States.

Many in the data visualization and evaluation communities recommend conveying the message or takeaway of the visualization in the visualization's title. This study tested that recommendation by examining how informative or generic titles impact a visualization's visual efficiency, aesthetics, credibility, and the perceived effectiveness of the hypothetical program examined. Furthermore, this study tested how simple or complex graphs, and positive, negative, or mixed results (i.e., valence of the results) affected outcomes. Participants were randomly assigned to one of 12 conditions, representing a 2 (graph: simple or complex) x 2 (title: generic or informative) x 3 (valence: positive, negative, mixed) between-subjects study. The results indicated that informative titles required less mental effort and were viewed as more aesthetically pleasing, but otherwise did not lead to greater accuracy, credibility, or perceived effectiveness. Furthermore, titles did not interact with graph type or the valence of the findings. While the results suggest it is worthwhile to consider adding an informative title to data visualizations as they can reduce mental effort for the viewer, the intended goal of the visualization should be taken into consideration. Considering the goal of the visualization can be a deciding factor of the type of graph and title that will best serve its intended purposes. Overall, this suggests that data visualization recommendations that impact evaluation reporting practices should be scrutinized more closely through research.
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http://dx.doi.org/10.1016/j.evalprogplan.2020.101896DOI Listing
February 2021

Experimental evidence of warming-induced disease emergence and its prediction by a trait-based mechanistic model.

Proc Biol Sci 2020 10 14;287(1936):20201526. Epub 2020 Oct 14.

Department of Ecology and Evolutionary Biology, University of Toronto, Toronto, Canada.

Predicting the effects of seasonality and climate change on the emergence and spread of infectious disease remains difficult, in part because of poorly understood connections between warming and the mechanisms driving disease. Trait-based mechanistic models combined with thermal performance curves arising from the metabolic theory of ecology (MTE) have been highlighted as a promising approach going forward; however, this framework has not been tested under controlled experimental conditions that isolate the role of gradual temporal warming on disease dynamics and emergence. Here, we provide experimental evidence that a slowly warming host-parasite system can be pushed through a critical transition into an epidemic state. We then show that a trait-based mechanistic model with MTE functional forms can predict the critical temperature for disease emergence, subsequent disease dynamics through time and final infection prevalence in an experimentally warmed system of and a microsporidian parasite. Our results serve as a proof of principle that trait-based mechanistic models using MTE subfunctions can predict warming-induced disease emergence in data-rich systems-a critical step towards generalizing the approach to other systems.
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http://dx.doi.org/10.1098/rspb.2020.1526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657857PMC
October 2020

Gingival Biopsy to Detect Mosaicism in Overgrowth Syndromes: Report of Two Cases of Megalencephaly-Capillary Malformation Syndrome with Periodontal Anomalies.

Case Rep Dent 2020 12;2020:8826945. Epub 2020 Sep 12.

Paul Sabatier Toulouse III University, Department of Paediatric Dentistry, CHU Toulouse, F-31000, France.

Background: Megalencephaly-capillary malformation (MCAP) is a rare overgrowth syndrome caused by postzygotic activating mutations in the gene.

Aim: To illustrate the benefits of gingival biopsy in the genetic diagnosis of overgrowth syndromes.

Design: Gingival biopsy was performed on a 13-year-old patient and a 16-year-old patient with MCAP and who suffered from periodontal disease. sequencing was performed on DNA extracted from gingival biopsies, blood, and saliva.

Results: Pathogenic p.Glu365Lys and p.Glu545Asp mutations were found in the gingival biopsies with an allelic frequency of 22% and 35%, respectively, while they were undetectable in blood or saliva. The genetic diagnosis of MCAP through detection of somatic mosaicism in a periodontal biopsy is unprecedented.

Conclusions: Considering the tissue distribution and level of somatic mosaicism for mutation, the composite embryologic origin of periodontium and its high fibroblast cell content make it an ideal target for molecular analysis in overgrowth syndromes, and multidisciplinary approach including paediatric dentists should be encouraged. In addition, our clinical findings suggest that periodontal disease is part of the MCAP phenotypic spectrum and should be systematically investigated.
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http://dx.doi.org/10.1155/2020/8826945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509567PMC
September 2020

Longitudinal study of the housing and mental health outcomes of tenants appearing in eviction court.

Soc Psychiatry Psychiatr Epidemiol 2021 Sep 14;56(9):1679-1686. Epub 2020 Sep 14.

National Center on Homelessness Among Veterans, U.S. Department of Veterans Affairs Central Office, Tampa, FL, USA.

Purpose: Millions of people are evicted from rental properties in the U.S. annually, but little is known about them and their mental health. This study followed a cohort of eviction court participants over time and assessed their housing and mental health outcomes.

