Publications by authors named "Matthew Baker"

408 Publications

Old age genetically confirmed frontotemporal lobar degeneration with TDP-43 has limbic predominant TDP-43 deposition.

Neuropathol Appl Neurobiol 2021 May 9. Epub 2021 May 9.

Department of Neurology, Mayo Clinic, 200 1stStreet SW, Rochester, MN, 55905, USA.

Aims: To assess the burden of transactive response DNA-binding protein of 43kDa (TDP-43) inclusions in a unique cohort of old-age patients with genetic-frontotemporal lobar degeneration (gFTLD-TDP) and compare these patients with sporadic old-age individuals with TDP-43, either in the presence of Alzheimer's disease (AD-TDP) or in isolation (pure-TDP).

Methods: The brain bank at Mayo Clinic-Jacksonville was searched for cases ≥75 years old at death with TDP-43 extending into middle frontal cortex. Cases were split into the following groups: 1) gFTLD-TDP (n=15) with progranulin (GRN)/C9ORF72 mutations; 2) AD-TDP (n=10)-cases with median Braak neurofibrillary tangle (NFT) stage VI, Thal phase V; 3) pure-TDP (n=10)-cases with median Braak NFT stage I, Thal phase I. Clinical data were abstracted; TDP-43 burden was calculated using digital pathology.

Results: Amnestic Alzheimer's dementia was the clinical diagnosis in ≥50% patients in each group. The distribution of TDP-43 burden in gFTLD-TDP and AD-TDP, but not pure-TDP, was limbic-predominant targeting CA1 and subiculum. Patients with gFTLD-TDP had higher burden in entorhinal cortex compared to AD-TDP.TDP-43 burden in middle frontal cortex did not differ between the three groups.

Conclusions: In old age it is challenging to clinically and pathologically differentiate gFTLD-TDP from AD-TDP and pure-TDP-43 based on burden. Like AD-TDP, old age gFTLD-TDP have a limbic predominant TDP-43 distribution. Given that amnestic Alzheimer's dementia was the most common clinical diagnosis regardless of group suggests that TDP-43 directly and indirectly targets limbic regions.
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http://dx.doi.org/10.1111/nan.12727DOI Listing
May 2021

Bioprinting Via a Dual-Gel Bioink Based on Poly(Vinyl Alcohol) and Solubilized Extracellular Matrix towards Cartilage Engineering.

Int J Mol Sci 2021 Apr 9;22(8). Epub 2021 Apr 9.

MERLN Institute for Technology Inspired Regenerative Medicine, Complex Tissue Regeneration, Maastricht University, 6229 Maastricht, The Netherlands.

Various hydrogel systems have been developed as biomaterial inks for bioprinting, including natural and synthetic polymers. However, the available biomaterial inks, which allow printability, cell viability, and user-defined customization, remains limited. Incorporation of biological extracellular matrix materials into tunable synthetic polymers can merge the benefits of both systems towards versatile materials for biofabrication. The aim of this study was to develop novel, cell compatible dual-component biomaterial inks and bioinks based on poly(vinyl alcohol) (PVA) and solubilized decellularized cartilage matrix (SDCM) hydrogels that can be utilized for cartilage bioprinting. In a first approach, PVA was modified with amine groups (PVA-A), and mixed with SDCM. The printability of the PVA-A/SDCM formulations cross-linked by genipin was evaluated. On the second approach, the PVA was functionalized with cis-5-norbornene-endo-2,3-dicarboxylic anhydride (PVA-Nb) to allow an ultrafast light-curing thiol-ene cross-linking. Comprehensive experiments were conducted to evaluate the influence of the SDCM ratio in mechanical properties, water uptake, swelling, cell viability, and printability of the PVA-based formulations. The studies performed with the PVA-A/SDCM formulations cross-linked by genipin showed printability, but poor shape retention due to slow cross-linking kinetics. On the other hand, the PVA-Nb/SDCM showed good printability. The results showed that incorporation of SDCM into PVA-Nb reduces the compression modulus, enhance cell viability, and bioprintability and modulate the swelling ratio of the resulted hydrogels. Results indicated that PVA-Nb hydrogels containing SDCM could be considered as versatile bioinks for cartilage bioprinting.
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http://dx.doi.org/10.3390/ijms22083901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069267PMC
April 2021

How mutations in RYR1 that cause malignant hyperthermia increase RYR1 sensitivity to activators.

Cell Calcium 2021 Apr 19;97:102412. Epub 2021 Apr 19.

Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, United States. Electronic address:

New electron cryomicroscopy structures of RYR1 show that mutations associated with Malignant Hyperthermia drive conformational changes in the cytoplasmic domains of the closed channel to more closely resemble those of the open channel.
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http://dx.doi.org/10.1016/j.ceca.2021.102412DOI Listing
April 2021

Underlying pathology identified after 20 years of disease course in two cases of slowly progressive frontotemporal dementia syndromes.

Neurocase 2021 Apr 27:1-11. Epub 2021 Apr 27.

Departments of Neurology, Mayo Clinic Rochester, Minnesota, USA.

We report two cases from the frontotemporal lobar degeneration (FTLD) spectrum with remarkably slow progression. The first case demonstrated insidious-onset behavioral symptoms and personality changes resembling behavioral variant of frontotemporal dementia, followed a benign course over 26 years, his brain autopsy revealed the diffuse form of argyrophilic grain disease. The second case presented with slowly progressive cognitive and motor deficits, reminiscent of the corticobasal syndrome, deteriorated slowly over 22 years, his brain autopsy revealed FTLD-TDP with C9ORF72 pathology. These two cases confirm the notion of slowly progressive frontotemporal lobar degeneration caused by an underlying FTLD pathology, rather than a phenocopy.
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http://dx.doi.org/10.1080/13554794.2021.1918723DOI Listing
April 2021

Long-read targeted sequencing uncovers clinicopathological associations for C9orf72-linked diseases.

