Publications by authors named "David James"

675 Publications

BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection.

Cell 2021 Mar 16. Epub 2021 Mar 16.

QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia. Electronic address:

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1β, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.
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http://dx.doi.org/10.1016/j.cell.2021.03.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962543PMC
March 2021

Dinaciclib, a Bimodal Agent Effective against Endometrial Cancer.

Cancers (Basel) 2021 Mar 6;13(5). Epub 2021 Mar 6.

Medical School, Swansea University, Singleton Park, Swansea SA2 8PP, UK.

Endometrial cancer (EC) is the sixth most prevalent female cancer globally and although high rates of success are achieved when diagnosed at an early stage, the 5-year survival rate for cancers diagnosed at Stages II-IV is below 50%. Improving patient outcomes will necessitate the introduction of novel therapies to the clinic. Pan-cyclin-dependent kinase inhibitors (CDKis) have been explored as therapies for a range of cancers due to their ability to simultaneously target multiple key cellular processes, such as cell cycle progression, transcription, and DNA repair. Few studies, however, have reported on their potential for the treatment of EC. Herein, we examined the effects of the pan-CDKi dinaciclib in primary cells isolated directly from tumors and EC cell lines. Dinaciclib was shown to elicit a bimodal action in EC cell lines, disrupting both cell cycle progression and phosphorylation of the RNA polymerase carboxy terminal domain, with a concomitant reduction in Bcl-2 expression. Furthermore, the therapeutic potential of combining dinaciclib and cisplatin was explored, with the drugs demonstrating synergy at specific doses in Type I and Type II EC cell lines. Together, these results highlight the potential of dinaciclib for use as an effective EC therapy.
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http://dx.doi.org/10.3390/cancers13051135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962054PMC
March 2021

Corrigendum to 'ABHD15 regulates adipose tissue lipolysis and hepatic lipid accumulation' [Molecular Metabolism 25 (2019) p.83-94].

Mol Metab 2021 Mar 26;48:101219. Epub 2021 Mar 26.

Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.molmet.2021.101219DOI Listing
March 2021

Predictors of varying levels of risks posed by fixated individuals to British public figures.

J Forensic Sci 2021 Mar 21. Epub 2021 Mar 21.

Fixated Threat Assessment Centre, London, UK.

Concerning approaches and communications to the Royal Family and other British public figures are relatively numerous. This paper examines over 2000 such cases logged over a three-year period in the United Kingdom. Using police and health data, the paper conducts a series of bivariate and multivariate analyses to demonstrate the predictors of what types of risk are posed by an individual case (e.g., communicate only, approach, security breach). The results showed that (a) the rates of serious mental disorders are higher among this sample than the general population base rate, (b) approachers were significantly more likely than communicators to suffer from serious mental disorders, (c) approachers were significantly more likely than communicators to have a history of substance use and abuse problems, (d) approachers were significantly more likely than communicators to have a history of violent behavior against property and persons, and (e) the motivations of approachers and communicators significantly differ. The paper concludes with a consideration of the implications for threat assessment and management.
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http://dx.doi.org/10.1111/1556-4029.14708DOI Listing
March 2021

High content, quantitative AFM analysis of the scalable biomechanical properties of extracellular vesicles.

Nanoscale 2021 Mar 17;13(12):6129-6141. Epub 2021 Mar 17.

Reproductive Biology and Gynaecological Oncology Group, Institute for Life Science 2, Medical School, Swansea University, Singleton Park, Swansea SA2 8PP, UK.

Extracellular vesicles (EVs) are studied extensively as natural biomolecular shuttles and for their diagnostic and therapeutic potential. This exponential rise in interest has highlighted the need for highly robust and reproducible approaches for EV characterisation. Here we optimise quantitative nanomechanical tools and demonstrate the advantages of EV population screening by atomic force microscopy (AFM). Our high-content informatics analytical tools are made available for use by the EV community for widespread, standardised determination of structural stability. Ultracentrifugation (UC) and sonication, the common mechanical techniques used for EV isolation and loading respectively, are used to demonstrate the utility of optimised PeakForce-Quantitative Nano Mechanics (PF-QNM) analysis. EVs produced at an industrial scale exhibited biochemical and biomechanical alterations after exposure to these common techniques. UC resulted in slight increases in physical dimensions, and decreased EV adhesion concurrent with a decrease in CD63 content. Sonicated EVs exhibited significantly reduced levels of CD81, a decrease in size, increased Young's modulus and decreased adhesive force. These biomechanical and biochemical changes highlight the effect of EV sample preparation techniques on critical properties linked to EV cellular uptake and biological function. PF-QNM offers significant additional information about the structural information of EVs following their purification and downstream processing, and the analytical tools will ensure consistency of analysis of AFM data by the EV community, as this technique continues to become more widely implemented.
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http://dx.doi.org/10.1039/d0nr09235eDOI Listing
March 2021

A first-in-human phase 0 clinical study of RNA interference-based spherical nucleic acids in patients with recurrent glioblastoma.

Sci Transl Med 2021 Mar;13(584)

Ken and Ruth Davee Department of Neurology, The Northwestern Malnati Brain Tumor Institute, Feinberg School of Medicine, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.

