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The process of identifying suitable genome-wide association (GWA) studies and formatting the data to calculate multiple polygenic risk scores on a single genome can be laborious. Here, we present a centralized polygenic risk score calculator currently containing over 250,000 genetic variant associations from the NHGRI-EBI GWAS Catalog for users to easily calculate sample-specific polygenic risk scores with comparable results to other available tools. Polygenic risk scores are calculated either online through the Polygenic Risk Score Knowledge Base (PRSKB; https://prs.byu.edu ) or via a command-line interface. We report study-specific polygenic risk scores across the UK Biobank, 1000 Genomes, and the Alzheimer's Disease Neuroimaging Initiative (ADNI), contextualize computed scores, and identify potentially confounding genetic risk factors in ADNI. We introduce a streamlined analysis tool and web interface to calculate and contextualize polygenic risk scores across various studies, which we anticipate will facilitate a wider adaptation of polygenic risk scores in future disease research.

AM Kolodziejczyk,1 GD Brzezinka,1 K Khurana,1,2 M Targosz-Korecka,1 M Szymonski11Research Centre for Nanometer-Scale Science and Advanced Materials, NANOSAM, Faculty of Physics, Astronomy and Applied Computer Science, Jagiellonian University, Krakow, Poland; 2Centre for Environmental Risk Assessment and Remediation (CERAR), University of South Australia, AustraliaBackground: There is increasing evidence that cell elastic properties should change considerably in response to chemical agents affecting the physiological state of the endothelium. In this work, a novel assay for testing prospective endothelium-targeted agents in vitro is presented.Materials and methods: The proposed methodology is based on nanoindentation spectroscopy using an atomic force microscope tip, which allows for quantitative evaluation of cell stiffness. As an example, we chose a pyridine derivative, 1-methylnicotinamide chloride (MNA), known to have antithrombotic and anti-inflammatory properties, as reported in recent in vivo experiments.Results: First, we determined a concentration range of MNA in which physiological parameters of the endothelial cells in vitro are not affected. Then, cell dysfunction was induced by incubation with tumor necrosis factor-alpha (TNF-α) and the cellular response to MNA treatment after TNF-α incubation was studied. In parallel to the nanoindentation spectroscopy, the endothelium phenotype was characterized using a fluorescence spectroscopy with F-actin labeling, and biochemical methods, such as secretion measurements of both nitric oxide (NO), and prostacyclin (PGI2) regulatory agents.Conclusion: We found that MNA could reverse the dysfunction of the endothelium caused by inflammation, if applied in the proper time and to the concentration scheme established in our investigations. A surprisingly close correlation was found between effective Young's modulus of the cells and actin polymerization/depolymerization processes in the endothelium cortical cytoskeleton, as well as NO and PGI2 levels. These results allow us to construct the physiological model of sequential intracellular pathways activated in the endothelium by MNA.Keywords: endothelium, cell stiffness, 1-methylnicotinamide chloride, atomic force microscopy, nanomechanical sensing

Introduction: We evaluated preliminary feasibility of a digital, culturally-informed approach to recruit and screen participants for the Alzheimer's Disease Neuroimaging Initiative (ADNI4)., Methods: Participants were recruited using digital advertising and completed digital surveys (e.g., demographics, medical exclusion criteria, 12-item Everyday Cognition Scale [ECog-12]), Novoic Storyteller speech-based cognitive test). Completion rates and assessment performance were compared between underrepresented populations (URPs: individuals from ethnoculturally minoritized or low education backgrounds) and non-URPs., Results: Of 3099 participants who provided contact information, 654 enrolled in the cohort, and 595 completed at least one assessment. Two hundred forty-seven participants were from URPs. Of those enrolled, 465 met ADNI4 inclusion criteria and 237 evidenced possible cognitive impairment from ECog-12 or Storyteller performance. URPs had lower ECog and Storyteller completion rates. Scores varied by ethnocultural group and educational level., Discussion: Preliminary results demonstrate digital recruitment and screening assessment of an older diverse cohort, including those with possible cognitive impairment, are feasible. Improving engagement and achieving educational diversity are key challenges., Highlights: A total of 654 participants enrolled in a digital cohort to facilitate ADNI4 recruitment. Culturally-informed digital ads aided enrollment of underrepresented populations. From those enrolled, 42% were from underrepresented ethnocultural and educational groups. Digital screening tools indicate > 50% of participants likely cognitively impaired. Completion rates and assessment performance vary by ethnocultural group and education., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disease. Although it leads to muscle weakness, affected individuals predominantly die from cardiomyopathy, which remains uncurable. Accumulating evidence suggests that an overexpression of utrophin may counteract some of the pathophysiological outcomes of DMD. The aim of this study was to investigate the role of utrophin in dystrophin-deficient human cardiomyocytes (CMs) and to test whether an overexpression of utrophin, implemented via the CRISPR-deadCas9-VP64 system, can improve their phenotype. We used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) lacking either dystrophin (DMD) or both dystrophin and utrophin (DMD KO/UTRN (+/-) ). We carried out proteome analysis, which revealed considerable differences in the proteins related to muscle contraction, cell-cell adhesion, and extracellular matrix organization. Furthermore, we evaluated the role of utrophin in maintaining the physiological properties of DMD hiPSC-CMs using atomic force microscopy, patch-clamp, and Ca 2+ oscillation analysis. Our results showed higher values of afterhyperpolarization and altered patterns of cytosolic Ca 2+ oscillations in DMD; the latter was further disturbed in DMD KO/UTRN (+/-) hiPSC-CMs. Utrophin upregulation improved both parameters. Our findings demonstrate for the first time that utrophin maintains the physiological functions of DMD hiPSC-CMs, and that its upregulation can compensate for the loss of dystrophin., Competing Interests: The authors declare that they have no conflict of interest and have no relationships with the industry., (© 2024 The Authors.)

