Publications by authors named "John Robinson"

620 Publications

A study protocol for a multicenter randomized pilot trial of a dyadic, tailored, web-based, psychosocial, and physical activity self-management program (TEMPO) for men with prostate cancer and their caregivers.

Pilot Feasibility Stud 2021 Mar 20;7(1):78. Epub 2021 Mar 20.

Canadian Centre for Applied Research in Cancer Control, Toronto, Canada.

Background: Prostate cancer predisposes patients and caregivers to a wide range of complex physical and psychosocial challenges, and interventions must incorporate a wide range of self-management strategies to help patients and their caregivers effectively cope with cancer challenges. To palliate this need, our team recently developed and evaluated the initial acceptability of a dyadic, Tailored, wEb-based, psychosocial, and physical activity self-Management PrOgram (TEMPO). TEMPO is a 10-week, interactive, web-based intervention consisting of five modules designed to help dyads manage their physical and psychosocial needs. It aims to teach dyads new self-management strategies and encourages them to increase their physical activity (PA) levels, mainly through walking and strength-based exercises. Initial acceptability evaluation of TEMPO revealed high user satisfaction, in addition to having a number of potential benefits for participants. After integrating suggested changes to TEMPO, the proposed pilot study aims to further test the acceptability and feasibility of TEMPO.

Methods: This study is a multicenter, stratified, parallel, two-group, pilot randomized control trial (RCT), where patient-caregiver dyads are randomized (stratified by anxiety level) to receive (a) TEMPO or (b) usual care. Participants (n goal = 40) are recruited across Canada at participating cancer centers and through self-referral (e.g., online recruitment). Patient inclusion criteria are (a) having received prostate cancer treatment within the past 2 years or scheduled to receive treatment, (b) identified a primary caregiver willing to participate in the study, and (c) has access to the Internet. Eligible caregivers are those identified by the patient as his primary source of support. Dyads complete a baseline questionnaire (T1) and another one 3 months later (T2) assessing various aspects of physical and emotional functioning (e.g., the Medical Outcomes Study (MOS) 12-item Short Form Health Survey (SF-12), the Hospital Anxiety and Depression Scale (HADS), and the Perceived Stress Scale (PSS)), self-management behaviors (e.g., the Health Education Impact Questionnaire (heiQ)), physical activity (the International Physical Activity Questionnaires (IPAQ) and the Multidimensional Self-efficacy for Exercise Scale (MSES)), and dyadic coping (the Dyadic Coping Inventory (DCI)). Dyads that used TEMPO are also asked to participate in a semi-structured exit interview exploring their overall experience with the program.

Discussion: This feasibility analysis will begin to develop the knowledge base on TEMPO's value for men with prostate cancer and their caregivers to inform a larger trial.

Trial Registration: NCT04304196.
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http://dx.doi.org/10.1186/s40814-021-00791-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980105PMC
March 2021

Enrichment of loss-of-function and copy number variants in ventricular cardiomyopathy genes in 'lone' atrial fibrillation.

Europace 2021 Mar 3. Epub 2021 Mar 3.

Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada.

Aims: Atrial fibrillation (AF) is a complex heritable disease whose genetic underpinnings remain largely unexplained, though recent work has suggested that the arrhythmia may develop secondary to an underlying atrial cardiomyopathy. We sought to evaluate for enrichment of loss-of-function (LOF) and copy number variants (CNVs) in genes implicated in ventricular cardiomyopathy in 'lone' AF.

Methods And Results: Whole-exome sequencing was performed in 255 early onset 'lone' AF cases, defined as arrhythmia onset prior to 60 years of age in the absence of known clinical risk factors. Subsequent evaluations were restricted to 195 cases of European genetic ancestry, as defined by principal component analysis, and focused on a pre-defined set of 43 genes previously implicated in ventricular cardiomyopathy. Bioinformatic analysis identified 6 LOF variants (3.1%), including 3 within the TTN gene, among cases in comparison with 4 of 503 (0.80%) controls [odds ratio: 3.96; 95% confidence interval (CI): 1.11-14.2; P = 0.033]. Further, two AF cases possessed a novel heterozygous 8521 base pair TTN deletion, confirmed with Sanger sequencing and breakpoint validation, which was absent from 4958 controls (P = 0.0014). Subsequent cascade screening in two families revealed evidence of co-segregation of a LOF variant with 'lone' AF.

Conclusion: 'Lone' AF cases are enriched in rare LOF variants from cardiomyopathy genes, findings primarily driven by TTN, and a novel TTN deletion, providing additional evidence to implicate atrial cardiomyopathy as an AF genetic sub-phenotype. Our results also highlight that AF may develop in the context of these variants in the absence of a discernable ventricular cardiomyopathy.
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http://dx.doi.org/10.1093/europace/euaa421DOI Listing
March 2021

Distinct microglial response against Alzheimer's amyloid and tau pathologies characterized by P2Y12 receptor.

Brain Commun 2021 29;3(1):fcab011. Epub 2021 Jan 29.

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Microglia are the resident phagocytes of the central nervous system, and microglial activation is considered to play an important role in the pathogenesis of neurodegenerative diseases. Recent studies with single-cell RNA analysis of CNS cells in Alzheimer's disease and diverse other neurodegenerative conditions revealed that the transition from homeostatic microglia to disease-associated microglia was defined by changes of gene expression levels, including down-regulation of the P2Y12 receptor gene (). However, it is yet to be clarified in Alzheimer's disease brains whether and when this down-regulation occurs in response to amyloid-β and tau depositions, which are core pathological processes in the disease etiology. To further evaluate the significance of P2Y12 receptor alterations in the neurodegenerative pathway of Alzheimer's disease and allied disorders, we generated an anti-P2Y12 receptor antibody and examined P2Y12 receptor expressions in the brains of humans and model mice bearing amyloid-β and tau pathologies. We observed that the brains of both Alzheimer's disease and non-Alzheimer's disease tauopathy patients and tauopathy model mice (rTg4510 and PS19 mouse lines) displayed declined microglial P2Y12 receptor levels in regions enriched with tau inclusions, despite an increase in the total microglial population. Notably, diminution of microglial immunoreactivity with P2Y12 receptor was noticeable prior to massive accumulations of phosphorylated tau aggregates and neurodegeneration in rTg4510 mouse brains, despite a progressive increase of total microglial population. On the other hand, Iba1-positive microglia encompassing compact and dense-cored amyloid-β plaques expressed P2Y12 receptor at varying levels in amyloid precursor protein (APP) mouse models (APP23 and mice). By contrast, neuritic plaques in Alzheimer's disease brains were associated with P2Y12 receptor-negative microglia. These data suggest that the down-regulation of microglia P2Y12 receptor, which is characteristic of disease-associated microglia, is intimately associated with tau rather than amyloid-β pathologies from an early stage and could be a sensitive index for neuroinflammatory responses to Alzheimer's disease-related neurodegenerative processes.
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http://dx.doi.org/10.1093/braincomms/fcab011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901060PMC
January 2021

Accelerated Clearance and Degradation of Cell-Free HIV by Neutralizing Antibodies Occurs via FcγRIIb on Liver Sinusoidal Endothelial Cells by Endocytosis.