Glioblastoma (GBM) is one of the most difficult cancers to effectively treat, in part because of the lack of precision therapies and limited therapeutic access to intracranial tumor sites due to the presence of the blood-brain and blood-tumor barriers. We have developed a precision medicine approach for GBM treatment that involves the use of brain-penetrant RNA interference-based spherical nucleic acids (SNAs), which consist of gold nanoparticle cores covalently conjugated with radially oriented and densely packed small interfering RNA (siRNA) oligonucleotides. On the basis of previous preclinical evaluation, we conducted toxicology and toxicokinetic studies in nonhuman primates and a single-arm, open-label phase 0 first-in-human trial (NCT03020017) to determine safety, pharmacokinetics, intratumoral accumulation and gene-suppressive activity of systemically administered SNAs carrying siRNA specific for the GBM oncogene Bcl2Like12 (Bcl2L12). Patients with recurrent GBM were treated with intravenous administration of siBcl2L12-SNAs (drug moniker: NU-0129), at a dose corresponding to 1/50th of the no-observed-adverse-event level, followed by tumor resection. Safety assessment revealed no grade 4 or 5 treatment-related toxicities. Inductively coupled plasma mass spectrometry, x-ray fluorescence microscopy, and silver staining of resected GBM tissue demonstrated that intravenously administered SNAs reached patient tumors, with gold enrichment observed in the tumor-associated endothelium, macrophages, and tumor cells. NU-0129 uptake into glioma cells correlated with a reduction in tumor-associated Bcl2L12 protein expression, as indicated by comparison of matched primary tumor and NU-0129-treated recurrent tumor. Our results establish SNA nanoconjugates as a potential brain-penetrant precision medicine approach for the systemic treatment of GBM.
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http://dx.doi.org/10.1126/scitranslmed.abb3945DOI Listing
March 2021

Further Insights on the Migration Biology of Monarch Butterflies, (Lepidoptera: Nymphalidae) from the Pacific Northwest.

Insects 2021 Feb 14;12(2). Epub 2021 Feb 14.

Irrigated Agriculture Research and Extension Center, Department of Entomology, Washington State University, Prosser, WA 99350, USA.

The fall migration of monarch butterflies, (L.), in the Pacific Northwest was studied during 2017-2019 by tagging 14,040 captive-reared and 450 wild monarchs. One hundred and twenty-two captive-reared monarchs (0.87%) were recovered at distances averaging 899.9 ± 98.6 km for Washington-released and 630.5 ± 19.9 km for Oregon-released monarchs. The greatest straight-line release to recovery distance was 1392.1 km. A mean travel rate of 20.7 ± 2.2 km/day and maximum travel of 46.1 km/day were recorded. Recovery rates were greater for Oregon-released monarchs (0.92%) than Washington-released (0.34%) or Idaho-released monarchs (0.30%). Most monarchs (106/122) were recovered SSW-S-SSE in California, with 82 at 18 coastal overwintering sites. Two migrants from Oregon were recovered just weeks after release ovipositing in Santa Barbara and Palo Alto, CA. Two migrants released in central Washington recovered up to 360.0 km to the SE, and recoveries from Idaho releases to the S and SE suggests that some Pacific Northwest migrants fly to an alternative overwintering destination. Monarchs released in southern Oregon into smoky, poor quality air appeared to be as successful at reaching overwintering sites and apparently lived just as long as monarchs released into non-smoky, good quality air. Migration and lifespan for monarchs infected with the protozoan parasite, (McLaughlin and Myers), appeared to be similar to the migration and survival of uninfected monarchs, although data are limited. Our data improve our understanding of western monarch migration, serving as a basis for further studies and providing information for conservation planning.
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http://dx.doi.org/10.3390/insects12020161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917764PMC
February 2021

A Rare Case of Congenitally Acquired Ocular Toxocariasis in A Five-Week-Old Infant.

Ocul Immunol Inflamm 2021 Mar 4:1-3. Epub 2021 Mar 4.

Department of Ophthalmology, Ochsner Medical Center, New Orleans, LA, USA.

: To report a case of strabismus in a five-week-old infant, likely secondary to a rare occurrence of congenitally acquired ocular toxocariasis.: Retrospective case report.: A five-week-old male infant with left exotropia was referred to pediatric ophthalmology and to a vitreoretinal specialist. Fundoscopic examination revealed a granuloma with associated retinal folds and tractional retinal detachment typical for ocular toxocariasis. Serology revealed positivity for antibodies, consistent with the clinical diagnosis of ocular toxocariasis.: Ocular toxocariasis is typically thought to be secondary to acquired infection secondary to fecal-oral transmission. In this case of early-onset strabismus secondary to ocular toxocariasis, it is hypothesized that this is a presentation of congenitally acquired toxocariasis.
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http://dx.doi.org/10.1080/09273948.2020.1866619DOI Listing
March 2021

Signaling Heterogeneity is Defined by Pathway Architecture and Intercellular Variability in Protein Expression.

iScience 2021 Feb 29;24(2):102118. Epub 2021 Jan 29.

Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia.

Insulin's activation of PI3K/Akt signaling, stimulates glucose uptake by enhancing delivery of GLUT4 to the cell surface. Here we examined the origins of intercellular heterogeneity in insulin signaling. Akt activation alone accounted for ~25% of the variance in GLUT4, indicating that additional sources of variance exist. The Akt and GLUT4 responses were highly reproducible within the same cell, suggesting the variance is between cells (extrinsic) and not within cells (intrinsic). Generalized mechanistic models (supported by experimental observations) demonstrated that the correlation between the steady-state levels of two measured signaling processes decreases with increasing distance from each other and that intercellular variation in protein expression (as an example of extrinsic variance) is sufficient to account for the variance in and between Akt and GLUT4. Thus, the response of a population to insulin signaling is underpinned by considerable single-cell heterogeneity that is largely driven by variance in gene/protein expression between cells.
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http://dx.doi.org/10.1016/j.isci.2021.102118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892930PMC
February 2021

Proteomics analysis of adipose depots after intermittent fasting reveals visceral fat preservation mechanisms.