Brain 2021 May;144(4):1082-1088

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

To examine the length of a hexanucleotide expansion in C9orf72, which represents the most frequent genetic cause of frontotemporal lobar degeneration and motor neuron disease, we employed a targeted amplification-free long-read sequencing technology: No-Amp sequencing. In our cross-sectional study, we assessed cerebellar tissue from 28 well-characterized C9orf72 expansion carriers. We obtained 3507 on-target circular consensus sequencing reads, of which 814 bridged the C9orf72 repeat expansion (23%). Importantly, we observed a significant correlation between expansion sizes obtained using No-Amp sequencing and Southern blotting (P = 5.0 × 10-4). Interestingly, we also detected a significant survival advantage for individuals with smaller expansions (P = 0.004). Additionally, we uncovered that smaller expansions were significantly associated with higher levels of C9orf72 transcripts containing intron 1b (P = 0.003), poly(GP) proteins (P = 1.3 × 10- 5), and poly(GA) proteins (P = 0.005). Thorough examination of the composition of the expansion revealed that its GC content was extremely high (median: 100%) and that it was mainly composed of GGGGCC repeats (median: 96%), suggesting that expanded C9orf72 repeats are quite pure. Taken together, our findings demonstrate that No-Amp sequencing is a powerful tool that enables the discovery of relevant clinicopathological associations, highlighting the important role played by the cerebellar size of the expanded repeat in C9orf72-linked diseases.
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http://dx.doi.org/10.1093/brain/awab006DOI Listing
May 2021

Subvisible Particles in Solutions of Remicade in Intravenous Saline Activate Immune System Pathways in In Vitro Human Cell Systems.

J Pharm Sci 2021 Apr 14. Epub 2021 Apr 14.

Department of Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, 80045. Electronic address:

Among patients that receive Remicade® therapy, more than 20% have adverse infusion related reactions and approximately 50% have immunogenic responses. Upon characterization of initial Remicade®-IV solution we observed a high concentration of subvisible particles that could inadvertently be delivered to patients. This solution was processed through the IV infusion system, mimicking the typical clinical administration setup - either with or without an in-line filter connected to the IV line. The samples generated thereafter were tested using various in vitro assays for activation of the innate immune system via cytokine release in whole blood and in peripheral blood mononuclear cell (PBMC) cultures, and activation of the Toll like receptors (TLRs). Activation of the adaptive immune system was evaluated by monitoring upregulation of surface receptors on dendritic cells (DCs) and CD4+ T cell proliferation in response to IV solution of Remicade®. Our results indicate that subvisible particles in Remicade®-saline solution have a significant role in activation of the immune system but there are extrinsic factors potentially contributed by the in-line filters or other process parameters that also contribute to immune system activation.
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http://dx.doi.org/10.1016/j.xphs.2021.04.005DOI Listing
April 2021

Social Determinants Matter For Hospital Readmission Policy: Insights From New York City.

Health Aff (Millwood) 2021 Apr;40(4):645-654

Merle Haberman is the senior director of health system economics, data, and analysis, Association of American Medical Colleges.

This study assessed the impact of individual social risk factor variables and social determinants of health (SDOH) measures on hospital readmission rates and penalties used in the Centers for Medicare and Medicaid Services (CMS) Hospital Readmissions Reduction Program (HRRP). Using 2012-16 hospital discharge data from New York City, we projected HRRP penalties by augmenting CMS's readmission model for heart attack, heart failure, and pneumonia with SDOH scores constructed at each of four geographic levels and a measure of individual-level social risk. Including additional SDOH scores in the model, especially those constructed with the most granular geographic data, along with social risk factor variables substantially affects projected penalties for hospitals treating the highest proportion of patients with high SDOH scores. Improved performance occurred even after we included peer-group stratification in the HRRP model pursuant to the 21st Century Cures Act. Small improvements in model accuracy were associated with substantial shifts in projected performance. Our results suggest that CMS's continued omission of relevant patient and geographic data from the HRRP readmission model misallocates penalties attributable to SDOH and social risk factor effects to hospitals with the largest share of high-risk patients.
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http://dx.doi.org/10.1377/hlthaff.2020.01742DOI Listing
April 2021

Corrigendum: Ancestral Sequence Reconstructions of MotB Are Proton-Motile and Require MotA for Motility.

Front Microbiol 2021 19;12:650373. Epub 2021 Mar 19.

School of Biotechnology and Biomolecular Sciences (BABS), University of New South Wales, Sydney, NSW, Australia.

[This corrects the article DOI: 10.3389/fmicb.2020.625837.].
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http://dx.doi.org/10.3389/fmicb.2021.650373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017333PMC
March 2021

Neurobehavioral Characteristics of FDG-PET Defined Right-Dominant Semantic Dementia: A Longitudinal Study.

Dement Geriatr Cogn Disord 2021 Mar 23:1-12. Epub 2021 Mar 23.

Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA,

Introduction: Semantic dementia (SD) is characterized by fluent speech, anomia, and loss of word and object knowledge with varying degrees of right and left anterior-medial temporal lobe hypometabolism on [18F] fluorodeoxyglucose (FDG)-PET. We assessed neurobehavioral features in SD patients across 3 FDG-PET-defined metabolic patterns and investigated progression over time.

Methods: Thirty-four patients with SD who completed FDG-PET were classified into a left- and right-dominant group based on the degree of hypometabolism in each temporal lobe. The left-dominant group was further subdivided depending on whether hypometabolism in the right temporal lobe was more or less than 2 standard deviations from controls (left+ group). Neurobehavioral characteristics determined using the Neuropsychiatric Inventory Questionnaire (NPI-Q) were compared across groups. Progression of NPI-Q scores and FDG-PET hypometabolism was assessed in 14 patients with longitudinal follow-up.