J Immunol 2021 Mar 10;206(6):1284-1296. Epub 2021 Feb 10.

Department of Internal Medicine, The Ohio State University, Columbus, OH 43210;

Neutralizing Abs suppress HIV infection by accelerating viral clearance from blood circulation in addition to neutralization. The elimination mechanism is largely unknown. We determined that human liver sinusoidal endothelial cells (LSEC) express FcγRIIb as the lone Fcγ receptor, and using humanized FcγRIIb mouse, we found that Ab-opsonized HIV pseudoviruses were cleared considerably faster from circulation than HIV by LSEC FcγRIIb. Compared with humanized FcγRIIb-expressing mice, HIV clearance was significantly slower in FcγRIIb knockout mice. Interestingly, a pentamix of neutralizing Abs cleared HIV faster compared with hyperimmune anti-HIV Ig (HIVIG), although the HIV Ab/Ag ratio was higher in immune complexes made of HIVIG and HIV than pentamix and HIV. The effector mechanism of LSEC FcγRIIb was identified to be endocytosis. Once endocytosed, both Ab-opsonized HIV pseudoviruses and HIV localized to lysosomes. This suggests that clearance of HIV, endocytosis, and lysosomal trafficking within LSEC occur sequentially and that the clearance rate may influence downstream events. Most importantly, we have identified LSEC FcγRIIb-mediated endocytosis to be the Fc effector mechanism to eliminate cell-free HIV by Abs, which could inform development of HIV vaccine and Ab therapy.
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http://dx.doi.org/10.4049/jimmunol.2000772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946731PMC
March 2021

Thermal noise and mechanical loss of SiO/TaO optical coatings at cryogenic temperatures.

Opt Lett 2021 Feb;46(3):592-595

Mechanical loss of dielectric mirror coatings sets fundamental limits for both gravitational wave detectors and cavity-stabilized optical local oscillators for atomic clocks. Two approaches are used to determine the mechanical loss: ringdown measurements of the coating quality factor and direct measurement of the coating thermal noise. Here we report a systematic study of the mirror thermal noise at 4, 16, 124, and 300 K by operating reference cavities at these temperatures. The directly measured thermal noise is used to extract the mechanical loss for / coatings, which are compared with previously reported values.
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http://dx.doi.org/10.1364/OL.413758DOI Listing
February 2021

The development and convergence of co-pathologies in Alzheimer's disease.

Brain 2021 Apr;144(3):953-962

Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Cerebral amyloid angiopathy (CAA), limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) and Lewy bodies occur in the absence of clinical and neuropathological Alzheimer's disease, but their prevalence and severity dramatically increase in Alzheimer's disease. To investigate how plaques, tangles, age and apolipoprotein E ε4 (APOE ε4) interact with co-pathologies in Alzheimer's disease, we analysed 522 participants ≥50 years of age with and without dementia from the Center for Neurodegenerative Disease Research (CNDR) autopsy program and 1340 participants in the National Alzheimer's Coordinating Center (NACC) database. Consensus criteria were applied for Alzheimer's disease using amyloid phase and Braak stage. Co-pathology was staged for CAA (neocortical, allocortical, and subcortical), LATE-NC (amygdala, hippocampal, and cortical), and Lewy bodies (brainstem, limbic, neocortical, and amygdala predominant). APOE genotype was determined for all CNDR participants. Ordinal logistic regression was performed to quantify the effect of independent variables on the odds of having a higher stage after checking the proportional odds assumption. We found that without dementia, increasing age associated with all pathologies including CAA (odds ratio 1.63, 95% confidence interval 1.38-1.94, P < 0.01), LATE-NC (1.48, 1.16-1.88, P < 0.01), and Lewy bodies (1.45, 1.15-1.83, P < 0.01), but APOE ε4 only associated with CAA (4.80, 2.16-10.68, P < 0.01). With dementia, increasing age associated with LATE-NC (1.30, 1.15-1.46, P < 0.01), while Lewy bodies associated with younger ages (0.90, 0.81-1.00, P = 0.04), and APOE ε4 only associated with CAA (2.36, 1.52-3.65, P < 0.01). A longer disease course only associated with LATE-NC (1.06, 1.01-1.11, P = 0.01). Dementia in the NACC cohort associated with the second and third stages of CAA (2.23, 1.50-3.30, P < 0.01), LATE-NC (5.24, 3.11-8.83, P < 0.01), and Lewy bodies (2.41, 1.51-3.84, P < 0.01). Pathologically, increased Braak stage associated with CAA (5.07, 2.77-9.28, P < 0.01), LATE-NC (5.54, 2.33-13.15, P < 0.01), and Lewy bodies (4.76, 2.07-10.95, P < 0.01). Increased amyloid phase associated with CAA (2.27, 1.07-4.80, P = 0.03) and Lewy bodies (6.09, 1.66-22.33, P = 0.01). In summary, we describe widespread distributions of CAA, LATE-NC and Lewy bodies that progressively accumulate alongside plaques and tangles in Alzheimer's disease dementia. CAA interacted with plaques and tangles especially in APOE ε4 positive individuals; LATE-NC associated with tangles later in the disease course; most Lewy bodies associated with moderate to severe plaques and tangles.
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http://dx.doi.org/10.1093/brain/awaa438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041349PMC
April 2021

Development, implementation, and evaluation of a multidisciplinary oncology sexual health clinic in a Canadian cancer care setting.

J Cancer Surviv 2021 Jan 5. Epub 2021 Jan 5.

Department of Psychosocial and Rehabilitation Oncology, Tom Baker Cancer Centre - Holy Cross Site, 2202 2nd St SW, Calgary, AB, T3S 2C1, Canada.

Purpose: Untreated cancer-related sexual health concerns cause significant distress for cancer survivors. To appropriately address the complex sexual health needs of cancer patients, we piloted a specialized, multidisciplinary oncology sexual health clinic within a tertiary cancer center. A quality assurance evaluation was conducted.