Cell Rep 2021 Mar;34(9):108804

Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW, Australia. Electronic address:

Intermittent fasting is a beneficial dietary treatment for obesity. But the response of each distinct adipose depot is currently poorly defined. Here we explore the response of key adipose depots to every-other-day fasting (EODF) in mice using proteomics. A key change in subcutaneous white adipose tissue (scWAT) and visceral WAT (vWAT) depots is an increase in mitochondrial protein content after EODF. This effect is correlated with increased fatty acid synthesis enzymes in both WAT depots but not in brown adipose tissue. Strikingly, EODF treatment downregulates lipolysis specifically in vWAT, mediated by a large decrease in the abundance of the catecholamine receptor (ADRB3). Together, these changes are important for preservation of the visceral lipid store during EODF. Enrichment analysis highlights downregulation of inflammatory collagen IV specifically in vWAT, allowing improved insulin sensitivity. This resource for adipose-depot-specific fasting adaptations in mice is available using a web-based interactive visualization.
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http://dx.doi.org/10.1016/j.celrep.2021.108804DOI Listing
March 2021

Neural stem cells secreting bispecific T cell engager to induce selective antiglioma activity.

Proc Natl Acad Sci U S A 2021 Mar;118(9)

Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;

Glioblastoma (GBM) is the most lethal primary brain tumor in adults. No treatment provides durable relief for the vast majority of GBM patients. In this study, we've tested a bispecific antibody comprised of single-chain variable fragments (scFvs) against T cell CD3ε and GBM cell interleukin 13 receptor alpha 2 (IL13Rα2). We demonstrate that this bispecific T cell engager (BiTE) (BiTE) engages peripheral and tumor-infiltrating lymphocytes harvested from patients' tumors and, in so doing, exerts anti-GBM activity ex vivo. The interaction of BiTE with T cells and IL13Rα2-expressing GBM cells stimulates T cell proliferation and the production of proinflammatory cytokines interferon γ (IFNγ) and tumor necrosis factor α (TNFα). We have modified neural stem cells (NSCs) to produce and secrete the BiTE (NSC). When injected intracranially in mice with a brain tumor, NSC show tropism for tumor, secrete BiTE, and remain viable for over 7 d. When injected directly into the tumor, NSC provide a significant survival benefit to mice bearing various IL13Rα2 GBMs. Our results support further investigation and development of this therapeutic for clinical translation.
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http://dx.doi.org/10.1073/pnas.2015800118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936285PMC
March 2021

PhosR enables processing and functional analysis of phosphoproteomic data.

Cell Rep 2021 Feb;34(8):108771

School of Mathematics and Statistics, The University of Sydney, Sydney, NSW, Australia; Computational Systems Biology Group, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia. Electronic address:

Mass spectrometry (MS)-based phosphoproteomics has revolutionized our ability to profile phosphorylation-based signaling in cells and tissues on a global scale. To infer the action of kinases and signaling pathways in phosphoproteomic experiments, we present PhosR, a set of tools and methodologies implemented in a suite of R packages facilitating comprehensive analysis of phosphoproteomic data. By applying PhosR to both published and new phosphoproteomic datasets, we demonstrate capabilities in data imputation and normalization by using a set of "stably phosphorylated sites" and in functional analysis for inferring active kinases and signaling pathways. In particular, we introduce a "signalome" construction method for identifying a collection of signaling modules to summarize and visualize the interaction of kinases and their collective actions on signal transduction. Together, our data and findings demonstrate the utility of PhosR in processing and generating biological knowledge from MS-based phosphoproteomic data.
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http://dx.doi.org/10.1016/j.celrep.2021.108771DOI Listing
February 2021

Design of synthetic promoters for controlled expression of therapeutic genes in retinal pigment epithelial cells.

Biotechnol Bioeng 2021 Feb 12. Epub 2021 Feb 12.

Department of Chemical and Biological Engineering, University of Sheffield, Sheffield, UK.

Age-related macular degeneration (AMD) associated with dysfunction of retinal pigment epithelial (RPE) cells is the most common cause of untreatable blindness. To advance gene therapy as a viable treatment for AMD there is a need for technologies that enable controlled, RPE-specific expression of therapeutic genes. Here we describe design, construction and testing of compact synthetic promoters with a pre-defined transcriptional activity and RPE cell specificity. Initial comparative informatic analyses of RPE and photoreceptor (PR) cell transcriptomic data identified conserved and overrepresented transcription factor regulatory elements (TFREs, 8-19 bp) specifically associated with transcriptionally active RPE genes. Both RPE-specific TFREs and those derived from the generically active cytomegalovirus-immediate early (CMV-IE) promoter were then screened in vitro to identify sequence elements able to control recombinant gene transcription in model induced pluripotent stem (iPS)-derived and primary human RPE cells. Two libraries of heterotypic synthetic promoters varying in predicted RPE specificity and transcriptional activity were designed de novo using combinations of up to 20 discrete TFREs in series (323-602 bp) and their transcriptional activity in model RPE cells was compared to that of the endogenous BEST1 promoter (661 bp, plus an engineered derivative) and the highly active generic CMV-IE promoter (650 bp). Synthetic promoters with a highpredicted specificity, comprised predominantly of endogenous TFREs exhibited a range of activities up to 8-fold that of the RPE-specific BEST1 gene promoter. Moreover, albeit at a lower predicted specificity, synthetic promoter transcriptional activity in model RPE cells was enhanced beyond that of the CMV-IE promoter when viral elements were utilized in combination with endogenous RPE-specific TFREs, with a reduction in promoter size of 15%. Taken together, while our data reveal an inverse relationship between synthetic promoter activity and cell-type specificity, cell context-specific control of recombinant gene transcriptional activity may be achievable.
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http://dx.doi.org/10.1002/bit.27713DOI Listing
February 2021

A co-receptor that represses beta-cell insulin action.