Results: The right-dominant group performed worse on the NPI-Q and had a greater frequency of abnormal behaviors and more severe disinhibition compared to the left-dominant group. Performance on the NPI-Q and severity of disinhibition correlated with right medial and lateral, but not left, temporal lobe hypometabolism. Severity of abnormal behaviors worsened over time in most left-dominant and left+ patients but appeared to improve in the 2 right-dominant patients with longitudinal follow-up. All groups showed progressive worsening of metabolism in both temporal lobes over time, with hypometabolism spreading from anteromedial to posterior temporal regions. However, the degree of temporal lobe asymmetry remained relatively constant over time.

Conclusion: In SD, neurobehavioral features, especially disinhibition, are associated with right medial and lateral temporal lobe hypometabolism and commonly develop over time even in patients that present with left-dominant patterns of hypometabolism.
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http://dx.doi.org/10.1159/000513979DOI Listing
March 2021

Loss of Tmem106b leads to cerebellum Purkinje cell death and motor deficits.

Brain Pathol 2021 Mar 11:e12945. Epub 2021 Mar 11.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

TMEM106B has been recently implicated in multiple neurodegenerative diseases. Here, Rademakers et al. report a late-onset cerebellar Purkinje cell loss and progressive decline in motor function and gait deficits in a conventional Tmem106b-/- mouse model. By using high-power microscopy and bulk RNA sequencing, the authors further identify lysosomal and immune dysfunction as potential underlying mechanisms of the Purkinje cell loss.
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http://dx.doi.org/10.1111/bpa.12945DOI Listing
March 2021

CD52 Is Elevated on B cells of SLE Patients and Regulates B Cell Function.

Front Immunol 2020 4;11:626820. Epub 2021 Feb 4.

VA Palo Alto Healthcare System, Palo Alto, CA, United States.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell dysregulation and breaks in tolerance that lead to the production of pathogenic autoantibodies. We performed single-cell RNA sequencing of B cells from healthy donors and individuals with SLE which revealed upregulated CD52 expression in SLE patients. We further demonstrate that SLE patients exhibit significantly increased levels of B cell surface CD52 expression and plasma soluble CD52, and levels of soluble CD52 positively correlate with measures of lupus disease activity. Using CD52-deficient JeKo-1 cells, we show that cells lacking surface CD52 expression are hyperresponsive to B cell receptor (BCR) signaling, suggesting an inhibitory role for the surface-bound protein. In healthy donor B cells, antigen-specific BCR-activation initiated CD52 cleavage in a phospholipase C dependent manner, significantly reducing cell surface levels. Experiments with recombinant CD52-Fc showed that soluble CD52 inhibits BCR signaling in a manner partially-dependent on Siglec-10. Moreover, incubation of unstimulated B cells with CD52-Fc resulted in the reduction of surface immunoglobulin and CXCR5. Prolonged incubation of B cells with CD52 resulted in the expansion of IgD+IgM anergic B cells. In summary, our findings suggest that CD52 functions as a homeostatic protein on B cells, by inhibiting responses to BCR signaling. Further, our data demonstrate that CD52 is cleaved from the B cell surface upon antigen engagement, and can suppress B cell function in an autocrine and paracrine manner. We propose that increased expression of CD52 by B cells in SLE represents a homeostatic mechanism to suppress B cell hyperactivity.
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http://dx.doi.org/10.3389/fimmu.2020.626820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917337PMC
February 2021

Latent trait modeling of tau neuropathology in progressive supranuclear palsy.

Acta Neuropathol 2021 05 26;141(5):667-680. Epub 2021 Feb 26.

Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.

Progressive supranuclear palsy (PSP) is the second most common neurodegenerative Parkinsonian disorder after Parkinson's disease, and is characterized as a primary tauopathy. Leveraging the considerable clinical and neuropathologic heterogeneity associated with PSP, we measured tau neuropathology as quantitative traits to perform a genome-wide association study (GWAS) within PSP to identify genes and biological pathways that underlie the PSP disease process. In 882 PSP cases, semi-quantitative scores for phosphorylated tau-immunoreactive coiled bodies (CBs), neurofibrillary tangles (NFTs), tufted astrocytes (TAs), and tau threads were documented from 18 brain regions, and converted to latent trait (LT) variables using the R ltm package. LT analysis utilizes a multivariate regression model that links categorical responses to unobserved covariates allowing for a reduction of dimensionality, generating a single, continuous variable to account for the multiple lesions and brain regions assessed. We first tested for association with PSP LTs and the top PSP GWAS susceptibility loci. Significant SNP/LT associations were identified at rs242557 (MAPT H1c sub-haplotype) with hindbrain CBs and rs1768208 (MOBP) with forebrain tau threads. Digital microscopy was employed to quantify phosphorylated tau burden in midbrain tectum and red nucleus in 795 PSP cases and tau burdens were used as quantitative phenotypes in GWAS. Top associations were identified at rs1768208 with midbrain tectum and red nucleus tau burden. Additionally, we performed a PSP LT GWAS on an initial cohort, a follow-up SNP panel (37 SNPs, P < 10) in an extended cohort, and a combined analysis. Top SNP/LT associations were identified at SNPs in or near SPTBN5/EHD4, SEC13/ATP2B2, EPHB1/PPP2R3A, TBC1D8, IFNGR1/OLIG3, ST6GAL1, HK1, CALB1, and SGCZ. Finally, testing for SNP/transcript associations using whole transcriptome and whole genome data identified significant expression quantitative trait loci at rs3088159/SPTBN5/EHD4 and rs154239/GHRL. Modeling tau neuropathology heterogeneity using LTs as quantitative phenotypes in a GWAS may provide substantial insight into biological pathways involved in PSP by affecting regional tau burden.
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http://dx.doi.org/10.1007/s00401-021-02289-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043857PMC
May 2021

Early economic evaluation to guide the development of a spectroscopic liquid biopsy for the detection of brain cancer.

Int J Technol Assess Health Care 2021 Feb 24;37:e41. Epub 2021 Feb 24.

Department of Pure and Applied Chemistry, University of Strathclyde, Technology and Innovation Centre, Glasgow, UK.