Methods: One hundred and twenty-one tenants were recruited from an eviction court in New Haven, Connecticut, and their housing, mental health, and psychosocial status were assessed at baseline, 1, 3, 6, and 9 months following their encounter with the court. Inverse probability weighting was used for missing data.

Results: At baseline, 42% of participants had appeared in eviction court before, 28% had experienced eviction, and 44% had been previously homeless. In addition, 39% screened positive for generalized anxiety disorder, 37% for posttraumatic stress disorder, 33% for major depressive disorder, and 17% reported suicidal ideation. At follow-up, participants experienced increased days of housing instability and homelessness over time with some persistent mental health symptoms. Less than one-quarter of participants received any mental health treatment during the 9-month follow-up period. About 54% of participants followed reported that they had to change their residence after their court appearance consistent with court records. Participants who had an eviction-related move experienced greater housing instability over time than participants who did not.

Conclusion: Together, these findings suggest that there is a sizable subgroup of adults who present to eviction court with persistent housing and mental health issues who do not receive adequate assistance in addressing these issues.
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http://dx.doi.org/10.1007/s00127-020-01953-2DOI Listing
September 2021

Optimization of a series of potent, selective and orally bioavailable SYK inhibitors.

Bioorg Med Chem Lett 2020 10 24;30(19):127433. Epub 2020 Jul 24.

Oncology R&D, AstraZeneca, Waltham, USA.

Spleen tyrosine kinase (SYK) is a non-receptor cytosolic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signaling, inhibition of SYK has been targeted in a variety of disease areas. Herein, we report the optimization of a series of potent and selective SYK inhibitors, focusing on improving metabolic stability, pharmacokinetics and hERG inhibition. As a result, we identified 30, which exhibited no hERG activity but unfortunately was poorly absorbed in rats and mice. We also identified a SYK chemical probe, 17, which exhibits excellent potency at SYK, and an adequate rodent PK profile to support in vivo efficacy/PD studies.
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http://dx.doi.org/10.1016/j.bmcl.2020.127433DOI Listing
October 2020

Dysregulation of protein degradation in the hippocampus is associated with impaired spatial memory during the development of obesity.

Behav Brain Res 2020 09 27;393:112787. Epub 2020 Jun 27.

Department of Animal and Poultry Science, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA; School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA. Electronic address:

Studies have shown that long-term exposure to high fat and other obesogenic diets results in insulin resistance and altered blood brain barrier permeability, dysregulation of intracellular signaling mechanisms, changes in DNA methylation levels and gene expression, and increased oxidative stress and neuroinflammation in the hippocampus, all of which are associated with impaired spatial memory. The ubiquitin-proteasome system controls the majority of protein degradation in cells and is a critical regulator of synaptic plasticity and memory formation. Yet, whether protein degradation in the hippocampus becomes dysregulated following weight gain and is associated with obesity-induced memory impairments is unknown. Here, we used a high fat diet procedure in combination with behavioral and subcellular fractionation protocols and a variety of biochemical assays to determine if ubiquitin-proteasome activity becomes altered in the hippocampus during obesity development and whether this is associated with impaired spatial memory. We found that only 6 weeks of exposure to a high fat diet was sufficient to impair performance on an object location task in rats and resulted in dynamic dysregulation of ubiquitin-proteasome activity in the nucleus and cytoplasm of cells in the hippocampus. Furthermore, these changes in the protein degradation process extended into cortical regions also involved in spatial memory formation. Collectively, these results indicate that weight gain-induced memory impairments may be due to altered ubiquitin-proteasome signaling that occurs during the early stages of obesity development.
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http://dx.doi.org/10.1016/j.bbr.2020.112787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423702PMC
September 2020

Predators drive community reorganization during experimental range shifts.

J Anim Ecol 2020 10 21;89(10):2378-2388. Epub 2020 Jul 21.

Department of Ecology, Behavior and Evolution, The University of California, San Diego, CA, USA.

Increased global temperatures caused by climate change are causing species to shift their ranges and colonize new sites, creating novel assemblages that have historically not interacted. Species interactions play a central role in the response of ecosystems to climate change, but the role of trophic interactions in facilitating or preventing range expansions is largely unknown. The goal of our study was to understand how predators influence the ability of range-shifting prey to successfully establish in newly available habitat following climate warming. We hypothesized that fish predation facilitates the establishment of colonizing zooplankton populations, because fish preferentially consume larger species that would otherwise competitively exclude smaller-bodied colonists. We conducted a mesocosm experiment with zooplankton communities and their fish predators from lakes of the Sierra Nevada Mountains in California, USA. We tested the effect of fish predation on the establishment and persistence of a zooplankton community when introduced in the presence of higher- and lower-elevation communities at two experimental temperatures in field mesocosms. We found that predators reduce the abundance of larger-bodied residents from the alpine and facilitate the establishment of new lower-elevation species. In addition, fish predation and warming independently reduced the average body size of zooplankton by up to 30%. This reduction in body size offset the direct effect of warming-induced increases in population growth rates, leading to no net change in zooplankton biomass or trophic cascade strength. We found support for a shift to smaller species with climate change through two mechanisms: (a) the direct effects of warming on developmental rates and (b) size-selective predation that altered the identity of species' that could colonize new higher elevation habitat. Our results suggest that predators can amplify the rate of range shifts by consuming larger-bodied residents and facilitating the establishment of new species. However, the effects of climate warming were dampened by reducing the average body size of community members, leading to no net change in ecosystem function, despite higher growth rates. This work suggests that trophic interactions play a role in the reorganization of regional communities under climate warming.
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http://dx.doi.org/10.1111/1365-2656.13289DOI Listing
October 2020