Nat Metab 2021 Feb;3(2):126-127

Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1038/s42255-021-00352-4DOI Listing
February 2021

Maintaining Standards in Colorectal Cancer Surgery During the Global Pandemic: A Cohort Study.

World J Surg 2021 03 9;45(3):655-661. Epub 2021 Jan 9.

Department of Colorectal Surgery, Oxford University Hospitals NHS Trust, Oxford, UK.

Aim: Cancer surgery in the COVID-19 pandemic presents many new challenges. For each patient, the risk of contracting COVID-19 during the perioperative period, with the potential for life-threatening sequelae (1), has to be weighed against the risk of delaying treatment. We assessed the response and short-term outcomes from elective colorectal cancer surgery during the pandemic at our institution.

Method: We report a prospective cohort study of all elective colorectal surgery cases performed at our Trust during the 11 weeks following the national UK lockdown on 23rd March 2020, compared with the same time period in 2019.

Results: Eighty-five colorectal operations were performed during the 2020 (COVID) time period, and 179 performed in the 2019 (non-COVID) time period. A significantly higher proportion of cases during the COVID period were cancer-related (66% vs 26%, p < 0.00001). There was no difference in length of hospital stay, complications or readmissions. There were no mortalities in either cohort. Among the cancer patients, there were no differences in TMN staging, R1 resection rate or lymph node yields. No elective patient tested positive for COVID-19 during the perioperative period.

Conclusion: At the height of the COVID pandemic, we maintained delivery the of high-quality elective colorectal cancer surgery, with no worsening of short-term outcomes and no compromise in the quality of cancer resections. Ongoing monitoring of this cohort is essential. The risks associated with COVID-19 will continue for some time, necessitating adaptive responses to maintain high-quality cancer services.
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http://dx.doi.org/10.1007/s00268-020-05928-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796814PMC
March 2021

Plasma Bile Acids More Closely Align With Insulin Resistance, Visceral and Hepatic Adiposity Than Total Adiposity.

J Clin Endocrinol Metab 2021 Mar;106(3):e1131-e1139

Department of Endocrinology & Diabetes, St Vincent's Hospital, Darlinghurst, Sydney, New South Wales, Australia.

Context: The etiological mechanism of bile acid (BA) effects on insulin resistance and obesity is unknown.

Objective: This work aimed to determine whether plasma BAs are elevated in human obesity and/or insulin resistance.

Methods: This observational study was conducted at an academic research center. Seventy-one adult volunteers formed 4 groups: lean insulin-sensitive (body mass index [BMI] ≤ 25 kg/m2, Homeostatic Model Assessment of Insulin Resistance [HOMA-IR] < 2.0, n = 19), overweight/obese nondiabetic who were either insulin sensitive (Obsensitive, BMI > 25 kg/m2, HOMA-IR < 1.5, n = 11) or insulin resistant (Obresistant, BMI > 25 kg/m2, HOMA-IR > 3.0, n = 20), and type 2 diabetes (T2D, n = 21). Main outcome measures included insulin sensitivity by hyperinsulinemic-euglycemic clamp, body composition by dual energy x-ray absorptiometry, abdominal fat distribution, and liver density by computed tomography and plasma BA.

Results: In the Obresistant group, glucose infusion rate/fat-free mass (GIR/FFM, an inverse measure of insulin resistance) was significantly lower, and visceral and liver fat higher, compared to lean and Obsensitive individuals, despite similar total adiposity in Obresistant and Obsensitive. Total BA concentrations were higher in Obresistant (2.62 ± 0.333 mmol/L, P = .03) and T2D (3.36 ± 0.582 mmol/L, P < .001) vs Obsensitive (1.16 ± 0.143 mmol/L), but were similar between Obsensitive and lean (2.31 ± 0.329 mmol/L) individuals. Total BAs were positively associated with waist circumference (R = 0.245, P = .041), visceral fat (R = 0.360, P = .002), and fibroblast growth factor 21 (R = 0.341, P = .004) and negatively associated with insulin sensitivity (R = -0.395, P = .001), abdominal subcutaneous fat (R = -0.352, P = .003), adiponectin (R = -0.375, P = .001), and liver fat (Hounsfield units, an inverse marker of liver fat, R = -0.245, P = .04). Conjugated BAs were additionally elevated in T2D individuals (P < .001).

Conclusions: BA concentrations correlated with abdominal, visceral, and liver fat in humans, though an etiological role in insulin resistance remains to be verified.
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http://dx.doi.org/10.1210/clinem/dgaa940DOI Listing
March 2021

Defining the protein and lipid constituents of tubular recycling endosomes.

J Biol Chem 2020 Dec 17. Epub 2020 Dec 17.

Biochemistry and Molecular Biology, University of Nebraska Medical Center, United States.