Objectives: An early economic evaluation to inform the translation into clinical practice of a spectroscopic liquid biopsy for the detection of brain cancer. Two specific aims are (1) to update an existing economic model with results from a prospective study of diagnostic accuracy and (2) to explore the potential of brain tumor-type predictions to affect patient outcomes and healthcare costs.

Methods: A cost-effectiveness analysis from a UK NHS perspective of the use of spectroscopic liquid biopsy in primary and secondary care settings, as well as a cost-consequence analysis of the addition of tumor-type predictions was conducted. Decision tree models were constructed to represent simplified diagnostic pathways. Test diagnostic accuracy parameters were based on a prospective validation study. Four price points (GBP 50-200, EUR 57-228) for the test were considered.

Results: In both settings, the use of liquid biopsy produced QALY gains. In primary care, at test costs below GBP 100 (EUR 114), testing was cost saving. At GBP 100 (EUR 114) per test, the ICER was GBP 13,279 (EUR 15,145), whereas at GBP 200 (EUR 228), the ICER was GBP 78,300 (EUR 89,301). In secondary care, the ICER ranged from GBP 11,360 (EUR 12,956) to GBP 43,870 (EUR 50,034) across the range of test costs.

Conclusions: The results demonstrate the potential for the technology to be cost-effective in both primary and secondary care settings. Additional studies of test use in routine primary care practice are needed to resolve the remaining issues of uncertainty-prevalence in this patient population and referral behavior.
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http://dx.doi.org/10.1017/S0266462321000143DOI Listing
February 2021

Trends in Double Networks as Bioprintable and Injectable Hydrogel Scaffolds for Tissue Regeneration.

ACS Biomater Sci Eng 2021 Feb 19. Epub 2021 Feb 19.

Advanced Functional Polymers Group, Department of Chemistry, Institute for Materials Research (IMO), Hasselt University, Martelarenlaan 42, 3500 Hasselt, Belgium.

Additive manufacturing and injection are essential tools in the rapidly developing field of personalized medicine and are particularly promising for applications in regenerative medicine. One of the biggest challenges in this vibrant research domain remains the processing of complex formulations with robust mechanical properties. Mimicking the native extracellular matrix associated with many tissues requires materials that have high degrees of functionality for performing the complex array of functions within the cellular environment. Furthermore, native tissues often possess outstanding mechanical properties, particularly in connective tissues. These exceptional mechanics are a challenge to emulate in their own right, especially considering the accompanying demands for additional functionality. Double-network hydrogels have emerged as strong candidates for tissue engineering because of the impressive mechanics and versatility in terms of chemical makeup. Combining advances in processing (i.e., additive manufacturing and injection) with dual-network hydrogel formulations has led to an impressive collection of results, making great strides toward systems capable of addressing the demanding environment surrounding tissues while being amenable to personalized fabrication techniques. This review provides a brief summary of the most contemporary trends collected from the literature describing dual-network hydrogels being demonstrated in additive manufacturing and injectable applications.
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http://dx.doi.org/10.1021/acsbiomaterials.0c01749DOI Listing
February 2021

Controlled experiments to explore the use of a multi-tissue approach to characterizing stress in wild-caught Pacific halibut ().

Conserv Physiol 2021 5;9(1):coab001. Epub 2021 Feb 5.

Fisheries, Aquatic Science, and Technology Laboratory, Alaska Pacific University, 4101 University Dr., Anchorage, AK 99508, USA.

The integration of multiple tissues in physiological and ecological analyses can enhance methodological approaches, increase applications for data and extend interpretation of results. Previous investigations of the stress response in fish have focused primarily on cortisol levels in a single matrix-blood plasma-which confines interpretations of cortisol levels to a short temporal frame. Epidermal mucus has been proposed as an alternative or complement to plasma that may provide a view to cortisol levels over a different temporal window allowing comparative assessment. Here, we explore the potential for multi-tissue cortisol analysis using both plasma and epidermal mucus in Pacific halibut (). The relative timing at which cortisol increased and decreased in the two matrices as well as cortisol concentrations at estimated peak levels were compared in two trials after (i) inducing cortisol synthesis by adrenocorticotropic hormone (ACTH) administration and (ii) inducing cortisol elimination using cortisol (hydrocortisone, 98%) injection. The ACTH treatment elicited a peak plasma cortisol response approximately 12 hours post-injection, while mucus cortisol concentrations peaked later at approximately 62 hours post-injection. Exogenous cortisol treatments suggested relatively little transfer of cortisol from plasma to mucus, potentially reflecting differential effects of endogenous and exogenous cortisol. Our results suggest the potential utility of mucus as a sampling matrix that provides an extended window for detection of the stress response as compared to plasma. Results also suggest the utility of a multi-tissue approach to cortisol analysis with potential applications to applied fisheries research. Increased understanding of the relative scale of the cortisol response to stress (e.g. capture) will allow researchers and managers to better interpret the physiological condition and survival outcome of fish subjected to regulatory discard.
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http://dx.doi.org/10.1093/conphys/coab001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868037PMC
February 2021

Association of Mitochondrial DNA Genomic Variation With Risk of Pick Disease.

Neurology 2021 03 10;96(13):e1755-e1760. Epub 2021 Feb 10.

From the Department of Neuroscience (R.R.V., M.C.B., A.I.S.-B., R.L.W., S.K., S.F.R., R.R., D.W.D., O.A.R.), Division of Biomedical Statistics and Informatics (M.G.H., P.W.J.), Department of Neurology (R.J.U., Z.K.W.), and Department of Clinical Genomics (O.A.R.), Mayo Clinic, Jacksonville, FL; Perelman School of Medicine (E.S., J.Q.T., V.M.V.D.) and Department of Neurology (M.G.), University of Pennsylvania, Philadelphia; and VIB-UAntwerp Center for Molecular Neurology (R.R.), University of Antwerp, Belgium.

Objective: To determine whether stable polymorphisms that define mitochondrial haplogroups in mitochondrial DNA (mtDNA) are associated with Pick disease risk, we genotyped 52 pathologically confirmed cases of Pick disease and 910 neurologically healthy controls and performed case-control association analysis.

