Publications by authors named "K J Thomas"

4,485 Publications

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Increased NOS coupling by the metabolite tetrahydrobiopterin (BH4) reduces preeclampsia/IUGR consequences.

Redox Biol 2022 Sep 30;55:102406. Epub 2022 Jul 30.

Institut Cochin U1016, INSERM UMR8104 CNRS, 24, rue du Fg St Jacques, Paris, France. Electronic address:

Preeclampsia (PE) is a high-prevalence pregnancy disease characterized by placental insufficiency, gestational hypertension, and proteinuria. Overexpression of the A isoform of the STOX1 transcription factor (STOX1A) recapitulates PE in mice, and STOX1A overexpressing trophoblasts recapitulate PE patients hallmarks in terms of gene expression and pathophysiology. STOX1 overexpression induces nitroso-redox imbalance and mitochondrial hyper-activation. Here, by a thorough analysis on cell models, we show that STOX1 overexpression in trophoblasts alters inducible nitric oxide synthase (iNOS), nitric oxide (NO) content, the nitroso-redox balance, the antioxidant defense, and mitochondrial function. This is accompanied by specific alterations of the Krebs cycle leading to reduced l-malate content. By increasing NOS coupling using the metabolite tetrahydrobiopterin (BH4) we restore this multi-step pathway in vitro. Moving in vivo on two different rodent models (STOX1 mice and RUPP rats, alike early onset and late onset preeclampsia, respectively), we show by transcriptomics that BH4 directly reverts STOX1-deregulated gene expression including glutathione metabolism, oxidative phosphorylation, cholesterol metabolism, inflammation, lipoprotein metabolism and platelet activation, successfully treating placental hypotrophy, gestational hypertension, proteinuria and heart hypertrophy. In the RUPP rats we show that the major fetal issue of preeclampsia, Intra Uterine Growth Restriction (IUGR), is efficiently corrected. Our work posits on solid bases BH4 as a novel potential therapy for preeclampsia.
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http://dx.doi.org/10.1016/j.redox.2022.102406DOI Listing
September 2022

Neuroinflammatory disease disrupts the blood-CNS barrier via crosstalk between proinflammatory and endothelial-to-mesenchymal-transition signaling.

Neuron 2022 Aug 4. Epub 2022 Aug 4.

Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112, USA; Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT 84112, USA. Electronic address:

Breakdown of the blood-central nervous system barrier (BCNSB) is a hallmark of many neuroinflammatory disorders, such as multiple sclerosis (MS). Using a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), we show that endothelial-to-mesenchymal transition (EndoMT) occurs in the CNS before the onset of clinical symptoms and plays a major role in the breakdown of BCNSB function. EndoMT can be induced by an IL-1β-stimulated signaling pathway in which activation of the small GTPase ADP ribosylation factor 6 (ARF6) leads to crosstalk with the activin receptor-like kinase (ALK)-SMAD1/5 pathway. Inhibiting the activation of ARF6 both prevents and reverses EndoMT, stabilizes BCNSB function, reduces demyelination, and attenuates symptoms even after the establishment of severe EAE, without immunocompromising the host. Pan-inhibition of ALKs also reduces disease severity in the EAE model. Therefore, multiple components of the IL-1β-ARF6-ALK-SMAD1/5 pathway could be targeted for the treatment of a variety of neuroinflammatory disorders.
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http://dx.doi.org/10.1016/j.neuron.2022.07.015DOI Listing
August 2022

Triangulating the New Frontier of Health Geo-Data: Assessing Tick-Borne Disease Risk as an Occupational Hazard among Vulnerable Populations.

Int J Environ Res Public Health 2022 Aug 2;19(15). Epub 2022 Aug 2.

Laboratory for Human Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA.