Once internalized, receptors reach the sorting endosome (SE) and are either targeted for degradation or recycled to the plasma membrane, a process mediated at least in part by tubular recycling endosomes (TRE). TRE may be efficient for sorting due to the ratio of large surface membrane area to luminal volume; following receptor segregation, TRE fission likely releases receptor-laden tubules and vesicles for recycling. Despite the importance of TRE networks for recycling, these unique structures remain poorly understood, and unresolved questions relate to their lipid and protein composition, and biogenesis. Our previous studies have depicted the endocytic protein MICAL-L1 as an essential TRE constituent, and newer studies show a similar localization for the GTP-binding protein Rab10. We demonstrate that TRE are enriched in both phosphatidic acid (PA) and phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), supporting the idea of MICAL-L1 recruitment by PA and Rab10 recruitment via PI(4,5)P2. Using siRNA knock-down, we demonstrate that Rab10-marked TRE remain prominent in cells upon MICAL-L1 or Syndapin2 depletion. However, depletion of Rab10 or its interaction partner, EHBP1, led to loss of MICAL-L1-marked TRE. We next used phospholipase D inhibitors to decrease PA synthesis, acutely disrupt TRE, and enable monitoring of TRE regeneration after inhibitor washout. Rab10 depletion prevented TRE regeneration, whereas MICAL-L1 knock-down did not. Surprisingly, EHBP1 depletion did not affect TRE regeneration under these conditions. Overall, our study supports a primary role for Rab10 and the requirement for PA and PI(4,5)P2 in TRE biogenesis and regeneration, with Rab10 likely linking SE to motor proteins and the microtubule network.
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http://dx.doi.org/10.1074/jbc.RA120.015992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948492PMC
December 2020

CASK modulates the assembly and function of the Mint1/Munc18-1 complex to regulate insulin secretion.

Cell Discov 2020 Dec 15;6(1):92. Epub 2020 Dec 15.

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China.

Calcium/calmodulin-dependent protein serine kinase (CASK) is a key player in vesicle transport and release in neurons. However, its precise role, particularly in nonneuronal systems, is incompletely understood. We report that CASK functions as an important regulator of insulin secretion. CASK depletion in mouse islets/β cells substantially reduces insulin secretion and vesicle docking/fusion. CASK forms a ternary complex with Mint1 and Munc18-1, and this event is regulated by glucose stimulation in β cells. The crystal structure of the CASK/Mint1 complex demonstrates that Mint1 exhibits a unique "whip"-like structure that wraps tightly around the CASK-CaMK domain, which contains dual hydrophobic interaction sites. When triggered by CASK binding, Mint1 modulates the assembly of the complex. Further investigation revealed that CASK-Mint1 binding is critical for ternary complex formation, thereby controlling Munc18-1 membrane localization and insulin secretion. Our work illustrates the distinctive molecular basis underlying CASK/Mint1/Munc18-1 complex formation and reveals the importance of the CASK-Mint1-Munc18 signaling axis in insulin secretion.
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http://dx.doi.org/10.1038/s41421-020-00216-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736295PMC
December 2020

Mesenchymal Stem Cells Successfully Deliver Oncolytic Virotherapy to Diffuse Intrinsic Pontine Glioma.

Clin Cancer Res 2021 Mar 3;27(6):1766-1777. Epub 2020 Dec 3.

Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

Purpose: Diffuse intrinsic pontine glioma (DIPG) is among the deadliest of pediatric brain tumors. Radiotherapy is the standard-of-care treatment for DIPG, but offers only transient relief of symptoms for patients with DIPG without providing significant survival benefit. Oncolytic virotherapy is an anticancer treatment that has been investigated for treating various types of brain tumors.

Experimental Design: Here, we have explored the use of mesenchymal stem cells (MSC) for oncolytic virus (OV) delivery and evaluated treatment efficacy using preclinical models of DIPG. The survivin promoter drives the conditional replication of OV used in our studies. The efficiency of OV entry into the cells is mediated by fiber modification with seven lysine residues (CRAd.S.pK7). Patients' samples and cell lines were analyzed for the expression of viral entry proteins and survivin. The ability of MSCs to deliver OV to DIPG was studied in the context of a low dose of irradiation.

Results: Our results show that DIPG cells and tumors exhibit robust expression of cell surface proteins and survivin that enable efficient OV entry and replication in DIPG cells. MSCs loaded with OV disseminate within a tumor and release OV throughout the DIPG brainstem xenografts in mice. Administration of OV-loaded MSCs with radiotherapy to mice bearing brainstem DIPG xenografts results in more prolonged survival relative to that conferred by either therapy alone ( < 0.01).

Conclusions: Our study supports OV, CRAd.S.pK7, encapsulated within MSCs as a therapeutic strategy that merits further investigation and potential translation for DIPG treatment.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956061PMC
March 2021

Calibration methods of charge sensitive amplifiers at the Colorado dust accelerator.

Rev Sci Instrum 2020 Nov;91(11):113301

Institute for Modeling Plasmas, Atmospheres, and Cosmic Dust (IMPACT), University of Colorado, Boulder, Colorado 80303, USA.

Charge sensitive amplifiers (CSAs) are electronic integrating circuits frequently used for detecting quick charge pulses such as those produced in semiconductor detector devices and electron multipliers. One of the limitations of highly sensitive CSA circuits is the accuracy with which they can be calibrated due to the necessity of using injection capacitors on the order of a few pF, which are difficult to calibrate and to disentangle from other stray capacitance in calibration circuits. This paper presents an alternate method for calibrating the electronics for CSAs with conductive detectors, referred to as the "external conductor" method, using the detector itself to form the injection circuit. The external conductor method is compared to the traditional injection capacitor method for an example detector. The new method results in an increase to the calibration factor of up to 70% over the value derived from a traditional injection capacitor, with an uncertainty in the new value of 2%. Finally, the results from the external conductor method are compared to a third, independent approach, which uses reference charged particles as calibration sources in the Colorado dust accelerator. The results of the charged particle approach corroborate the external conductor calibration to within the stated uncertainty.
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http://dx.doi.org/10.1063/5.0020018DOI Listing
November 2020

Production of trimeric SARS-CoV-2 spike protein by CHO cells for serological COVID-19 testing.