Methods: Fifty-two pathologically confirmed cases of Pick disease from Mayo Clinic Florida (n = 38) and the University of Pennsylvania (n = 14) and 910 neurologically healthy controls collected from Mayo Clinic Florida were genotyped for unique mtDNA haplogroup-defining variants. Mitochondrial haplogroups were determined, and in a case-control analysis, associations of mtDNA haplogroups with risk of Pick disease were evaluated with logistic regression models that were adjusted for age and sex.

Results: No individual mtDNA haplogroups or superhaplogroups were significantly associated with risk of Pick disease after adjustment for multiple testing ( < 0.0021, considered significant). However, nominally significant ( < 0.05) associations toward an increased risk of Pick disease were observed for mtDNA haplogroup W (5.8% cases vs 1.6% controls, odds ratio [OR] 4.78, = 0.020) and subhaplogroup H4 (5.8% cases vs 1.2% controls, OR 4.82, = 0.021).

Conclusion: Our findings indicate that mtDNA variation is not a disease driver but may influence disease susceptibility. Ongoing genetic assessments in larger cohorts of Pick disease are currently underway.
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http://dx.doi.org/10.1212/WNL.0000000000011649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055308PMC
March 2021

Optimisation of an Electrochemical DNA Sensor for Measuring KRAS G12D and G13D Point Mutations in Different Tumour Types.

Biosensors (Basel) 2021 Feb 5;11(2). Epub 2021 Feb 5.

Department of Biomedical Engineering, University of Strathclyde, 40 George Street, Glasgow G1 1QE, UK.

Circulating tumour DNA (ctDNA) is widely used in liquid biopsies due to having a presence in the blood that is typically in proportion to the stage of the cancer and because it may present a quick and practical method of capturing tumour heterogeneity. This paper outlines a simple electrochemical technique adapted towards point-of-care cancer detection and treatment monitoring from biofluids using a label-free detection strategy. The mutations used for analysis were the KRAS G12D and G13D mutations, which are both important in the initiation, progression and drug resistance of many human cancers, leading to a high mortality rate. A low-cost DNA sensor was developed to specifically investigate these common circulating tumour markers. Initially, we report on some developments made in carbon surface pre-treatment and the electrochemical detection scheme which ensure the most sensitive measurement technique is employed. Following pre-treatment of the sensor to ensure homogeneity, DNA probes developed specifically for detection of the KRAS G12D and G13D mutations were immobilized onto low-cost screen printed carbon electrodes using diazonium chemistry and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride/N-hydroxysuccinimide coupling. Prior to electrochemical detection, the sensor was functionalised with target DNA amplified by standard and specialist PCR methodologies (6.3% increase). Assay development steps and DNA detection experiments were performed using standard voltammetry techniques. Sensitivity (as low as 0.58 ng/μL) and specificity (>300%) was achieved by detecting mutant KRAS G13D PCR amplicons against a background of wild-type KRAS DNA from the representative cancer sample and our findings give rise to the basis of a simple and very low-cost system for measuring ctDNA biomarkers in patient samples. The current time to receive results from the system was 3.5 h with appreciable scope for optimisation, thus far comparing favourably to the UK National Health Service biopsy service where patients can wait for weeks for biopsy results.
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http://dx.doi.org/10.3390/bios11020042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914712PMC
February 2021

SARS-CoV-2 Infections and Serologic Responses Among Military Personnel Deployed on the USNS COMFORT to New York City During the COVID-19 Pandemic.

Open Forum Infect Dis 2021 Feb 23;8(2):ofaa654. Epub 2021 Jan 23.

Naval Medical Center Portsmouth, Portsmouth, Virginia, USA.

Background: Coronavirus disease 2019 (COVID-19) presents a unique challenge to United States Navy hospital ships. The aim of this study was to determine the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among US Navy personnel deployed on the USNS COMFORT to augment the inpatient health care capacity in New York City.

Methods: This was a cross-sectional study conducted on USNS COMFORT crewmembers returning to Norfolk, Virginia, following deployment. Participants completed an electronic questionnaire and provided a serum sample at Day 14 post-deployment. Polymerase chain reaction (PCR) results from testing of symptomatic crewmembers during deployment and Day 0 and Day 14 post-deployment screening swabs conducted on all crewmembers, per military order, were abstracted. SARS-CoV-2 infection was defined as a positive SARS-CoV-2 spike glycoprotein immunoglobulin G antibody or PCR result.

Results: Of the ship's total complement of 1200 crewmembers, 450 were enrolled: 432 (96.0%) completed the questionnaire and provided a serum sample. The median age of participants (interquartile range) was 30 (24-39) years, 50.8% were female, 58.6% were White, and 14.0% were Black; 80.1% had a clinical role during deployment. The cumulative prevalence of SARS-CoV-2 infection was 3.01% (13/432; 95% CI, 1.61%-5.09%). Twelve of 13 infections occurred in health care providers, and 8 of 13 were asymptomatic. The antibody profile of infected crewmembers varied by suspected timing of infection.

Conclusions: We observed a low prevalence of SARS-CoV-2 infection among USNS COMFORT crewmembers despite the inherent risk of a shipboard deployment to an area with high rates of community transmission. Our findings suggest that early infection control measures mitigated the spread of SARS-CoV-2 among crewmembers.
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http://dx.doi.org/10.1093/ofid/ofaa654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856331PMC
February 2021

Cryo-EM model validation recommendations based on outcomes of the 2019 EMDataResource challenge.

Nat Methods 2021 02 4;18(2):156-164. Epub 2021 Feb 4.

Department of Chemistry, University of Florida, Gainesville, FL, USA.