Methods: During once monthly half-day clinics, a multidisciplinary team of psychologists, advanced practice nurses, and radiation and gynecological oncologists offered specialist integrated care to oncology patients. Patients completed assessment questionnaires prior to each clinic appointment and a follow-up telephone interview approximately 4 months after their initial appointment.

Results: Over the 2-year pilot, 224 patients were referred to the cancer center's broader sexual health program; 100 patients were triaged to the clinic. A total of 79 new and 58 follow-up appointments were offered. Average wait time for an initial visit was 97 days. Patients' most frequent concerns included vulvovaginal atrophy, dyspareunia, reduced sexual desire, and erectile dysfunction. Self-reported sexual distress was well above the clinical cutoff at baseline (N = 77, M = 29.78, SD = 12.74). A significant reduction in sexual distress was observed at follow-up (N = 67, M = 21.90, SD = 11.34, t(66) = 7.41, p < 0.001).

Conclusions: Referral rates indicate a high demand for specialized sexual health services within cancer care. Ongoing specialist care is needed to appropriately address the multifaceted sexual concerns of cancer survivors and to adequately manage high distress and symptom comorbidity.

Implications For Cancer Survivors: Results inform a more comprehensive characterization of the presenting concerns of cancer survivors seeking multidisciplinary sexual health care.
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http://dx.doi.org/10.1007/s11764-020-00967-8DOI Listing
January 2021

Rational selection of building blocks for the assembly of bispecific antibodies.

MAbs 2021 Jan-Dec;13(1):1870058

Department of Therapeutics Discovery, Amgen Research, Amgen Inc ., Thousand Oaks, CA USA.

Bispecific antibodies, engineered to recognize two targets simultaneously, demonstrate exceptional clinical potential for the therapeutic intervention of complex diseases. However, these molecules are often composed of multiple polypeptide chains of differing sequences. To meet industrial scale productivity, enforcing the correct quaternary assembly of these chains is critical. Here, we describe Chain Selectivity Assessment (CSA), a high-throughput method to rationally select parental monoclonal antibodies (mAbs) to make bispecific antibodies requiring correct heavy/light chain pairing. By deploying CSA, we have successfully identified mAbs that exhibit a native preference toward cognate chain pairing that enables the production of hetero-IgGs without additional engineering. Furthermore, CSA also identified rare light chains (LCs) that permit positive binding of the non-cognate arm in the common LC hetero-IgGs, also without engineering. This rational selection of parental mAbs with favorable developability characteristics is critical to the successful development of bispecific molecules with optimal manufacturability properties.
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http://dx.doi.org/10.1080/19420862.2020.1870058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808324PMC
January 2021

Precision Metrology Meets Cosmology: Improved Constraints on Ultralight Dark Matter from Atom-Cavity Frequency Comparisons.

Phys Rev Lett 2020 Nov;125(20):201302

JILA, National Institute of Standards and Technology and University of Colorado, Boulder, Colorado 80309-0440, USA.

We conduct frequency comparisons between a state-of-the-art strontium optical lattice clock, a cryogenic crystalline silicon cavity, and a hydrogen maser to set new bounds on the coupling of ultralight dark matter to standard model particles and fields in the mass range of 10^{-16}-10^{-21}  eV. The key advantage of this two-part ratio comparison is the differential sensitivity to time variation of both the fine-structure constant and the electron mass, achieving a substantially improved limit on the moduli of ultralight dark matter, particularly at higher masses than typical atomic spectroscopic results. Furthermore, we demonstrate an extension of the search range to even higher masses by use of dynamical decoupling techniques. These results highlight the importance of using the best-performing atomic clocks for fundamental physics applications, as all-optical timescales are increasingly integrated with, and will eventually supplant, existing microwave timescales.
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http://dx.doi.org/10.1103/PhysRevLett.125.201302DOI Listing
November 2020

3D printed auxetic nasopharyngeal swabs for COVID-19 sample collection.

J Mech Behav Biomed Mater 2021 02 12;114:104175. Epub 2020 Nov 12.

School of Engineering, University of Wolverhampton, Telford Innovation Campus, Telford, TF2 9NT, UK; 6DME Ltd., Stirchley Road, Telford, TF3 1EB, UK.

The COVID-19 pandemic has resulted in worldwide shortages of nasopharyngeal swabs required for sample collection. While the shortages are becoming acute due to supply chain disruptions, the demand for testing has increased both as a prerequisite to lifting restrictions and in preparation for the second wave. One of the potential solutions to this crisis is the development of 3D printed nasopharyngeal swabs that behave like traditional swabs. However, the opportunity to digitally conceive and fabricate swabs allows for design improvements that can potentially reduce patient pain and discomfort. The study reports the progress that has been made on the development of auxetic nasopharyngeal swabs that can shrink under axial resistance. This allows the swab to navigate through the nasal cavity with significantly less stress on the surrounding tissues. This is achieved through systematically conceived negative Poisson's ratio (-υ) structures in a biocompatible material. Finite element (FE) and surrogate modelling techniques were employed to identify the most optimal swab shape that allows for the highest negative strain (-ε) under safe stress (σ). The influence and interaction effects of the geometrical parameters on the swab's performance were also characterised. The research demonstrates a new viewpoint for the development of functional nasopharyngeal swabs that can be 3D printed to reduce patient discomfort. The methodology can be further exploited to address various challenges in biomedical devices and redistributed manufacturing.
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http://dx.doi.org/10.1016/j.jmbbm.2020.104175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660972PMC
February 2021

Identifying predictors of patient radiation dose during uterine artery embolisation.

J Med Radiat Sci 2020 Nov 13. Epub 2020 Nov 13.

Discipline of Medical Imaging Science, School of Health Sciences, Faculty of Medicine and Health, The University of Sydney, New South Wales, Australia.

Introduction: Uterine artery embolisation (UAE) is regarded as a safe and effective treatment for symptomatic uterine fibroids and/or adenomyosis. Dose reduction during UAE is critical for this reproductive-age patient population to minimise the risks of radiation-induced effects. The aim of this study was to identify the predictors of radiation dose which can be controlled and optimised for patients during UAE.

Methods: A total of 150 patients between June 2018 and August 2019 were included in this study. Demographic and clinical information such as age, body mass index (BMI), total number of fibroids, total fibroid volume, total uterus volume and dosimetric measurements on Dose Area Product (DAP), Air Kerma (AK) and fluoroscopy time were recorded. Total digital subtraction angiography (DSA), total conventional roadmap (CRM), total last-image hold (LIH) and total fluoroscopy were calculated from the dose report. Multiple linear regression analysis was used to identify the independent predictor variables of total dose (DAP) using a regression model.