Sierra Nevada mountain lake microbial communities are structured by temperature, resources and geographic location.

Mol Ecol 2020 06 24;29(11):2080-2093. Epub 2020 Jun 24.

Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA.

Warming, eutrophication (nutrient fertilization) and brownification (increased loading of allochthonous organic matter) are three global trends impacting lake ecosystems. However, the independent and synergistic effects of resource addition and warming on autotrophic and heterotrophic microorganisms are largely unknown. In this study, we investigate the independent and interactive effects of temperature, dissolved organic carbon (DOC, both allochthonous and autochthonous) and nitrogen (N) supply, in addition to the effect of spatial variables, on the composition, richness, and evenness of prokaryotic and eukaryotic microbial communities in lakes across elevation and N deposition gradients in the Sierra Nevada mountains of California, USA. We found that both prokaryotic and eukaryotic communities are structured by temperature, terrestrial (allochthonous) DOC and latitude. Prokaryotic communities are also influenced by total and aquatic (autochthonous) DOC, while eukaryotic communities are also structured by nitrate. Additionally, increasing N availability was associated with reduced richness of prokaryotic communities, and both lower richness and evenness of eukaryotes. We did not detect any synergistic or antagonistic effects as there were no interactions among temperature and resource variables. Together, our results suggest that (a) organic and inorganic resources, temperature, and geographic location (based on latitude and longitude) independently influence lake microbial communities; and (b) increasing N supply due to atmospheric N deposition may reduce richness of both prokaryotic and eukaryotic microbes, probably by reducing niche dimensionality. Our study provides insight into abiotic processes structuring microbial communities across environmental gradients and their potential roles in material and energy fluxes within and between ecosystems.
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http://dx.doi.org/10.1111/mec.15469DOI Listing
June 2020

Endothelin-1 Mediates the Systemic and Renal Hemodynamic Effects of GPR81 Activation.

Hypertension 2020 05 23;75(5):1213-1222. Epub 2020 Mar 23.

From the University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Scotland, United Kingdom (N.K.J., K.S., A.C., R.I.M., A.T., C.M.M., C.C., B.R.C., L.D., D.E.W.L., P.W.H., D.J.W., N.D., J.W.D., J.J.M., M.A.B.).

GPR81 (G-protein-coupled receptor 81) is highly expressed in adipocytes, and activation by the endogenous ligand lactate inhibits lipolysis. GPR81 is also expressed in the heart, liver, and kidney, but roles in nonadipose tissues are poorly defined. GPR81 agonists, developed to improve blood lipid profile, might also provide insights into GPR81 physiology. Here, we assessed the blood pressure and renal hemodynamic responses to the GPR81 agonist, AZ'5538. In male wild-type mice, intravenous AZ'5538 infusion caused a rapid and sustained increase in systolic and diastolic blood pressure. Renal artery blood flow, intrarenal tissue perfusion, and glomerular filtration rate were all significantly reduced. AZ'5538 had no effect on blood pressure or renal hemodynamics in mice. mRNA was expressed in renal artery vascular smooth muscle, in the afferent arteriole, in glomerular and medullary perivascular cells, and in pericyte-like cells isolated from kidney. Intravenous AZ'5538 increased plasma ET-1 (endothelin 1), and pretreatment with BQ123 (endothelin-A receptor antagonist) prevented the pressor effects of GPR81 activation, whereas BQ788 (endothelin-B receptor antagonist) did not. Renal ischemia-reperfusion injury, which increases renal extracellular lactate, increased the renal expression of genes encoding ET-1, KIM-1 (Kidney Injury Molecule 1), collagen type 1-α1, TNF-α (tumor necrosis factor-α), and F4/80 in wild-type mice but not in mice. In summary, activation of GPR81 in vascular smooth muscle and perivascular cells regulates renal hemodynamics, mediated by release of the potent vasoconstrictor ET-1. This suggests that lactate may be a paracrine regulator of renal blood flow, particularly relevant when extracellular lactate is high as occurs during ischemic renal disease.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176350PMC
May 2020

Sterically hindered Re- and Mn-CO reduction catalysts for solar energy conversion.