This paper describes outcomes of the 2019 Cryo-EM Model Challenge. The goals were to (1) assess the quality of models that can be produced from cryogenic electron microscopy (cryo-EM) maps using current modeling software, (2) evaluate reproducibility of modeling results from different software developers and users and (3) compare performance of current metrics used for model evaluation, particularly Fit-to-Map metrics, with focus on near-atomic resolution. Our findings demonstrate the relatively high accuracy and reproducibility of cryo-EM models derived by 13 participating teams from four benchmark maps, including three forming a resolution series (1.8 to 3.1 Å). The results permit specific recommendations to be made about validating near-atomic cryo-EM structures both in the context of individual experiments and structure data archives such as the Protein Data Bank. We recommend the adoption of multiple scoring parameters to provide full and objective annotation and assessment of the model, reflective of the observed cryo-EM map density.
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http://dx.doi.org/10.1038/s41592-020-01051-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864804PMC
February 2021

Realizing tissue integration with supramolecular hydrogels.

Acta Biomater 2021 04 27;124:1-14. Epub 2021 Jan 27.

Department of Complex Tissue Regeneration, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, 6211 LK, Maastricht, the Netherlands. Electronic address:

Biomaterial matrices must permit tissue growth and maturation for the success of tissue regeneration strategies. Naturally, this accommodation is achieved via the dynamic remodeling of a cell's extracellular matrix (ECM). Synthetically, hydrolytic or enzymatic degradation are often engineered into materials for this purpose. More recently, supramolecular interactions have been used to provide a biomimetic and tunable mechanism to facilitate tissue formation via their dynamic and reversible non-covalent interactions. By engineering the mechanical and bioactive properties of a material, supramolecular chemists are able to design permissivity into the construct and facilitate tissue integration in-vivo. Furthermore, via the reversibility of non-covalent interactions, injectability and responsiveness can be designed for enhanced delivery and spatio-temporal control. In this review, we delineate the basic considerations needed when designing permissive supramolecular hydrogels for tissue engineering with an eye toward tissue growth and integration. We highlight three archetypal hydrogel systems that have shown well-documented tissue integration in vivo, and provide avenues to assess tissue in-growth. Careful design and assessment of the biomedical potential of a supramolecular hydrogels can inspire the creation of robust and dynamic implants for new tissue engineering applications.
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http://dx.doi.org/10.1016/j.actbio.2021.01.034DOI Listing
April 2021

Ancestral Sequence Reconstructions of MotB Are Proton-Motile and Require MotA for Motility.

Front Microbiol 2020 23;11:625837. Epub 2020 Dec 23.

School of Biotechnology and Biomolecular Sciences (BABS), University of New South Wales, Sydney, NSW, Australia.

The bacterial flagellar motor (BFM) is a nanomachine that rotates the flagellum to propel many known bacteria. The BFM is powered by ion transit across the cell membrane through the stator complex, a membrane protein. Different bacteria use various ions to run their BFM, but the majority of BFMs are powered by either proton (H) or sodium (Na) ions. The transmembrane (TM) domain of the B-subunit of the stator complex is crucial for ion selectivity, as it forms the ion channel in complex with TM3 and TM4 of the A-subunit. In this study, we reconstructed and engineered thirteen ancestral sequences of the stator B-subunit to evaluate the functional properties and ionic power source of the stator proteins at reconstruction nodes to evaluate the potential of ancestral sequence reconstruction (ASR) methods for stator engineering and to test specific motifs previously hypothesized to be involved in ion-selectivity. We found that all thirteen of our reconstructed ancient B-subunit proteins could assemble into functional stator complexes in combination with the contemporary MotA-subunit to restore motility in stator deleted strains. The flagellar rotation of the thirteen ancestral MotBs was found to be Na independent which suggested that the F30/Y30 residue was not significantly correlated with sodium/proton phenotype, in contrast to what we had reported previously. Additionally, four among the thirteen reconstructed B-subunits were compatible with the A-subunit of and able to function in a sodium-independent manner. Overall, this work demonstrates the use of ancestral reconstruction to generate novel stators and quantify which residues are correlated with which ionic power source.
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http://dx.doi.org/10.3389/fmicb.2020.625837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787011PMC
December 2020

A Prospective Observational Registry of Repository Corticotropin Injection (Acthar® Gel) for the Treatment of Multiple Sclerosis Relapse.

Front Neurol 2020 22;11:598496. Epub 2020 Dec 22.

Mallinckrodt Pharmaceuticals, Bedminster, NJ, United States.

Effective relapse treatment is critical for minimizing disability in patients with multiple sclerosis (MS). Repository corticotropin injection (RCI; Acthar® Gel) has demonstrated efficacy for the treatment of MS exacerbations. However, there is limited real-world evidence available regarding the relationship between the use of RCI for MS relapses and patient demographics, disease characteristics, and dosing regimens. In this multicenter, prospective, observational registry, patients receiving RCI for acute MS relapse were characterized, and recovery and safety outcomes were described. Patients were invited by their treating clinician to participate in the registry during a routine care visit. The decision to initiate RCI occurred before determination of study eligibility. All treatment decisions were made at the discretion of the patient's health care provider and were not mandated by the study design or protocol. Each enrolled patient was followed for up to 24 Months or until the date of study termination. The primary endpoint was the change from baseline in MS Impact Scale Version 1 (MSIS-29v1) physical subscale scores at Month 2. Additional assessments included the MSIS-29v1 psychological subscale, Expanded Disability Status Scale (EDSS), Clinical Global Impression of Improvement (CGI-I), Work Productivity and Activity Impairment Questionnaire: MS (WPAI:MS), and Health Resource Utilization (HRU) questionnaire. Of 145 patients enrolled, 82 (56.6%) completed 24 Months of follow-up. Mean MSIS-29v1 physical subscale scores improved at 2 Months (-8.0; = 0.0002) and 6 Months (-9.6; < 0.0001). Mean MSIS-29v1 psychological subscale scores also improved at 2 Months (-7.9; = 0.0040) and 6 Months (-9.9; = 0.0012). Mean EDSS scores improved at 2 Months (-0.4; < 0.0001) and 6 Months (-0.5; < 0.0001). CGI-I scores indicated improvement in 63.4% of 71 patients at 2 Months and 61.4% of 57 patients at 6 Months (both < 0.0001). Improvements on the WPAI:MS activity impairment domain ( < 0.001) and reductions in outpatient, specialist, and emergency department visits were observed at 2 and 6 Months. A total of 35 (28.0%) patients reported 83 adverse events; 11 (8.8%) patients reported 16 serious adverse events. This observational study found significant improvements in MS assessment scores after RCI treatment and supports the efficacy and tolerability of RCI for MS relapse. This trial is registered on ClinicalTrials.gov with the identifier NCT02633033.
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http://dx.doi.org/10.3389/fneur.2020.598496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783159PMC
December 2020

Phase II, randomised, double-blind, multicentre study evaluating the safety and efficacy of filgotinib and lanraplenib in patients with lupus membranous nephropathy.