Biotechnol Bioeng 2021 02 11;118(2):1013-1021. Epub 2020 Nov 11.

Department of Chemical and Biological Engineering, University of Sheffield, Mappin St., Sheffield, UK.

We describe scalable and cost-efficient production of full length, His-tagged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein trimer by Chinese hamster ovary (CHO) cells that can be used to detect SARS-CoV-2 antibodies in patient sera at high specificity and sensitivity. Transient production of spike in both human embryonic kidney (HEK) and CHO cells mediated by polyethyleneimine was increased significantly (up to 10.9-fold) by a reduction in culture temperature to 32°C to permit extended duration cultures. Based on these data GS-CHO pools stably producing spike trimer under the control of a strong synthetic promoter were cultured in hypothermic conditions with combinations of bioactive small molecules to increase yield of purified spike product 4.9-fold to 53 mg/L. Purification of recombinant spike by Ni-chelate affinity chromatography initially yielded a variety of co-eluting protein impurities identified as host cell derived by mass spectrometry, which were separated from spike trimer using a modified imidazole gradient elution. Purified CHO spike trimer antigen was used in enzyme-linked immunosorbent assay format to detect immunoglobulin G antibodies against SARS-CoV-2 in sera from patient cohorts previously tested for viral infection by polymerase chain reaction, including those who had displayed coronavirus disease 2019 (COVID-19) symptoms. The antibody assay, validated to ISO 15189 Medical Laboratories standards, exhibited a specificity of 100% and sensitivity of 92.3%. Our data show that CHO cells are a suitable host for the production of larger quantities of recombinant SARS-CoV-2 trimer which can be used as antigen for mass serological testing.
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http://dx.doi.org/10.1002/bit.27615DOI Listing
February 2021

Gravitational Test beyond the First Post-Newtonian Order with the Shadow of the M87 Black Hole.

Authors:
Dimitrios Psaltis Lia Medeiros Pierre Christian Feryal Özel Kazunori Akiyama Antxon Alberdi Walter Alef Keiichi Asada Rebecca Azulay David Ball Mislav Baloković John Barrett Dan Bintley Lindy Blackburn Wilfred Boland Geoffrey C Bower Michael Bremer Christiaan D Brinkerink Roger Brissenden Silke Britzen Dominique Broguiere Thomas Bronzwaer Do-Young Byun John E Carlstrom Andrew Chael Chi-Kwan Chan Shami Chatterjee Koushik Chatterjee Ming-Tang Chen Yongjun Chen Ilje Cho John E Conway James M Cordes Geoffrey B Crew Yuzhu Cui Jordy Davelaar Mariafelicia De Laurentis Roger Deane Jessica Dempsey Gregory Desvignes Jason Dexter Ralph P Eatough Heino Falcke Vincent L Fish Ed Fomalont Raquel Fraga-Encinas Per Friberg Christian M Fromm Charles F Gammie Roberto García Olivier Gentaz Ciriaco Goddi José L Gómez Minfeng Gu Mark Gurwell Kazuhiro Hada Ronald Hesper Luis C Ho Paul Ho Mareki Honma Chih-Wei L Huang Lei Huang David H Hughes Makoto Inoue Sara Issaoun David J James Buell T Jannuzi Michael Janssen Wu Jiang Alejandra Jimenez-Rosales Michael D Johnson Svetlana Jorstad Taehyun Jung Mansour Karami Ramesh Karuppusamy Tomohisa Kawashima Garrett K Keating Mark Kettenis Jae-Young Kim Junhan Kim Jongsoo Kim Motoki Kino Jun Yi Koay Patrick M Koch Shoko Koyama Michael Kramer Carsten Kramer Thomas P Krichbaum Cheng-Yu Kuo Tod R Lauer Sang-Sung Lee Yan-Rong Li Zhiyuan Li Michael Lindqvist Rocco Lico Jun Liu Kuo Liu Elisabetta Liuzzo Wen-Ping Lo Andrei P Lobanov Colin Lonsdale Ru-Sen Lu Jirong Mao Sera Markoff Daniel P Marrone Alan P Marscher Iván Martí-Vidal Satoki Matsushita Yosuke Mizuno Izumi Mizuno James M Moran Kotaro Moriyama Monika Moscibrodzka Cornelia Müller Gibwa Musoke Alejandro Mus Mejías Hiroshi Nagai Neil M Nagar Ramesh Narayan Gopal Narayanan Iniyan Natarajan Roberto Neri Aristeidis Noutsos Hiroki Okino Héctor Olivares Tomoaki Oyama Daniel C M Palumbo Jongho Park Nimesh Patel Ue-Li Pen Vincent Piétu Richard Plambeck Aleksandar PopStefanija Ben Prather Jorge A Preciado-López Venkatessh Ramakrishnan Ramprasad Rao Mark G Rawlings Alexander W Raymond Bart Ripperda Freek Roelofs Alan Rogers Eduardo Ros Mel Rose Arash Roshanineshat Helge Rottmann Alan L Roy Chet Ruszczyk Benjamin R Ryan Kazi L J Rygl Salvador Sánchez David Sánchez-Arguelles Mahito Sasada Tuomas Savolainen F Peter Schloerb Karl-Friedrich Schuster Lijing Shao Zhiqiang Shen Des Small Bong Won Sohn Jason SooHoo Fumie Tazaki Remo P J Tilanus Michael Titus Pablo Torne Tyler Trent Efthalia Traianou Sascha Trippe Ilse van Bemmel Huib Jan van Langevelde Daniel R van Rossum Jan Wagner John Wardle Derek Ward-Thompson Jonathan Weintroub Norbert Wex Robert Wharton Maciek Wielgus George N Wong Qingwen Wu Doosoo Yoon André Young Ken Young Ziri Younsi Feng Yuan Ye-Fei Yuan Shan-Shan Zhao

Phys Rev Lett 2020 Oct;125(14):141104

Department of Astrophysics, Institute for Mathematics, Astrophysics and Particle Physics (IMAPP), Radboud University, P.O. Box 9010, 6500 GL Nijmegen, Netherlands.