Dalton Trans 2020 Apr;49(14):4230-4243

Department of Chemistry, University of Sheffield, S3 7HF, UK.

Novel molecular Re and Mn tricarbonyl complexes bearing a bipyridyl ligand functionalised with sterically hindering substituents in the 6,6'-position, [M(HPEAB)(CO)3(X)] (M/X = Re/Cl, Mn/Br; HPEAB = 6,6'-{N-(4-hexylphenyl)-N(ethyl)-amido}-2,2'-bipyridine) have been synthesised, fully characterised including by single crystal X-ray crystallography, and their propensity to act as catalysts for the electrochemical and photochemical reduction of CO2 has been established. Controlled potential electrolysis showed that the catalysts are effective for electrochemical CO2-reduction, yielding CO as the product (in MeCN for the Re-complex, in 95 : 5 (v/v) MeCN : H2O mixture for the Mn-complex). The recyclability of the catalysts was demonstrated through replenishment of CO2 within solution. The novel catalysts had similar reduction potentials to previously reported complexes of similar structure, and results of the foot-of-the-wave analysis showed comparable maximum turnover rates, too. The tentative mechanisms for activation of the pre-catalysts were proposed on the basis of IR-spectroelectrochemical data aided by DFT calculations. It is shown that the typical dimerisation of the Mn-catalyst was prevented by incorporation of sterically hindering groups, whilst the Re-catalyst undergoes the usual mechanism following chloride ion loss. No photochemical CO2 reduction was observed for the rhenium complex in the presence of a sacrificial donor (triethylamine), which was attributed to the short triplet excited state lifetime (3.6 ns), insufficient for diffusion-controlled electron transfer. Importantly, [Mn(HPEAB)(CO)3Br] can act as a CO2 reduction catalyst when photosensitised by a zinc porphyrin under red light irradiation (λ > 600 nm) in MeCN : H2O (95 : 5); there has been only one reported example of photoactivating Mn-catalysts with porphyrins in this manner. Thus, this work demonstrates the wide utility of sterically protected Re- and Mn-diimine carbonyl catalysts, where the rate and yield of CO-production can be adjusted based on the metal centre and catalytic conditions, with the advantage of suppressing unwanted side-reactions through steric protection of the vacant coordination site.
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http://dx.doi.org/10.1039/d0dt00252fDOI Listing
April 2020

Ecosystem effects of the world's largest invasive animal.

Ecology 2020 05 18;101(5):e02991. Epub 2020 Feb 18.

Unidad de Ecología en Sistemas Acuáticos-UDESA, Universidad Pedagógica y Tecnológica de Colombia, Avenida Central del Norte 39-115, Tunja, Boyacá, Colombia.

The keystone roles of mega-fauna in many terrestrial ecosystems have been lost to defaunation. Large predators and herbivores often play keystone roles in their native ranges, and some have established invasive populations in new biogeographic regions. However, few empirical examples are available to guide expectations about how mega-fauna affect ecosystems in novel environmental and evolutionary contexts. We examined the impacts on aquatic ecosystems of an emerging population of hippopotamus (Hippopotamus amphibus) that has been growing in Colombia over the last 25 yr. Hippos in Africa fertilize lakes and rivers by grazing on land and excreting wastes in the water. Stable isotopes indicate that terrestrial sources contribute more carbon in Colombian lakes containing hippo populations, and daily dissolved oxygen cycles suggest that their presence stimulates ecosystem metabolism. Phytoplankton communities were more dominated by cyanobacteria in lakes with hippos, and bacteria, zooplankton, and benthic invertebrate communities were similar regardless of hippo presence. Our results suggest that hippos recapitulate their role as ecosystem engineers in Colombia, importing terrestrial organic matter and nutrients with detectable impacts on ecosystem metabolism and community structure in the early stages of invasion. Ongoing range expansion may pose a threat to water resources.
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http://dx.doi.org/10.1002/ecy.2991DOI Listing
May 2020

Glucocorticoid receptor activation stimulates the sodium-chloride cotransporter and influences the diurnal rhythm of its phosphorylation.

Am J Physiol Renal Physiol 2019 12 7;317(6):F1536-F1548. Epub 2019 Oct 7.

British Heart Foundation Centre for Cardiovascular Science, Edinburgh Medical School, The University of Edinburgh, United Kingdom.