Results: Total DSA, total CRM and total LIH were identified as the determinants of dose for UAE (P < 0.05) and together accounted for 95.2% of the variance.

Conclusions: This study identified the key imaging predictors of dose for UAE. Total DSA, total CRM and total LIH were shown to have a greater impact on the outcome DAP compared to other demographic or dosimetric measurements. Optimisation of these predictors during future UAE procedures can facilitate radiation dose reduction to the pelvis and reproductive organs.
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http://dx.doi.org/10.1002/jmrs.450DOI Listing
November 2020

In-situ microwave-assisted catalytic upgrading of heavy oil: experimental validation and effect of catalyst pore structure on activity.

Chem Eng J 2020 Oct 22:127420. Epub 2020 Oct 22.

Faculty of Engineering, University of Nottingham, Nottingham NG7 2RD, UK.

In-situ combustion alone may not provide sufficient heating for downhole, catalytic upgrading of heavy oil in the Toe-to-Heel Air Injection (THAI) process. In this study, a new microwave heating technique has been proposed as a strategy to provide the requisite heating. Microwave technology is alone able to provide rapid heating which can be targeted at the catalyst packing and/or the incoming oil in its immediate vicinity. It was demonstrated, contrary to previous assertions, that heavy oil can be heated directly with microwaves to 425°C, which is the temperature needed for successful catalytic upgrading, without the need for an additional microwave susceptor. Upgrading of > 3.2° API points, a reduction in viscosity to less than 100 cP, and > 12% reduction in sulfur content was achieved using commercially available hydrodesulfurization (HDS) catalyst. The HDS catalyst induced dehydrogenation, with nearly 20% hydrogen detected in the gas product. Hence, in THAI field settings, part of the oil-in-place could be sacrificed for dehydrogenation, with the produced hydrogen directed to aid hydrodesulfurization and improve upgrading. Further, this could provide a route for downhole hydrogen production, which can contribute to the efforts towards the hydrogen economy. A single, unified model of evolving catalyst structure was developed. The model incorporated the unusual gas sorption data, computerized x-ray tomography and electron microprobe characterization, as well as the reaction behavior. The proposed model also highlighted the significant impact of the particular catalyst fabrication process on the catalytic activity.
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http://dx.doi.org/10.1016/j.cej.2020.127420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578747PMC
October 2020

Acceptability and Usefulness of a Dyadic, Tailored, Web-Based, Psychosocial and Physical Activity Self-Management Program (TEMPO): A Qualitative Study.

J Clin Med 2020 Oct 13;9(10). Epub 2020 Oct 13.

College of Nursing, University of Manitoba; Winnipeg, MB R3T 2N2, Canada.

Caregivers of men with prostate cancer report high burden, and there is a need to develop cost-effective programs to support them in their roles. This study reports on the acceptability of a dyadic, ailored, wb-based, psychosocial and physical activity (PA) self-anagement rgram called TEMPO. TEMPO was accessed by a convenience sample of 19 men with prostate cancer and their caregivers ( = 18), as well as six health care professionals (HCPs). User feedback was gathered via semi-structured qualitative interviews. Data were analyzed using thematic analysis. Most dyads were satisfied with TEMPO, particularly with the dyadic feature of TEMPO, the focus on goal setting to integrate self-management, and the extensive health library. The patients and caregivers motivated each other as they worked through TEMPO. Most goals to achieve during TEMPO pertained to increasing PA, followed by learning physical symptom management. One unanticipated benefit of TEMPO for the dyads was improved communication. HCPs agreed that TEMPO was a novel approach to online cancer self-management and they echoed the benefits reported by dyads. Key suggestions for improving TEMPO were to reduce repetition, tailor content, add more exercise ideas, and have more printing options. This study provides a strong foundation on which to plan a larger trial.
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http://dx.doi.org/10.3390/jcm9103284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650635PMC
October 2020

Simplifying Detection of Copy-Number Variations in Maturity-Onset Diabetes of the Young.

Can J Diabetes 2021 Feb 8;45(1):71-77. Epub 2020 Jun 8.

Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.

Objectives: Copy-number variations (CNVs) are large-scale deletions or duplications of DNA that have required specialized detection methods, such as microarray-based genomic hybridization or multiplex ligation probe amplification. However, recent advances in bioinformatics have made it possible to detect CNVs from next-generation DNA sequencing (NGS) data. Maturity-onset diabetes of the young (MODY) 5 is a subtype of autosomal-dominant diabetes that is often caused by heterozygous deletions involving the HNF1B gene on chromosome 17q12. We evaluated the utility of bioinformatic processing of raw NGS data to detect chromosome 17q12 deletions in MODY5 patients.

Methods: NGS data from 57 patients clinically suspected to have MODY but who were negative for pathogenic mutations using a targeted panel were re-examined using a CNV calling tool (CNV Caller, VarSeq version 1.4.3). Potential CNVs for MODY5 were then confirmed using whole-exome sequencing, cytogenetic analysis and breakpoint analysis when possible.

Results: Whole-gene deletions in HNF1B, ranging from 1.46 to 1.85 million basepairs in size, were detected in 3 individuals with features of MODY5. These were confirmed by independent methods to be part of a more extensive 17q12 deletion syndrome. Two additional patients carrying a 17q12 deletion were subsequently diagnosed using this method.

Conclusions: Large-scale deletions are the most common cause of MODY5 and can be detected directly from NGS data, without the need for additional methods.
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http://dx.doi.org/10.1016/j.jcjd.2020.06.001DOI Listing
February 2021

Mechanical performance of additively manufactured pure silver antibacterial bone scaffolds.

J Mech Behav Biomed Mater 2020 12 22;112:104090. Epub 2020 Sep 22.

Department of Engineering and Design, University of Sussex, Brighton, BN1 9RH, United Kingdom.