The 2017 Event Horizon Telescope (EHT) observations of the central source in M87 have led to the first measurement of the size of a black-hole shadow. This observation offers a new and clean gravitational test of the black-hole metric in the strong-field regime. We show analytically that spacetimes that deviate from the Kerr metric but satisfy weak-field tests can lead to large deviations in the predicted black-hole shadows that are inconsistent with even the current EHT measurements. We use numerical calculations of regular, parametric, non-Kerr metrics to identify the common characteristic among these different parametrizations that control the predicted shadow size. We show that the shadow-size measurements place significant constraints on deviation parameters that control the second post-Newtonian and higher orders of each metric and are, therefore, inaccessible to weak-field tests. The new constraints are complementary to those imposed by observations of gravitational waves from stellar-mass sources.
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http://dx.doi.org/10.1103/PhysRevLett.125.141104DOI Listing
October 2020

Heparan Sulfate Synthesized by Regulates Receptor Tyrosine Kinase Signaling and Promotes Resistance to EGFR Inhibitors in GBM.

Mol Cancer Res 2021 01 7;19(1):150-161. Epub 2020 Oct 7.

Department of Neurological Surgery, Brain Tumor Center, University of California, San Francisco, San Francisco, California.

Signaling from multiple receptor tyrosine kinases (RTK) contributes to therapeutic resistance in glioblastoma (GBM). Heparan sulfate (HS), present on cell surfaces and in the extracellular matrix, regulates cell signaling via several mechanisms. To investigate the role for HS in promoting RTK signaling in GBM, we generated neural progenitor cells deficient for HS by knockout of the essential HS-biosynthetic enzyme , and studied tumor initiation and progression. HS-null cells had decreased proliferation, invasion, and reduced activation of multiple RTKs compared with control. tumor establishment was significantly decreased, and rate of tumor growth reduced with HS-deficient cells implanted in an HS-poor microenvironment. To investigate if HS regulates RTK activation through platelet-derived growth factor receptor α (PDGFRα) signaling, we removed cell surface HS in patient-derived GBM lines and identified reduced cell surface PDGF-BB ligand. Reduced ligand levels were associated with decreased phosphorylation of PDGFRα, suggesting HS promotes ligand-receptor interaction. Using human GBM tumorspheres and a murine GBM model, we show that ligand-mediated signaling can partially rescue cells from targeted RTK inhibition and that this effect is regulated by HS. Indeed, tumor cells deficient for HS had increased sensitivity to EGFR inhibition and . IMPLICATIONS: Our study shows that HS expressed on tumor cells and in the tumor microenvironment regulates ligand-mediated signaling, promoting tumor cell proliferation and invasion, and these factors contribute to decreased tumor cell response to targeted RTK inhibition.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785678PMC
January 2021

Kinetic Trans-omic Analysis Reveals Key Regulatory Mechanisms for Insulin-Regulated Glucose Metabolism in Adipocytes.

iScience 2020 Aug 20;23(9):101479. Epub 2020 Aug 20.

Molecular Genetics Research Laboratory, Graduate School of Science, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, Japan; Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address:

Insulin regulates glucose metabolism through thousands of regulatory mechanisms; however, which regulatory mechanisms are keys to control glucose metabolism remains unknown. Here, we performed kinetic trans-omic analysis by integrating isotope-tracing glucose flux and phosphoproteomic data from insulin-stimulated adipocytes and built a kinetic mathematical model to identify key allosteric regulatory and phosphorylation events for enzymes. We identified nine reactions regulated by allosteric effectors and one by enzyme phosphorylation and determined the regulatory mechanisms for three of these reactions. Insulin stimulated glycolysis by promoting Glut4 activity by enhancing phosphorylation of AS160 at S595, stimulated fatty acid synthesis by promoting Acly activity through allosteric activation by glucose 6-phosphate or fructose 6-phosphate, and stimulated glutamate synthesis by alleviating allosteric inhibition of Gls by glutamate. Most of glycolytic reactions were regulated by amounts of substrates and products. Thus, phosphorylation or allosteric modulator-based regulation of only a few key enzymes was sufficient to change insulin-induced metabolism.
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http://dx.doi.org/10.1016/j.isci.2020.101479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479629PMC
August 2020

Insulin signaling requires glucose to promote lipid anabolism in adipocytes.

J Biol Chem 2020 09 28;295(38):13250-13266. Epub 2020 Jul 28.