The sodium-chloride cotransporter (NCC) in the distal convoluted tubule contributes importantly to sodium balance and blood pressure (BP) regulation. NCC phosphorylation determines transport activity and has a diurnal rhythm influenced by glucocorticoids. Disturbing this rhythm induces "nondipping" BP, an abnormality that increases cardiovascular risk. The receptor through which glucocorticoids regulate NCC is not known. In this study, we found that acute administration of corticosterone to male C57BL6 mice doubled NCC phosphorylation without affecting total NCC abundance in both adrenalectomized and adrenal-intact mice. Corticosterone also increased the whole kidney expression of canonical clock genes: period circadian protein homolog 1 (), , cryptochrome 1, and aryl hydrocarbon receptor nuclear translocator-like protein 1. In adrenal-intact mice, chronic blockade of glucocorticoid receptor (GR) with RU486 did not change total NCC but prevented corticosterone-induced NCC phosphorylation and activation of clock genes. Blockade of mineralocorticoid receptor (MR) with spironolactone reduced the total pool of NCC but did not affect stimulation by corticosterone. The diurnal rhythm of NCC phosphorylation, measured at 6-h intervals, was blunted by chronic GR blockade, and a similar dampening of diurnal variation was seen in GR heterozygous null mice. These effects on NCC phosphorylation did not reflect altered rhythmicity of plasma corticosterone or serum and glucocorticoid-induced kinase 1 activity. Both mineralocorticoids and glucocorticoids emerge as regulators of NCC, acting via distinct receptor pathways. MR activation provides maintenance of the NCC protein pool; GR activation dynamically regulates NCC phosphorylation and establishes the diurnal rhythm of NCC activity. This study has implications for circadian BP homeostasis, particularly in individuals with abnormal glucocorticoid signaling as is found in chronic stress and corticosteroid therapy.
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http://dx.doi.org/10.1152/ajprenal.00372.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962506PMC
December 2019

Job Burnout Among Mental Health Staff at a Veterans Affairs Psychosocial Rehabilitation Center.

Community Ment Health J 2020 02 5;56(2):294-297. Epub 2019 Oct 5.

VA Connecticut Healthcare System, 950 Campbell Ave 151D, West Haven, CT, 06516, USA.

Mental health providers who serve clients with severe mental illness may be particularly prone to job burnout given the nature of the work. This study examined levels of job burnout among mental health providers who serve clients with severe mental illness. Forty-two mental health staff at a Veterans Affairs psychosocial rehabilitation center completed an online survey that assessed burnout and work-life balance. Maslach Burnout Inventory (MBI) scores were compared to published scores of workers in other professions. Participants reported moderate MBI Emotional Exhaustion, Depersonalization, and Personal Accomplishment scores and overall had lower burnout scores than other healthcare providers and service workers. Being younger and white were associated with higher MBI Emotional Exhaustion scores. These findings suggest job burnout among mental health staff is a concern that should be closely monitored even among staff who express a sense of personal accomplishment from the work.
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http://dx.doi.org/10.1007/s10597-019-00487-5DOI Listing
February 2020

Males and Females Differ in the Subcellular and Brain Region Dependent Regulation of Proteasome Activity by CaMKII and Protein Kinase A.

Neuroscience 2019 10 23;418:1-14. Epub 2019 Aug 23.

School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; Fralin Biomedical Research Institute, Translational Biology, Medicine and Health, Roanoke, VA, USA. Electronic address:

The ubiquitin-proteasome system (UPS) controls the degradation of ~90% of short-lived proteins in cells and is involved in activity- and learning-dependent synaptic plasticity in the brain. Calcium/calmodulin dependent protein kinase II (CaMKII) and Protein Kinase A (PKA) can regulate activity of the proteasome. However, there have been a number of conflicting reports regarding under what conditions CaMKII and PKA regulate proteasome activity in the brain. Furthermore, this work has been done exclusively in males, leaving questions about whether these kinases also regulate the proteasome in females. Here, using subcellular fractionation protocols in combination with in vitro pharmacology and proteasome activity assays, we investigated the conditions under which CaMKII and PKA regulate proteasome activity in the brains of male and female rats. In males, nuclear proteasome chymotrypsin activity was regulated by PKA in the amygdala but CaMKII in the hippocampus. Conversely, in females CaMKII regulated nuclear chymotrypsin activity in the amygdala, but not hippocampus. Additionally, in males CaMKII and PKA regulated proteasome trypsin activity in the cytoplasm of hippocampal, but not amygdala cells, while in females both CaMKII and PKA could regulate this activity in the nucleus of cells in both regions. Proteasome peptidylglutamyl activity was regulated by CaMKII and PKA activity in the nuclei of amygdala and hippocampus cells in males. However, in females PKA regulated nuclear peptidylglutamyl activity in the amygdala, but not hippocampus. Collectively, these results suggest that CaMKII- and PKA-dependent regulation of proteasome activity in the brain varies significantly across subcellular compartments and between males and females.
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http://dx.doi.org/10.1016/j.neuroscience.2019.08.031DOI Listing
October 2019

Analyzing Resistance to Design Selective Chemical Inhibitors for AAA Proteins.

Cell Chem Biol 2019 09 27;26(9):1263-1273.e5. Epub 2019 Jun 27.

Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY 10065, USA. Electronic address:

Drug-like inhibitors are often designed by mimicking cofactor or substrate interactions with enzymes. However, as active sites are comprised of conserved residues, it is difficult to identify the critical interactions needed to design selective inhibitors. We are developing an approach, named RADD (resistance analysis during design), which involves engineering point mutations in the target to generate active alleles and testing compounds against them. Mutations that alter compound potency identify residues that make key interactions with the inhibitor and predict target-binding poses. Here, we apply this approach to analyze how diaminotriazole-based inhibitors bind spastin, a microtubule-severing AAA (ATPase associated with diverse cellular activities) protein. The distinct binding poses predicted for two similar inhibitors were confirmed by a series of X-ray structures. Importantly, our approach not only reveals how selective inhibition of the target can be achieved but also identifies resistance-conferring mutations at the early stages of the design process.
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http://dx.doi.org/10.1016/j.chembiol.2019.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754270PMC
September 2019

Cryptic dispersal networks shape biodiversity in an invaded landscape.

Ecology 2019 08 3;100(8):e02738. Epub 2019 Jun 3.

Department of Ecology and Evolutionary, Princeton University, 106A Guyot Hall, Princeton, New Jersey, 08544, USA.

Species interact with the physical world in complex ways, and life-history strategies could cause species to differ in how they experience the connectedness of the same landscape. As a consequence, dispersal limitation might be present but not captured by distance-based measures of connectivity. To test these ideas, we surveyed plant communities that live on discrete patches of serpentine habitat embedded within an invaded nonserpentine habitat matrix. Species in these communities differ in dispersal mode (gravity, animal, or wind); thus we used satellite imagery to quantify landscape features that might differentially influence connectivity for some dispersal- mode groups over others (surface streams, animal paths). Our data yielded two key insights: first, dispersal limitation appeared to be absent using a conventional distance-based measure of connectivity, but emerged after considering forms of landscape connectivity relevant to each dispersal mode. Second, the landscape variables that emerged as most important to each dispersal mode were generally consistent with our predictions based on species' putative dispersal vectors, but also included unexpected interactive effects. For example, the richness of animal-dispersed species was positively associated with animal connectivity when patches were close in space, but when patches were isolated, animals had a strong negative effect. This finding alludes to the reduced ability of animals to disperse seeds between suitable patches in invaded landscapes because of increased inter-patch distances. Real landscapes include complex spatial flows of energy and matter, which, as our work demonstrates, sets up ecological opportunity for organisms to differ in how they disperse in a common landscape.
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http://dx.doi.org/10.1002/ecy.2738DOI Listing
August 2019

The LOTUS: A Journey to Value-Based, Patient-Centered Care.

Creat Nurs 2019 Feb;25(1):17-24

In response to the merger of our 248-bed community hospital with a new health system, a multidisciplinary team began a journey of holistic transformation via the evolution of a new rounding process called Leadership, Ownership, Transformation, Unity, and Sustainability (LOTUS) in the 20-bed ICU. Morphing from a hierarchical practice structure with limited engagement of multidisciplinary members, the LOTUS initiative (named for the blossom whose petals surround its core, the patient) afforded each discipline (petal) an equal voice and allowed a once-fragmented team to work cohesively, collaboratively, and at the highest level of the scope of practice for each discipline, thus affording expert guidance during care planning while providing a method to collect quality metrics. LOTUS allows us to view our patients in a new way as we refocused goal determination on patients and their families. The restructuring and evolution into a high-functioning team was targeted with the goal of enhancing quality critical care for patients, which, in the literature, has correlated with improved patient safety and decreased mortality and ICU length of stay.
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http://dx.doi.org/10.1891/1078-4535.25.1.17DOI Listing
February 2019

Experiences with interferon-free hepatitis C therapies: addressing barriers to adherence and optimizing treatment outcomes.

BMC Health Serv Res 2019 Feb 1;19(1):91. Epub 2019 Feb 1.

Center for Healthcare Organization and Implementation Research (CHOIR), Edith Nourse Rogers VA Medical Center, 200 Springs Road (152), Bedford, MA, 01730, USA.

Background: Millions of Americans are living with hepatitis C, the leading cause of liver disease in the United States. Medication treatment can cure hepatitis C. We sought to understand factors that contribute to hepatitis C treatment completion from the perspectives of patients and providers.

Methods: We conducted semi-structured interviews at three Veterans Affairs Medical Centers. Patients were asked about their experiences with hepatitis C treatments and perspectives on care. Providers were asked about observations regarding patient responses to medications and perspectives about factors resulting in treatment completion. Transcripts were analyzed using a grounded thematic approach-an inductive analysis that lets themes emerge from the data.

Results: Contributors to treatment completion included Experience with Older Treatments, Hope for Improvement, Symptom Relief, Tailored Organized Routines, and Positive Patient-Provider Relationship. Corresponding barriers also emerged, including pill burden and skepticism about treatment effectiveness and safety.