Implant infection is a serious complication resulting in pain, mortality, prolonged recovery, and antimicrobial resistance (AMR). Reducing the risk-of-infection associated with tissue implants require imminent attention, where pure silver (Ag) offers enormous potential. However, the printability, mechanical performance nor microbial resistance of additively manufactured (AM) pure Ag is unavailable in literature. This is critical as Ag is thought to play a vital role in the development of AM patient-specific infection resistant implants in the decade to come. The study therefore additively manufactured 99.9% pure-Ag through selective laser melting (SLM) and systematically investigates its mechanical performance. The validated SLM process parameters were then used to conceive two fully porous bone scaffold each at approximately 68 and 90% (wt.) porosity. While the study brings to attention the potential defects in SLM pure-Ag through X-ray nanotomography (X-ray nCT), the mechanical properties of porous Ag scaffolds were found to be similar to cancellous bone. The study achieved the highest SLM pure-Ag density of 97% with Young's modulus (E), elastic limit (σ), yield strength (σ), ultimate strength (σ) and ultimate strain (ε) in the range of 15.5-17.8 GPa, 50.7-57.7 MPa, 57.6-67.2 MPa, 82.4-95.9 MPa and 0.07-0.10 respectively. The antimicrobial efficacy of printed silver was tested against the common implant infection-causing Staphylococcus aureus and led to 90% and 99.9% kill in 4 and 14 h respectively. The study, therefore, is a first step towards achieving a new generation Ag-based AM infection resistant porous implants.
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http://dx.doi.org/10.1016/j.jmbbm.2020.104090DOI Listing
December 2020

Efficacy and Safety of nab-Paclitaxel vs Paclitaxel on Survival in Patients With Platinum-Refractory Metastatic Urothelial Cancer: The Canadian Cancer Trials Group BL.12 Randomized Clinical Trial.

JAMA Oncol 2020 Sep 17. Epub 2020 Sep 17.

Canadian Cancer Trials Group (CCTG), Queen's University, Kingston, Ontario, Canada.

Importance: Treatment options for platinum-refractory metastatic urothelial cancer (mUC) are limited, and outcomes remain poor. Nab-paclitaxel is an albumin-bound formulation of paclitaxel showing promising activity and tolerability in a prior single-arm trial.

Objectives: To evaluate the efficacy and safety of nab-paclitaxel vs paclitaxel in platinum-refractory mUC.

Design, Setting, And Participants: In this investigator-initiated, open-label, phase 2 randomized clinical trial conducted across Canada and Australia from January 2014 to April 2017, eligible patients had histologically confirmed, radiologically evident mUC of the urinary tract. Mixed histologic findings, except small cell, were permitted provided UC was the predominant histologic finding. All patients had received platinum-based chemotherapy either in the metastatic setting or were within 12 months of perioperative chemotherapy. Patients with prior taxane chemotherapy were not included. Patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 to 2 and adequate organ function.

Interventions: Patients were randomized to nab-paclitaxel, 260 mg/m2, or paclitaxel, 175 mg/m2, every 3 weeks.

Main Outcomes And Measures: The primary end point was progression-free survival (PFS).

Results: Among 199 patients, median age was 67 (range, 24-88) years; 144 (72%) were men; 167 (84%) were ECOG PS 0-1; 59 (30%) had liver metastases; and 110 (55%) were within 6 months of prior platinum-based chemotherapy. At a median follow-up of 16.4 months, there was no significant difference between nab-paclitaxel vs paclitaxel for median PFS (3.4 months vs 3.0 months; hazard ratio [HR], 0.92; 90% CI, 0.68-1.23; 1-sided P = .31). Median overall survival was 7.5 months for nab-paclitaxel vs 8.8 months for paclitaxel (HR, 0.95; 90% CI, 0.70-1.30; 1-sided P = .40); and objective response rate (ORR) was 22% for nab-paclitaxel vs 25% for paclitaxel (P = .97). Grade 3/4 adverse events were more frequent with nab-paclitaxel (64/97 [66%]) compared with paclitaxel (45/97 [46%]), P = .009; but peripheral sensory neuropathy was similar (all grades, 72/97 [74%] vs 64/97 [66%]; grade 3/4, 7/97 [7%] vs 3/97 [3%]; P = .27). There were no apparent differences in scores for health-related quality of life.

Conclusions And Relevance: In this open-label, phase 2 randomized clinical trial of patients with platinum-refractory mUC, nab-paclitaxel had similar efficacy to paclitaxel; but worse toxic effects. The ORR with either taxane, however, was higher than previously reported and similar to those reported for the immune checkpoint inhibitors, suggesting that the taxanes remain a reasonable option in this setting.

Trial Registration: ClinicalTrials.gov Identifier: NCT02033993.
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http://dx.doi.org/10.1001/jamaoncol.2020.3927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499236PMC
September 2020

Digest: Transgenerational stress memory mechanisms in Arabidopsis thaliana.

Evolution 2020 10 18;74(10):2423-2424. Epub 2020 Sep 18.

Department of Biology, Western University, London, Ontario, Canada.

Arabidopsis thaliana accessions have shown genetic diversity and type of stressor to be important determinants of transgenerational stress memory. Alvarez et al. found that certain accessions showed reversible phenotypic plasticity, supporting a model of transgenerational stress memory based upon epigenetic changes. The main proposed epigenetic regulators include DNA methylation, histone modifications, and RNA silencing via small noncoding RNA.
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http://dx.doi.org/10.1111/evo.14096DOI Listing
October 2020

Eliminating the First Inactive State and Stabilizing the Active State of the Cardiac Regulatory System Alters Behavior in Solution and in Ordered Systems.

Biochemistry 2020 09 9;59(37):3487-3497. Epub 2020 Sep 9.

Department of Biochemistry & Molecular Biology, Brody School of Medicine at East Carolina University, Greenville, North Carolina, United States.

Calcium binding to troponin C (TnC) is insufficient for full activation of myosin ATPase activity by actin-tropomyosin-troponin. Previous attempts to investigate full activation utilized ATP-free myosin or chemically modified myosin to stabilize the active state of regulated actin. We utilized the Δ14-TnT and the A8V-TnC mutants to stabilize the activated state at saturating Ca and to eliminate one of the inactive states at low Ca. The observed effects differed in solution studies and in the more ordered in vitro motility assay and in skinned cardiac muscle preparations. At saturating Ca, full activation with Δ14-TnT·A8V-TnC decreased the apparent for actin-activated ATPase activity compared to bare actin filaments. Rates of in vitro motility increased at both high and low Ca with Δ14-TnT; the maximum shortening speed at high Ca increased 1.8-fold. Cardiac muscle preparations exhibited increased Ca sensitivity and large increases in resting force with either Δ14-TnT or Δ14-TnT·A8V-TnC. We also observed a significant increase in the maximal rate of tension redevelopment. The results of full activation with Ca and Δ14-TnT·A8V-TnC confirmed and extended several earlier observations using other means of reaching full activation. Furthermore, at low Ca, elimination of the first inactive state led to partial activation. This work also confirms, in three distinct experimental systems, that troponin is able to stabilize the active state of actin-tropomyosin-troponin without the need for high-affinity myosin binding. The results are relevant to the reason for two inactive states and for the role of force producing myosin in regulation.
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http://dx.doi.org/10.1021/acs.biochem.0c00430DOI Listing
September 2020

Limbic-predominant age-related TDP-43 encephalopathy differs from frontotemporal lobar degeneration.