Background: Development of validated biomarkers to detect early Alzheimer disease (AD) neuropathology is needed for therapeutic AD trials. Abnormal concentrations of "core" AD biomarkers, cerebrospinal fluid (CSF) amyloid beta1-42, total tau, and phosphorylated tau correlate well with neuroimaging biomarkers and autopsy findings. Nevertheless, given the limitations of established CSF and neuroimaging biomarkers, accelerated development of blood-based AD biomarkers is underway., Content: Here we describe the clinical significance of CSF and plasma AD biomarkers to detect disease pathology throughout the Alzheimer continuum and correlate with imaging biomarkers. Use of the AT(N) classification by CSF and imaging biomarkers provides a more objective biologically based diagnosis of AD than clinical diagnosis alone. Significant progress in measuring CSF AD biomarkers using extensively validated highly automated assay systems has facilitated their transition from research use only to approved in vitro diagnostics tests for clinical use. We summarize development of plasma AD biomarkers as screening tools for enrollment and monitoring participants in therapeutic trials and ultimately in clinical care. Finally, we discuss the challenges for AD biomarkers use in clinical trials and precision medicine, emphasizing the possible ethnocultural differences in the levels of AD biomarkers., Summary: CSF AD biomarker measurements using fully automated analytical platforms is possible. Building on this experience, validated blood-based biomarker tests are being implemented on highly automated immunoassay and mass spectrometry platforms. The progress made developing analytically and clinically validated plasma AD biomarkers within the AT(N) classification scheme can accelerate use of AD biomarkers in therapeutic trials and routine clinical practice., (© Association for Diagnostics & Laboratory Medicine 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The battle against emerging viral infections has been uneven, as there is currently no broad-spectrum drug available to contain the spread of novel pathogens throughout the population. Consequently, the pandemic outbreak that occurred in early 2020 laid bare the almost empty state of the pandemic box. Therefore, the development of novel treatments with broad specificity has become a paramount concern in this post-pandemic era. Here, we propose copolymers of poly (sodium 2-(acrylamido)-2-methyl-1-propanesulfonate) (PAMPS) and poly (sodium 11-(acrylamido)undecanoate (AaU), both block (PAMPS 75 -b-PAaU n ) and random (P(AMPS m -co-AaU n )) that show efficacy against a broad range of alpha and betacoronaviruses. Owing to their intricate architecture, these polymers exhibit a highly distinctive mode of action, modulating nano-mechanical properties of cells and thereby influencing viral replication. Through the employment of confocal and atomic force microscopy techniques, we discerned perturbations in actin and vimentin filaments, which correlated with modification of cellular elasticity and reduction of glycocalyx layer. Intriguingly, this process was reversible upon polymer removal from the cells. To ascertain the applicability of our findings, we assessed the efficacy and underlying mechanism of the inhibitors using fully differentiated human airway epithelial cultures, wherein near-complete abrogation of viral replication was documented. Given their mode of action, these polymers can be classified as biologically active nanomaterials that exploit a highly conserved molecular target-cellular plasticity-proffering the potential for truly broad-spectrum activity while concurrently for drug resistance development is minimal., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests Krzysztof Pyrc reports financial support was provided by 10.13039/501100004281National Science Centre Poland. Maria Nowakowska reports financial support was provided by 10.13039/501100004281National Science Centre Poland., (© 2023 The Authors.)