Conclusion: Despite the improved side-effect profile of newer HCV medications, multiple barriers to treatment completion remain. However, providers and patients were able to identify avenues for addressing such barriers.
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http://dx.doi.org/10.1186/s12913-019-3904-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359844PMC
February 2019

Development of a quantification method for adenosine in tumors by LC-MS/MS with dansyl chloride derivatization.

Anal Biochem 2019 03 5;568:78-88. Epub 2018 Nov 5.

DMPK Oncology, IMED Biotech Unit, AstraZeneca, Boston, MA, USA. Electronic address:

Adenosine is known to be an important signaling molecule in many physiological processes and has recently been shown to be an important molecule in oncology. A fit for purpose method has been developed for the quantification of adenosine in murine tumor samples using pre-column derivatization and liquid chromatography-mass spectrometry (LC-MS/MS). To overcome adenosine quantification challenges, derivatization with dansyl chloride was employed. This derivatization technique, following protein precipitation and liquid-liquid extraction, improved the sensitivity and selectivity of adenosine in tumor samples through the reduction of endogenous interference and matrix effects. This method utilizes a mouse plasma calibration curve, qualified over a range of 0.019 μM-37 μM. The 15 min derivatization incubation time and 1 min chromatographic run time allow for higher throughput. The following established method overcomes challenges associated with the quantification of low molecular weight, polar, endogenous molecules, such as adenosine, using derivatization and LC-MS/MS. With the additional analysis of murine tumors, this method will contribute to the understanding of the impact adenosine plays in the tumor microenvironment and the bearing it has on targeted cancer therapies.
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http://dx.doi.org/10.1016/j.ab.2018.11.004DOI Listing
March 2019

Amino acid composition reveals functional diversity of zooplankton in tropical lakes related to geography, taxonomy and productivity.

Oecologia 2018 07 16;187(3):719-730. Epub 2018 Apr 16.

Grupo de Limnología Amazónica, Universidad Nacional de Colombia, Sede Amazonia, Leticia, Colombia.

Variation in resource use among species determines their potential for competition and co-existence, as well as their impact on ecosystem processes. Planktonic crustaceans consume a range of micro-organisms that vary among habitats and species, but these differences in resource consumption are difficult to characterize due to the small size of the organisms. Consumers acquire amino acids from their diet, and the composition of tissues reflects both the use of different resources and their assimilation in proteins. We examined the amino acid composition of common crustacean zooplankton from 14 tropical lakes in Colombia in three regions (the Amazon floodplain, the eastern range of the Andes, and the Caribbean coast). Amino acid composition varied significantly among taxonomic groups and the three regions. Functional richness in amino acid space was greatest in the Amazon, the most productive region, and tended to be positively related to lake trophic status, suggesting the niche breadth of the community could increase with ecosystem productivity. Functional evenness increased with lake trophic status, indicating that species were more regularly distributed within community-wide niche space in more productive lakes. These results show that zooplankton resource use in tropical lakes varies with both habitat and taxonomy, and that lake productivity may affect community functional diversity and the distribution of species within niche space.
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http://dx.doi.org/10.1007/s00442-018-4130-6DOI Listing
July 2018

Empirical evidence that metabolic theory describes the temperature dependency of within-host parasite dynamics.

PLoS Biol 2018 02 7;16(2):e2004608. Epub 2018 Feb 7.

Department of Ecology and Evolutionary Biology, University of Toronto, Toronto, Ontario, Canada.

The complexity of host-parasite interactions makes it difficult to predict how host-parasite systems will respond to climate change. In particular, host and parasite traits such as survival and virulence may have distinct temperature dependencies that must be integrated into models of disease dynamics. Using experimental data from Daphnia magna and a microsporidian parasite, we fitted a mechanistic model of the within-host parasite population dynamics. Model parameters comprising host aging and mortality, as well as parasite growth, virulence, and equilibrium abundance, were specified by relationships arising from the metabolic theory of ecology. The model effectively predicts host survival, parasite growth, and the cost of infection across temperature while using less than half the parameters compared to modeling temperatures discretely. Our results serve as a proof of concept that linking simple metabolic models with a mechanistic host-parasite framework can be used to predict temperature responses of parasite population dynamics at the within-host level.
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http://dx.doi.org/10.1371/journal.pbio.2004608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819823PMC
February 2018

Pulsatility of glucocorticoid hormones in pregnancy: Changes with gestation and obesity.

Clin Endocrinol (Oxf) 2018 04 29;88(4):592-600. Epub 2018 Jan 29.

Tommy's Centre for Maternal and Fetal Health, Medical Research Council Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK.