Brain 2020 09;143(9):2844-2857

Department of Pathology, University of Kentucky, Lexington, KY, USA.

TAR-DNA binding protein-43 (TDP-43) proteinopathy is seen in multiple brain diseases. A standardized terminology was recommended recently for common age-related TDP-43 proteinopathy: limbic-predominant, age-related TDP-43 encephalopathy (LATE) and the underlying neuropathological changes, LATE-NC. LATE-NC may be co-morbid with Alzheimer's disease neuropathological changes (ADNC). However, there currently are ill-defined diagnostic classification issues among LATE-NC, ADNC, and frontotemporal lobar degeneration with TDP-43 (FTLD-TDP). A practical challenge is that different autopsy cohorts are composed of disparate groups of research volunteers: hospital- and clinic-based cohorts are enriched for FTLD-TDP cases, whereas community-based cohorts have more LATE-NC cases. Neuropathological methods also differ across laboratories. Here, we combined both cases and neuropathologists' diagnoses from two research centres-University of Pennsylvania and University of Kentucky. The study was designed to compare neuropathological findings between FTLD-TDP and pathologically severe LATE-NC. First, cases were selected from the University of Pennsylvania with pathological diagnoses of either FTLD-TDP (n = 33) or severe LATE-NC (mostly stage 3) with co-morbid ADNC (n = 30). Sections from these University of Pennsylvania cases were cut from amygdala, anterior cingulate, superior/mid-temporal, and middle frontal gyrus. These sections were stained for phospho-TDP-43 immunohistochemically and evaluated independently by two University of Kentucky neuropathologists blinded to case data. A simple set of criteria hypothesized to differentiate FTLD-TDP from LATE-NC was generated based on density of TDP-43 immunoreactive neuronal cytoplasmic inclusions in the neocortical regions. Criteria-based sensitivity and specificity of differentiating severe LATE-NC from FTLD-TDP cases with blind evaluation was ∼90%. Another proposed neuropathological feature related to TDP-43 proteinopathy in aged individuals is 'Alpha' versus 'Beta' in amygdala. Alpha and Beta status was diagnosed by neuropathologists from both universities (n = 5 raters). There was poor inter-rater reliability of Alpha/Beta classification (mean κ = 0.31). We next tested a separate cohort of cases from University of Kentucky with either FTLD-TDP (n = 8) or with relatively 'pure' severe LATE-NC (lacking intermediate or severe ADNC; n = 14). The simple criteria were applied by neuropathologists blinded to the prior diagnoses at University of Pennsylvania. Again, the criteria for differentiating LATE-NC from FTLD-TDP was effective, with sensitivity and specificity ∼90%. If more representative cases from each cohort (including less severe TDP-43 proteinopathy) had been included, the overall accuracy for identifying LATE-NC was estimated at >98% for both cohorts. Also across both cohorts, cases with FTLD-TDP died younger than those with LATE-NC (P < 0.0001). We conclude that in most cases, severe LATE-NC and FTLD-TDP can be differentiated by applying simple neuropathological criteria.
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http://dx.doi.org/10.1093/brain/awaa219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526723PMC
September 2020

Identification of Genes Required for Resistance to Peptidomimetic Antibiotics by Transposon Sequencing.

Front Microbiol 2020 23;11:1681. Epub 2020 Jul 23.

Department of Plant and Microbial Biology, University of Zurich, Zurich, Switzerland.

is an opportunistic human pathogen and a leading cause of nosocomial infections. Due to its high intrinsic and adaptive resistance to antibiotics, infections caused by this organism are difficult to treat and new therapeutic options are urgently needed. Novel peptidomimetic antibiotics that target outer membrane (OM) proteins have shown great promise for the treatment of infections. Here, we have performed genome-wide mutant fitness profiling using transposon sequencing (Tn-Seq) to identify resistance determinants against the recently described peptidomimetics L27-11, compounds 3 and 4, as well as polymyxin B2 (PMB) and colistin (COL). We identified a set of 13 core genes that affected resistance to all tested antibiotics, many of which encode enzymes involved in the modification of the lipopolysaccharide (LPS) or control their expression. We also identified fitness determinants that are specific for antibiotics with similar structures that may indicate differences in their modes of action. These results provide new insights into resistance mechanisms against these peptide antibiotics, which will be important for future clinical development and efforts to further improve their potency.
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http://dx.doi.org/10.3389/fmicb.2020.01681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390954PMC
July 2020

"The biggest barrier is to inclusion itself": the experience of citizenship for adults with mental health problems.

J Ment Health 2020 Aug 7:1-8. Epub 2020 Aug 7.

Department of Psychiatry, Yale University, New Haven, CT, USA.

Background: Citizenship has been promoted within mental health for several decades however, its application in the field of mental health policy and practice is relatively novel. The voices of people who experience mental health problems (MHPs) are often absent in ongoing discourses about citizenship.

Aims: To explore how adults with experience of MHPs and other life disruptions identify potential barriers to citizenship.

Method: A community based participatory research approach was adopted with peer researchers. Six focus groups (N = 40) using semi-structured interviews were conducted, consisting of participants who had experience of MHPs and other life disruption(s) within the last 5 years. The focus groups were audio recorded, transcribed verbatim and analysed in NVIVO using a thematic approach.

Results: Three major themes associated with participants lived experiences of barriers to citizenship were identified: 'stigmatisation (internal & external) creates further divide'; 'being socially excluded leads to isolation'; and 'a sense of difference (as perceived by the self and others)'.

Conclusions: Those who have experienced major life disruption(s) face multi-level barriers to citizenship. An awareness of such barriers has important implications for mental health research, policy and practice. Citizenship-oriented implementation strategies that aim to address multi-level barriers merit further investigation.
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http://dx.doi.org/10.1080/09638237.2020.1803491DOI Listing
August 2020

ADNC-RS, a clinical-genetic risk score, predicts Alzheimer's pathology in autopsy-confirmed Parkinson's disease and Dementia with Lewy bodies.

Acta Neuropathol 2020 10 4;140(4):449-461. Epub 2020 Aug 4.

Departments of Neurology, University of Pennsylvania, 3 West Gates, 3400 Spruce Street, Philadelphia, PA, 19104, USA.