RMD Open 2020 12;6(3)

Nephrology, The University of Tennessee Health Science Center College of Medicine Chattanooga, Chattanooga, Tennessee, USA.

Objectives: Patients with lupus membranous nephropathy (LMN) are at risk for prolonged proteinuria and progressive chronic kidney disease. There are no proven effective treatments for LMN, and controlled trials are lacking. This trial assessed the preferential Janus kinase 1 (JAK1) inhibitor filgotinib and the spleen tyrosine kinase inhibitor lanraplenib in patients with LMN.

Methods: This was a phase II, randomised, double-blind trial conducted at 15 centres in the USA to evaluate the safety and efficacy of filgotinib or lanraplenib for the treatment of LMN. Eligible patients were randomised 1:1 to receive either filgotinib or lanraplenib in a blinded fashion for up to 52 weeks. The primary endpoint was the per cent change in 24-hour urine protein from baseline to week 16.

Results: Nine patients were randomised to receive filgotinib (n=5) or lanraplenib (n=4). Four patients in the filgotinib group and one patient in the lanraplenib group completed week 16. There was a median reduction of 50.7% in 24-hour urine protein after 16 weeks of treatment with filgotinib (n=4), and the median Systemic Lupus Erythematosus Disease Activity Index from the Safety of Estrogens in Lupus National Assessment score remained stable. Filgotinib treatment was well tolerated. Limited conclusions can be drawn about treatment with lanraplenib.

Conclusion: The number of patients treated in this study was small, and only limited conclusions can be drawn. There may be a therapeutic benefit with filgotinib treatment, which may support future investigations with filgotinib or other JAK inhibitors in patients with LMN.

Trial Registration Number: NCT03285711.
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http://dx.doi.org/10.1136/rmdopen-2020-001490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780527PMC
December 2020

Interrogation of Status in Gliomas by Fourier Transform Infrared Spectroscopy.

Cancers (Basel) 2020 Dec 8;12(12). Epub 2020 Dec 8.

WestCHEM, Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of Strathclyde, 99 George St., Glasgow G1 1RD, UK.

Mutations in the isocitrate dehydrogenase 1 () gene are found in a high proportion of diffuse gliomas. The presence of the mutation is a valuable diagnostic, prognostic and predictive biomarker for the management of patients with glial tumours. Techniques involving vibrational spectroscopy, e.g., Fourier transform infrared (FTIR) spectroscopy, have previously demonstrated analytical capabilities for cancer detection, and have the potential to contribute to diagnostics. The implementation of FTIR microspectroscopy during surgical biopsy could present a fast, label-free method for molecular genetic classification. For example, the rapid determination of status in a patient with a glioma diagnosis could inform intra-operative decision-making between alternative surgical strategies. In this study, we utilized synchrotron-based FTIR microanalysis to probe tissue microarray sections from 79 glioma patients, and distinguished the positive class (-mutated) from the -wildtype glioma, with a sensitivity and specificity of 82.4% and 83.4%, respectively. We also examined the ability of attenuated total reflection (ATR)-FTIR spectroscopy in detecting the biomolecular events and global epigenetic and metabolic changes associated with mutations in the enzyme, in blood serum samples collected from an additional 72 brain tumour patients. Centrifugal filtration enhanced the diagnostic ability of the classification models, with balanced accuracies up to ~69%. Identification of the molecular status from blood serum prior to biopsy could further direct some patients to alternative treatment strategies.
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http://dx.doi.org/10.3390/cancers12123682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762605PMC
December 2020

Detection of Glycine as a Model Protein in Blood Serum Using 2D-IR Spectroscopy.

Anal Chem 2021 01 9;93(2):920-927. Epub 2020 Dec 9.

Department of Chemistry and York Biomedical Research Institute, University of York, Heslington, York YO10 5DD, U.K.

Glycine (Gly) is used as a model system to evaluate the ability of ultrafast two-dimensional infrared (2D-IR) spectroscopy to detect and quantify the low-molecular-weight proteinaceous components of blood serum. Combining data acquisition schemes to suppress absorption bands of HO that overlap with the protein amide I band with analysis of peak patterns appearing in the off-diagonal region of the 2D-IR spectrum allows separation of the Gly spectral signature from that of the dominant protein fraction of serum in a transmission-mode 2D-IR measurement without any sample manipulation, e.g., filtration or drying. 2D-IR spectra of blood serum samples supplemented with varying concentrations of Gly were obtained, and a range of data analysis methods compared, leading to a detection limit of ∼3 mg/mL for Gly. The reported methodology provides a platform for a critical assessment of the sensitivity of 2D-IR for measuring the concentrations of amino acids, peptides, and low-molecular-weight proteins present in serum samples. We conclude that, in the case of several clinically relevant diagnostic molecules and their combinations, the potential exists for 2D-IR to complement IR absorption methods as the benefits of the second frequency dimension offered by 2D-IR spectroscopy outweigh the added technical complexity of the measurement.
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http://dx.doi.org/10.1021/acs.analchem.0c03567DOI Listing
January 2021

Lewy Body Disease is a Contributor to Logopenic Progressive Aphasia Phenotype.