Determining interventions to combat disease often requires complex analyses of spatial-temporal data to improve health outcomes. For some vulnerable populations, obtaining sufficient data for related analyses is especially difficult, thus exacerbating related healthcare, research, and public health efforts. In the United States (U.S.), migrant and seasonal workers are especially affected in this regard, with data on health interventions and outcomes largely absent from official sources. In response, this study offers a multi-modal approach that involves triangulating geographically specified health data that incorporate reports on canine tick species, Lyme disease (LD) incidence, and patient symptom severity indicating potential subsequent disease burden. Spatial alignment of data at the U.S. county level was used to reveal and better understand tick-borne disease (TBD) incidence and risk among the identified populations. Survey data from migrant and seasonal workers in Texas were employed to determine TBD risk based on symptoms, occupations, and locations. Respondents who were found to have a higher likelihood of a TBD were also considerably more likely to report the most common symptoms of LD and other TBDs on the Horowitz Multiple Systemic Infectious Disease Syndrome Questionnaire. Those in the highly likely scoring group also reported more poor health and mental health days. Overall, a notable number of respondents (22%) were likely or highly likely to have a TBD, with particular relevance attributed to county of residence and living conditions. Also of note, almost a third of those reporting severe symptoms had received a previous Lyme disease diagnosis. These findings underscore the need for further surveillance among vulnerable populations at risk for TBDs.
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http://dx.doi.org/10.3390/ijerph19159449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9368420PMC
August 2022

Developmental trajectories of cortical thickness by functional brain network: The roles of pubertal timing and socioeconomic status.

Dev Cogn Neurosci 2022 Aug 5;57:101145. Epub 2022 Aug 5.

Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.

The human cerebral cortex undergoes considerable changes during development, with cortical maturation patterns reflecting regional heterogeneity that generally progresses in a posterior-to-anterior fashion. However, the organizing principles that govern cortical development remain unclear. In the current study, we characterized age-related differences in cortical thickness (CT) as a function of sex, pubertal timing, and two dissociable indices of socioeconomic status (i.e., income-to-needs and maternal education) in the context of functional brain network organization, using a cross-sectional sample (n = 789) diverse in race, ethnicity, and socioeconomic status from the Lifespan Human Connectome Project in Development (HCP-D). We found that CT generally followed a linear decline from 5 to 21 years of age, except for three functional networks that displayed nonlinear trajectories. We found no main effect of sex or age by sex interaction for any network. Earlier pubertal timing was associated with reduced mean CT and CT in seven networks. We also found a significant age by maternal education interaction for mean CT across cortex and CT in the dorsal attention network, where higher levels of maternal education were associated with steeper age-related decreases in CT. Taken together, our results suggest that these biological and environmental variations may impact the emerging functional connectome.
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http://dx.doi.org/10.1016/j.dcn.2022.101145DOI Listing
August 2022

Interactive Effects of Pulse Pressure and Tau Imaging on Longitudinal Cognition.

J Alzheimers Dis 2022 Aug 1. Epub 2022 Aug 1.

Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.

Background: Studies have demonstrated that both tau and cardiovascular risk are associated with cognitive decline, but the possible synergistic effects of these pathologic markers remain unclear.

Objective: To explore the interaction of AD biomarkers with a specific vascular risk marker (pulse pressure) on longitudinal cognition.

Methods: Participants included 139 older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Biomarkers of tau, amyloid-β (Aβ), and vascular risk (pulse pressure) were assessed. Neuropsychological assessment provided memory, language, and executive function domain composite scores at baseline and 1-year follow-up. Multiple linear regression examined interactive effects of pulse pressure with tau PET independent of Aβ PET and Aβ PET independent of tau PET on baseline and 1-year cognitive outcomes.

Results: The interaction between pulse pressure and tau PET significantly predicted 1-year memory performance such that the combined effect of high pulse pressure and high tau PET levels was associated with lower memory at follow-up but not at baseline. In contrast, Aβ PET did not significantly interact with pulse pressure to predict baseline or 1-year outcomes in any cognitive domain. Main effects revealed a significant effect of tau PET on memory, and no significant effects of Aβ PET or pulse pressure on any cognitive domain.

Conclusion: Results indicate that tau and an indirect marker of arterial stiffening (pulse pressure) may synergistically contribute to memory decline, whereas Aβ may have a lesser role in predicting cognitive progression. Tau and vascular pathology (particularly in combination) may represent valuable targets for interventions intended to slow cognitive decline.
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http://dx.doi.org/10.3233/JAD-220026DOI Listing
August 2022
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