Objective: Hypothalamic-pituitary-adrenal axis (HPA) activity is decreased in obese pregnancy and associates with increased foetal size. Pulsatile release of glucocorticoid hormones regulates their action in target tissues. Glucocorticoids are essential for normal foetal growth, but little is known about glucocorticoid pulsatility in pregnancy. We aimed to investigate the ultradian rhythm of glucocorticoid secretion during obese and lean pregnancy and nonpregnancy.

Design: Serum cortisol, cortisone, corticosterone and 11-dehydrocorticosterone were measured by LC-MS/MS from samples obtained at 10-minute intervals between 08.00-11.00 hours and 16.00-19.00 hours, from 8 lean (BMI <25 kg/m ) and 7 obese (BMI > 35 kg/m ) pregnant women between 16-24 weeks gestation and again at 30-36 weeks), and nonpregnant controls (lean n = 3, obese n = 4) during the luteal phase of their menstrual cycle. Interstitial fluid cortisol was measured by ELISA, from samples obtained using a portable microdialysis and automated collection device at 20-minute intervals over 24 hours.

Results: Serum cortisol AUC, highest peak and lowest trough increased significantly with gestation in lean and obese pregnant compared with nonpregnant subjects. Pulsatility of cortisol was detected in interstitial fluid. In pregnant subjects, interstitial fluid pulse frequency was significantly lower with advancing gestation in obese, but not in lean.

Conclusions: We demonstrate cortisol pulsatility in interstitial fluid. Pulse frequency is altered with increased gestation and BMI. This may be a novel mechanism to explain decreased HPA activity in obese pregnancy.
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http://dx.doi.org/10.1111/cen.13548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5887976PMC
April 2018

Structure-Based Design of Selective Noncovalent CDK12 Inhibitors.

ChemMedChem 2018 02 26;13(3):231-235. Epub 2018 Jan 26.

Oncology, IMED Biotech Unit, AstraZeneca, Boston, MA, USA.

Cyclin-dependent kinase (CDK) 12 knockdown via siRNA decreases the transcription of DNA-damage-response genes and sensitizes BRCA wild-type cells to poly(ADP-ribose) polymerase (PARP) inhibition. To recapitulate this effect with a small molecule, we sought a potent, selective CDK12 inhibitor. Crystal structures and modeling informed hybridization between dinaciclib and SR-3029, resulting in lead compound 5 [(S)-2-(1-(6-(((6,7-difluoro-1H-benzo[d]imidazol-2-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol]. Further structure-guided optimization delivered a series of selective CDK12 inhibitors, including compound 7 [(S)-2-(1-(6-(((6,7-difluoro-1H-benzo[d]imidazol-2-yl)methyl)amino)-9-isopropyl-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol]. Profiling of this compound across CDK9, 7, 2, and 1 at high ATP concentration, single-point kinase panel screening against 352 targets at 0.1 μm, and proteomics via kinase affinity matrix technology demonstrated the selectivity. This series of compounds inhibits phosphorylation of Ser2 on the C-terminal repeat domain of RNA polymerase II, consistent with CDK12 inhibition. These selective compounds were also acutely toxic to OV90 as well as THP1 cells.
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http://dx.doi.org/10.1002/cmdc.201700695DOI Listing
February 2018

Combined tumor genomic profiling and exome sequencing in a breast cancer family implicates ATM in tumorigenesis: A proof of principle study.

Genes Chromosomes Cancer 2017 11 16;56(11):788-799. Epub 2017 Aug 16.

INSERM U1218, Mammary & Leukemic Oncogenesis group, Université de Bordeaux, Bordeaux, France.

Familial breast cancers (BCs) account for 10%-20% of all diagnosed BCs, yet only 20% of such tumors arise in the context of a germline mutation in known tumor suppressor genes such as BRCA1 or BRCA2. The vast genetic heterogeneity which characterizes non BRCA1 and non BRCA2 (or BRCAx) families makes grouped studies impossible to perform. Next generation sequencing techniques, however, allow individual families to be studied to identify rare and or private mutations but the high number of genetic variants identified need to be sorted using pathogenicity or recurrence criteria. An additional sorting criterion may be represented by the identification of candidate regions defined by tumor genomic rearrangements. Indeed, comparative genomic hybridization (CGH) using single nucleotide polymorphism (SNP) arrays allows the detection of conserved ancestral haplotypes within recurrent regions of loss of heterozygosity, common to several familial tumors, which can highlight genomic loci harboring a germline mutation in cancer predisposition genes. The combination of both exome sequencing and SNP array-CGH for a series of familial BC revealed a germline ATM mutation associated with a loss of the wild-type allele in two BC from a BRCAx family. The analysis of additional breast tumors from ten BC families in which a germline ATM mutation had been identified revealed a high frequency of wild-type allele loss. This result argues strongly in favor of the involvement of ATM in these tumors as a tumor suppressor gene and confirms that germline ATM mutations are involved in a subset of familial BC.
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http://dx.doi.org/10.1002/gcc.22482DOI Listing
November 2017
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