Ann Neurol 2021 03 17;89(3):520-533. Epub 2020 Dec 17.

Department of Neurology, Mayo Clinic, Rochester, MN.

Objective: The objective of this study was to describe clinical features, [ F]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) metabolism and digital pathology in patients with logopenic progressive aphasia (LPA) and pathologic diagnosis of diffuse Lewy body disease (DLBD) and compare to patients with LPA with other pathologies, as well as patients with classical features of probable dementia with Lewy bodies (pDLB).

Methods: This is a clinicopathologic case-control study of 45 patients, including 20 prospectively recruited patients with LPA among whom 6 were diagnosed with LPA-DLBD. We analyzed clinical features and compared FDG-PET metabolism in LPA-DLBD to an independent group of patients with clinical pDLB and regional α-synuclein burden on digital pathology to a second independent group of autopsied patients with DLBD pathology and antemortem pDLB (DLB-DLBD).

Results: All patients with LPA-DLBD were men. Neurological, speech, and neuropsychological characteristics were similar across LPA-DLBD, LPA-Alzheimer's disease (LPA-AD), and LPA-frontotemporal lobar degeneration (LPA-FTLD). Genetic screening of AD, DLBD, and FTLD linked genes were negative with the exception of APOE ε4 allele present in 83% of LPA-DLBD patients. Seventy-five percent of the patients with LPA-DLBD showed a parietal-dominant pattern of hy pometabolism; LPA-FTLD - temporal-dominant pattern, whereas LPA-AD showed heterogeneous patterns of hypometabolism. LPA-DLBD had more asymmetrical hypometabolism affecting frontal lobes, with relatively spared occipital lobe in the nondominantly affected hemisphere, compared to pDLB. LPA-DLBD had minimal atrophy on gross brain examination, higher cortical Lewy body counts, and higher α-synuclein burden in the middle frontal and inferior parietal cortices compared to DLB-DLBD.

Interpretation: Whereas AD is the most frequent underlying pathology of LPA, DLBD can also be present and may contribute to the LPA phenotype possibly due to α-synuclein-associated functional impairment of the dominant parietal lobe. ANN NEUROL 2021;89:520-533.
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http://dx.doi.org/10.1002/ana.25979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040336PMC
March 2021

A Rare Cause of Diffuse Forearm Swelling in an Infant.

Pediatr Rev 2020 Dec;41(12):652-654

George Washington University School of Medicine, Washington, DC.

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http://dx.doi.org/10.1542/pir.2019-0154DOI Listing
December 2020

Assessment of the concordance between individual-level and area-level measures of socio-economic deprivation in a cancer patient cohort in England and Wales.

BMJ Open 2020 11 26;10(11):e041714. Epub 2020 Nov 26.

Inequalities in Cancer Outcomes Network, Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK.

Objectives: Most research on health inequalities uses aggregated deprivation scores assigned to the small area where the patient lives; however, the concordance between aggregate area-level deprivation measures and personal deprivation experienced by individuals living in the area is poorly understood. Our objective was to examine the agreement between individual and ecological deprivation. We tested the concordance between metrics of income, occupation and education at individual and area levels, and assessed the reliability of area-based deprivation measures to predict individual deprivation circumstances.

Setting: England and Wales.

Participants: A cancer patient cohort of 9547 individuals extracted from the Office for National Statistics Longitudinal Study.

Outcomes: We quantified the concordance between measures of income, occupation and education at individual and area level. In addition, we used ROC (receiver operating characteristic) curves and the area under the curve (AUC) to assess the reliability of area-based deprivation measures to predict individual deprivation circumstances.

Results: We found low concordance between individual-level and area-level indicators of deprivation (Cramer's statistics range between 0.07 and 0.20). The most commonly used indicator in health inequalities research, area-based income deprivation, was a poor predictor of individual income status (AUC between 0.56 and 0.59), whereas education and occupation were slightly better predictors (AUC between 0.62 and 0.65). The results were consistent across sexes and across six major cancer types.

Conclusions: Our results indicate that ecological deprivation measures capture only part of the relationship between deprivation and health outcomes, especially with respect to income measurement. This has important implications for our understanding of the relationship between deprivation and health, and, as a consequence, healthcare policy. The results have a wide-reaching impact for the way in which we measure and monitor inequalities, and in turn, fund and organise current UK healthcare policy aimed at reducing them.
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http://dx.doi.org/10.1136/bmjopen-2020-041714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692821PMC
November 2020

quids at Pinwheel Cave, California, provide unambiguous confirmation of the ingestion of hallucinogens at a rock art site.

Proc Natl Acad Sci U S A 2020 12 23;117(49):31026-31037. Epub 2020 Nov 23.

University of California Cooperative Extension, Bakersfield, CA 93307.

While debates have raged over the relationship between trance and rock art, unambiguous evidence of the consumption of hallucinogens has not been reported from any rock art site in the world. A painting possibly representing the flowers of on the ceiling of a Californian rock art site called Pinwheel Cave was discovered alongside fibrous quids in the same ceiling. Even though Native Californians are historically documented to have used to enter trance states, little evidence exists to associate it with rock art. A multianalytical approach to the rock art, the quids, and the archaeological context of this site was undertaken. Liquid chromatography-mass spectrometry (LC-MS) results found hallucinogenic alkaloids scopolamine and atropine in the quids, while scanning electron microscope analysis confirms most to be Three-dimensional (3D) analyses of the quids indicate the quids were likely masticated and thus consumed in the cave under the paintings. Archaeological evidence and chronological dating shows the site was well utilized as a temporary residence for a range of activities from Late Prehistory through Colonial Periods. This indicates that was ingested in the cave and that the rock painting represents the plant itself, serving to codify communal rituals involving this powerful entheogen. These results confirm the use of hallucinogens at a rock art site while calling into question previous assumptions concerning trance and rock art imagery.
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http://dx.doi.org/10.1073/pnas.2014529117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733795PMC
December 2020