Growing evidence suggests overlap between Alzheimer's disease (AD) and Parkinson's disease (PD) pathophysiology in a subset of patients. Indeed, 50-80% of autopsy cases with a primary clinicopathological diagnosis of Lewy body disease (LBD)-most commonly manifesting during life as PD-have concomitant amyloid-beta and tau pathology, the defining pathologies of AD. Here we evaluated common genetic variants in genome-wide association with AD as predictors of concomitant AD pathology in the brains of people with a primary clinicopathological diagnosis of PD or Dementia with Lewy Bodies (DLB), diseases both characterized by neuronal Lewy bodies. In the first stage of our study, 127 consecutive autopsy-confirmed cases of PD or DLB from a single center were assessed for AD neuropathological change (ADNC), and these same cases were genotyped at 20 single nucleotide polymorphisms (SNPs) found by genome-wide association study to associate with risk for AD. In these 127 training set individuals, we developed a logistic regression model predicting the presence of ADNC, using backward stepwise regression for model selection and tenfold cross-validation to estimate performance. The best-fit model generated a risk score for ADNC (ADNC-RS) based on age at disease onset and genotype at three SNPs (APOE, BIN1, and SORL1 loci), with an area under the receiver operating curve (AUC) of 0.751 in our training set. In the replication stage of our study, we assessed model performance in a separate test set of the next 81 individuals genotyped in our center. In the test set, the AUC was 0.781, and individuals with ADNC-RS in the top quintile had four-fold increased likelihood of having AD pathology at autopsy compared with those in each of the lowest two quintiles. Finally, in the validation stage of our study, we applied our ADNC-RS model to 70 LBD individuals from 20 Alzheimer's Disease Research Centers (ADRC) whose autopsy and genetic data were available in the National Alzheimer's Coordinating Center (NACC) database. In this validation set, the AUC was 0.754. Thus, in patients with autopsy-confirmed PD or DLB, a simple model incorporating three AD-risk SNPs and age at disease onset substantially enriches for concomitant AD pathology at autopsy, with implications for identifying LBD patients in which targeting amyloid-beta or tau is a therapeutic strategy.
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http://dx.doi.org/10.1007/s00401-020-02199-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864557PMC
October 2020

Defining and predicting transdiagnostic categories of neurodegenerative disease.

Nat Biomed Eng 2020 08 3;4(8):787-800. Epub 2020 Aug 3.

Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA.

The prevalence of concomitant proteinopathies and heterogeneous clinical symptoms in neurodegenerative diseases hinders the identification of individuals who might be candidates for a particular intervention. Here, by applying an unsupervised clustering algorithm to post-mortem histopathological data from 895 patients with degeneration in the central nervous system, we show that six non-overlapping disease clusters can simultaneously account for tau neurofibrillary tangles, α-synuclein inclusions, neuritic plaques, inclusions of the transcriptional repressor TDP-43, angiopathy, neuron loss and gliosis. We also show that membership to the six transdiagnostic disease clusters, which explains more variance in cognitive phenotypes than can be explained by individual diagnoses, can be accurately predicted from scores of the Mini-Mental Status Exam, protein levels in cerebrospinal fluid, and genotype at the APOE and MAPT loci, via cross-validated multiple logistic regression. This combination of unsupervised and supervised data-driven tools provides a framework that could be used to identify latent disease subtypes in other areas of medicine.
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http://dx.doi.org/10.1038/s41551-020-0593-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946378PMC
August 2020

Digest: Parasite adaptation to light alters transmission and fecundity†.

Evolution 2020 08 24;74(8):1881-1882. Epub 2020 Jul 24.

Department of Biology, Western University, London, Ontario, Canada.

Natural variation as well as human impacts can alter the light environment in lakes in ways that affect aquatic host-parasite interactions. In laboratory infection assays, Rogalski and Duffy (2020) determine that the bacterial parasite Pasteuria ramosa adapts to solar radiation by increasing its transmission potential to its zooplankton host, Daphnia dentifera. Local adaptation to light can allow P. ramosa spores to retain their infectivity following light exposure. Future work should determine the underlying drivers of P. ramosa light adaptation and how adaptation might alter ecosystem dynamics.
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http://dx.doi.org/10.1111/evo.14064DOI Listing
August 2020

Thorn-shaped astrocytes in the depth of cortical sulci in Western Pacific ALS/Parkinsonism-Dementia complex.

Acta Neuropathol 2020 10 13;140(4):591-593. Epub 2020 Jul 13.

Center for Neurodegenerative Disease Research (CNDR), Institute On Aging and Department of Pathology and Laboratory Medicine, University of Pennsylvania, 3600 Spruce Street, 3 Maloney Building, Philadelphia, PA, 19104-4283, USA.

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http://dx.doi.org/10.1007/s00401-020-02192-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986993PMC
October 2020

Tau immunophenotypes in chronic traumatic encephalopathy recapitulate those of ageing and Alzheimer's disease.

Brain 2020 05;143(5):1572-1587

Department of Neurosurgery, Penn Center for Brain Injury and Repair, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Traumatic brain injury (TBI) is a risk factor for neurodegenerative disease, including chronic traumatic encephalopathy (CTE). Preliminary consensus criteria define the pathognomonic lesion of CTE as patchy tau pathology within neurons and astrocytes at the depths of cortical sulci. However, the specific tau isoform composition and post-translational modifications in CTE remain largely unexplored. Using immunohistochemistry, we performed tau phenotyping of CTE neuropathologies and compared this to a range of tau pathologies, including Alzheimer's disease, primary age-related tauopathy, ageing-related tau astrogliopathy and multiple subtypes of frontotemporal lobar degeneration with tau inclusions. Cases satisfying preliminary consensus diagnostic criteria for CTE neuropathological change (CTE-NC) were identified (athletes, n = 10; long-term survivors of moderate or severe TBI, n = 4) from the Glasgow TBI Archive and Penn Neurodegenerative Disease Brain Bank. In addition, material from a range of autopsy-proven ageing-associated and primary tauopathies in which there was no known history of exposure to TBI was selected as non-injured controls (n = 32). Each case was then stained with a panel of tau antibodies specific for phospho-epitopes (PHF1, CP13, AT100, pS262), microtubule-binding repeat domains (3R, 4R), truncation (Tau-C3) or conformation (GT-7, GT-38) and the extent and distribution of staining assessed. Cell types were confirmed with double immunofluorescent labelling. Results demonstrate that astroglial tau pathology in CTE is composed of 4R-immunoreactive thorn-shaped astrocytes, echoing the morphology and immunophenotype of astrocytes encountered in ageing-related tau astrogliopathy. In contrast, neurofibrillary tangles of CTE contain both 3R and 4R tau, with post-translational modifications and conformations consistent with Alzheimer's disease and primary age-related tauopathy. Our observations establish that the astroglial and neurofibrillary tau pathologies of CTE are phenotypically distinct from each other and recapitulate the tau immunophenotypes encountered in ageing and Alzheimer's disease. As such, the immunohistochemical distinction of CTE neuropathology from other mixed 3R/4R tauopathies of Alzheimer's disease and ageing may rest solely on the pattern and distribution of pathology.
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http://dx.doi.org/10.1093/brain/awaa071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241956PMC
May 2020

Cardiac troponin and tropomyosin bind to F-actin cooperatively, as revealed by fluorescence microscopy.