School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. Electronic address:

Adipose tissue is essential for metabolic homeostasis, balancing lipid storage and mobilization based on nutritional status. This is coordinated by insulin, which triggers kinase signaling cascades to modulate numerous metabolic proteins, leading to increased glucose uptake and anabolic processes like lipogenesis. Given recent evidence that glucose is dispensable for adipocyte respiration, we sought to test whether glucose is necessary for insulin-stimulated anabolism. Examining lipogenesis in cultured adipocytes, glucose was essential for insulin to stimulate the synthesis of fatty acids and glyceride-glycerol. Importantly, glucose was dispensable for lipogenesis in the absence of insulin, suggesting that distinct carbon sources are used with or without insulin. Metabolic tracing studies revealed that glucose was required for insulin to stimulate pathways providing carbon substrate, NADPH, and glycerol 3-phosphate for lipid synthesis and storage. Glucose also displaced leucine as a lipogenic substrate and was necessary to suppress fatty acid oxidation. Together, glucose provided substrates and metabolic control for insulin to promote lipogenesis in adipocytes. This contrasted with the suppression of lipolysis by insulin signaling, which occurred independently of glucose. Given previous observations that signal transduction acts primarily before glucose uptake in adipocytes, these data are consistent with a model whereby insulin initially utilizes protein phosphorylation to stimulate lipid anabolism, which is sustained by subsequent glucose metabolism. Consequently, lipid abundance was sensitive to glucose availability, both during adipogenesis and in flies Together, these data highlight the importance of glucose metabolism to support insulin action, providing a complementary regulatory mechanism to signal transduction to stimulate adipose anabolism.
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http://dx.doi.org/10.1074/jbc.RA120.014907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504926PMC
September 2020

All major cholesterol-dependent cytolysins use glycans as cellular receptors.

Sci Adv 2020 May 22;6(21):eaaz4926. Epub 2020 May 22.

Institute for Glycomics, Griffith University, Gold Coast, QLD 4222, Australia.

Cholesterol-dependent cytolysins (CDCs) form pores in cholesterol-rich membranes, but cholesterol alone is insufficient to explain their cell and host tropism. Here, we show that all eight major CDCs have high-affinity lectin activity that identifies glycans as candidate cellular receptors. Streptolysin O, vaginolysin, and perfringolysin O bind multiple glycans, while pneumolysin, lectinolysin, and listeriolysin O recognize a single glycan class. Addition of exogenous carbohydrate receptors for each CDC inhibits toxin activity. We present a structure for suilysin domain 4 in complex with two distinct glycan receptors, P antigen and αGal/Galili. We report a wide range of binding affinities for cholesterol and for the cholesterol analog pregnenolone sulfate and show that CDCs bind glycans and cholesterol independently. Intermedilysin binds to the sialyl-TF -glycan on its erythrocyte receptor, CD59. Removing sialyl-TF from CD59 reduces intermedilysin binding. Glycan-lectin interactions underpin the cellular tropism of CDCs and provide molecular targets to block their cytotoxic activity.
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http://dx.doi.org/10.1126/sciadv.aaz4926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244308PMC
May 2020

Core functional nodes and sex-specific pathways in human ischaemic and dilated cardiomyopathy.

Nat Commun 2020 06 2;11(1):2843. Epub 2020 Jun 2.

Precision Cardiovascular Laboratory, The University of Sydney, Sydney, NSW, Australia.

Poor access to human left ventricular myocardium is a significant limitation in the study of heart failure (HF). Here, we utilise a carefully procured large human heart biobank of cryopreserved left ventricular myocardium to obtain direct molecular insights into ischaemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM), the most common causes of HF worldwide. We perform unbiased, deep proteomic and metabolomic analyses of 51 left ventricular (LV) samples from 44 cryopreserved human ICM and DCM hearts, compared to age-, gender-, and BMI-matched, histopathologically normal, donor controls. We report a dramatic reduction in serum amyloid A1 protein in ICM hearts, perturbed thyroid hormone signalling pathways and significant reductions in oxidoreductase co-factor riboflavin-5-monophosphate and glycolytic intermediate fructose-6-phosphate in both; unveil gender-specific changes in HF, including nitric oxide-related arginine metabolism, mitochondrial substrates, and X chromosome-linked protein and metabolite changes; and provide an interactive online application as a publicly-available resource.
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http://dx.doi.org/10.1038/s41467-020-16584-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266817PMC
June 2020

Thalamic and prefrontal GABA concentrations but not GABA receptor densities are altered in high-functioning adults with autism spectrum disorder.

Mol Psychiatry 2020 May 6. Epub 2020 May 6.

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 94305, USA.

The gamma aminobutyric acid (GABA) neurotransmission system has been implicated in autism spectrum disorder (ASD). Molecular neuroimaging studies incorporating simultaneous acquisitions of GABA concentrations and GABA receptor densities can identify objective molecular markers in ASD. We measured both total GABA receptor densities by using [F]flumazenil positron emission tomography ([F]FMZ-PET) and GABA concentrations by using proton magnetic resonance spectroscopy (H-MRS) in 28 adults with ASD and 29 age-matched typically developing (TD) individuals. Focusing on the bilateral thalami and the left dorsolateral prefrontal cortex (DLPFC) as our regions of interest, we found no differences in GABA receptor densities between ASD and TD groups. However, H-MRS measurements revealed significantly higher GABA/Water (GABA normalized by water signal) in the left DLPFC of individuals with ASD than that of TD controls. Furthermore, a significant gender effect was observed in the thalami, with higher GABA/Water in males than in females. Hypothesizing that thalamic GABA correlates with ASD symptom severity in gender-specific ways, we stratified by diagnosis and investigated the interaction between gender and thalamic GABA/Water in predicting Autism-Spectrum Quotient (AQ) and Ritvo Autism Asperger's Diagnostic Scale-Revised (RAADS-R) total scores. We found that gender is a significant effect modifier of thalamic GABA/Water's relationship with AQ and RAADS-R scores for individuals with ASD, but not for TD controls. When we separated the ASD participants by gender, a negative correlation between thalamic GABA/Water and AQ was observed in male ASD participants. Remarkably, in female ASD participants, a positive correlation between thalamic GABA/Water and AQ was found.
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http://dx.doi.org/10.1038/s41380-020-0756-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644591PMC
May 2020