FEBS Open Bio 2020 07 18;10(7):1362-1372. Epub 2020 Jun 18.

South Dakota State University, Brookings, SD, USA.

In cardiac muscle, binding of troponin (Tn) and tropomyosin (Tpm) to filamentous (F)-actin forms thin filaments capable of Ca -dependent regulation of contraction. Tpm binds to F-actin in a head-to-tail fashion, while Tn stabilizes these linkages. Valuable structural and functional information has come from biochemical, X-ray, and electron microscopy data. However, the use of fluorescence microscopy to study thin filament assembly remains relatively underdeveloped. Here, triple fluorescent labeling of Tn, Tpm, and F-actin allowed us to track thin filament assembly by fluorescence microscopy. It is shown here that Tn and Tpm molecules self-organize on actin filaments and give rise to decorated and undecorated regions. Binding curves based on colocalization of Tn and Tpm on F-actin exhibit cooperative binding with a dissociation constant K of ~ 0.5 µm that is independent of the Ca concentration. Binding isotherms based on the intensity profile of fluorescently labeled Tn and Tpm on F-actin show that binding of Tn is less cooperative relative to Tpm. Computational modeling of Tn-Tpm binding to F-actin suggests two equilibrium steps involving the binding of an initial Tn-Tpm unit (nucleation) and subsequent recruitment of adjacent Tn-Tpm units (elongation) that stabilize the assembly. The results presented here highlight the utility of employing fluorescence microscopy to study supramolecular protein assemblies.
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http://dx.doi.org/10.1002/2211-5463.12876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327902PMC
July 2020

Distribution patterns of tau pathology in progressive supranuclear palsy.

Acta Neuropathol 2020 08 7;140(2):99-119. Epub 2020 May 7.

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of tau pathologies across different brain regions. Tau pathology uniformly predominates in the neurons of the pallido-nigro-luysian axis in different clinical subtypes. However, clinical subtypes are distinguished not only by total tau load but rather cell-type (neuronal versus glial) specific vulnerability patterns of brain regions suggesting distinct dynamics or circuit-specific segregation of propagation of tau pathologies. For Richardson syndrome (n = 81) we recognize six sequential steps of involvement of brain regions by the combination of cellular tau pathologies. This is translated to six stages for the practical neuropathological diagnosis by the evaluation of the subthalamic nucleus, globus pallidus, striatum, cerebellum with dentate nucleus, and frontal and occipital cortices. This system can be applied to further clinical subtypes by emphasizing whether they show caudal (cerebellum/dentate nucleus) or rostral (cortical) predominant, or both types of pattern. Defining cell-specific stages of tau pathology helps to identify preclinical or early-stage cases for the better understanding of early pathogenic events, has implications for understanding the clinical subtype-specific dynamics of disease-propagation, and informs tau-neuroimaging on distribution patterns.
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http://dx.doi.org/10.1007/s00401-020-02158-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360645PMC
August 2020

Asymmetrical gene flow in five co-distributed syngnathids explained by ocean currents and rafting propensity.

Proc Biol Sci 2020 05 6;287(1926):20200657. Epub 2020 May 6.

Department of Biology, City College of New York, 160 Convent Avenue, New York, NY 10031, USA.

Ocean circulation driving macro-algal rafting is believed to serve as an important mode of dispersal for many marine organisms, leading to predictions on population-level genetic connectivity and the directionality of effective dispersal. Here, we use genome-wide single nucleotide polymorphism data to investigate whether gene flow directionality in two seahorses () and three pipefishes () follows the predominant ocean circulation patterns in the Gulf of Mexico and northwestern Atlantic. In addition, we explore whether gene flow magnitudes are predicted by traits related to active dispersal ability and habitat preference. We inferred demographic histories of these co-distributed syngnathid species, and coalescent model-based estimates indicate that gene flow directionality is in agreement with ocean circulation data that predicts eastward and northward macro-algal transport. However, the magnitude to which ocean currents influence this pattern appears strongly dependent on the species-specific traits related to rafting propensity and habitat preferences. Higher levels of gene flow and stronger directionality are observed in , and , which closely associated with the pelagic macro-algae spp., compared to and the / sister-species pair, which prefer near shore habitats and are weakly associated with pelagic . This study highlights how the combination of population genomic inference together with ocean circulation data can help explain patterns of population structure and diversity in marine ecosystems.
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http://dx.doi.org/10.1098/rspb.2020.0657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282920PMC
May 2020

Contribution of mixed pathology to medial temporal lobe atrophy in Alzheimer's disease.

Alzheimers Dement 2020 06 22;16(6):843-852. Epub 2020 Apr 22.

Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Introduction: It is unclear how different proteinopathies (tau, transactive response DNA-binding protein 43 [TDP-43], amyloid β [Aβ], and α-synuclein) contribute to atrophy within medial temporal lobe (MTL) subregions in Alzheimer's disease (AD).

Methods: We utilized antemortem structural magnetic resonance imaging (MRI) data to measure MTL substructures and examined the relative contribution of tau, TDP-43, Aβ, and α-synuclein measured in post-mortem tissue from 92 individuals with intermediate to high AD neuropathology. Receiver-operating characteristic (ROC) curves were analyzed for each subregion in order to discriminate TDP-43-negative and TDP-43-positive patients.

Results: TDP-43 was strongly associated with anterior MTL regions, whereas tau was relatively more associated with the posterior hippocampus. Among the MTL regions, the anterior hippocampus showed the highest area under the ROC curve (AUC).

Discussion: We found specific contributions of different pathologies on MTL substructure in this population with AD neuropathology. The anterior hippocampus may be a relevant region to detect concomitant TDP-43 pathology in the MTL of patients with AD.
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http://dx.doi.org/10.1002/alz.12079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7715004PMC
June 2020