Hyperpolarized (HP) xenon-129 ( 129 Xe), when dissolved in blood, has two NMR resonances: one in red blood cells (RBC) and one in plasma. The impact of numerous blood components on these resonances, however, has not yet been investigated. This study evaluates the effects of elevated glucose levels on the chemical shift (CS) and T2* relaxation times of HP 129 Xe dissolved in sterile citrated sheep blood for the first time. HP 129 Xe was mixed with sheep blood samples premixed with a stock glucose solution using a liquid-gas exchange module. Magnetic resonance spectroscopy was performed on a 3T clinical MRI scanner using a custom-built quadrature dual-tuned 129 Xe/ 1 H coil. We observed an additional resonance for the RBCs ( 129 Xe-RBC1) for the increased glucose levels. The CS of 129 Xe-RBC1 and 129 Xe-plasma peaks did not change with glucose levels, while the CS of 129 Xe-RBC2 (original RBC resonance) increased linearly at a rate of 0.015 ± 0.002 ppm/mM with glucose level. 129 Xe-RBC1 T2* values increased nonlinearly from 1.58 ± 0.24 ms to 2.67 ± 0.40 ms. As a result of the increased glucose levels in blood samples, the novel additional HP 129 Xe dissolved phase resonance was observed in blood and attributed to the 129 Xe bound to glycated hemoglobin (HbA 1c ).

Aims: Endothelial dysfunction (ED) and red blood cell distribution width (RDW) are both prognostic factors in heart failure (HF), but the relationship between them is not clear. In this study, we used a unique mouse model of chronic HF driven by cardiomyocyte-specific overexpression of activated Gαq protein (Tgαq*44 mice) to characterize the relationship between the development of peripheral ED and the occurrence of structural nanomechanical and biochemical changes in red blood cells (RBCs)., Methods and Results: Systemic ED was detected in vivo in 8-month-old Tgαq*44 mice, as evidenced by impaired acetylcholine-induced vasodilation in the aorta and increased endothelial permeability in the brachiocephalic artery. ED in the aorta was associated with impaired nitric oxide (NO) production in the aorta and diminished systemic NO bioavailability. ED in the aorta was also characterized by increased superoxide and eicosanoid production. In 4- to 6-month-old Tgαq*44 mice, RBC size and membrane composition displayed alterations that did not result in significant changes in their nanomechanical and functional properties. However, 8-month-old Tgαq*44 mice presented greatly accentuated structural and size changes and increased RBC stiffness. In 12-month-old Tgαq*44 mice, the erythropathy was featured by severely altered RBC shape and elasticity, increased RDW, impaired RBC deformability, and increased oxidative stress (gluthatione (GSH)/glutathione disulfide (GSSG) ratio). Moreover, RBCs taken from 12-month-old Tgαq*44 mice, but not from 12-month-old FVB mice, coincubated with aortic rings from FVB mice, induced impaired endothelium-dependent vasodilation and this effect was partially reversed by an arginase inhibitor [2(S)-amino-6-boronohexanoic acid]., Conclusion: In the Tgαq*44 murine model of HF, systemic ED accelerates erythropathy and, conversely, erythropathy may contribute to ED. These results suggest that erythropathy may be regarded as a marker and a mediator of systemic ED in HF. RBC arginase and possibly other RBC-mediated mechanisms may represent novel therapeutic targets for systemic ED in HF., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Extracellular vesicles, especially the larger fraction (LEVs - large extracellular vesicles), are believed to be an important means of intercellular communication. Earlier studies on LEVs have shown their healing properties, especially in the vascular cells of diabetic patients. Uptake of LEVs by endothelial cells and internalization of their cargo have also been demonstrated. Endothelial cells change their properties under hyperglycemic conditions (HGC), which reduces their activity and is the cause of endothelial dysfunction. The aim of our study was to investigate how human umbilical vein endothelial cells (HUVECs) change their biological properties: shape, mobility, cell surface stiffness, as well as describe the activation of metabolic pathways after exposure to the harmful effects of HGC and the administration of LEVs released by endothelial cells. We obtained LEVs from HUVEC cultures in HGC and normoglycemia (NGC) using the filtration and ultracentrifugation methods. We assessed the size of LEVs and the presence of biomarkers such as phosphatidylserine, CD63, beta-actin and HSP70. We analyzed the LEVs uptake efficiency by HUVECs, HUVEC shape, actin cytoskeleton remodeling, surface stiffness and finally gene expression by mRNA analysis. Under HGC conditions, HUVECs were larger and had a stiffened surface and a strengthened actin cortex compared to cells under NGC condition. HGC also altered the activation of metabolic pathways, especially those related to intracellular transport, metabolism, and organization of cellular components. The most interesting observation in our study is that LEVs did not restore cell motility disturbed by HGC. Although, LEVs were not able to reverse this deleterious effect of HGC, they activated transcription of genes involved in protein synthesis and vesicle trafficking in HUVECs., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background and Objectives: To determine the diagnostic accuracy of a plasma Aβ42/Aβ40 assay in classifying amyloid PET status across global research studies using samples collected by multiple centers that utilize different blood collection and processing protocols., Methods: Plasma samples (n = 465) were obtained from 3 large Alzheimer disease (AD) research cohorts in the United States (n = 182), Australia (n = 183), and Sweden (n = 100). Plasma Aβ42/Aβ40 was measured by a high precision immunoprecipitation mass spectrometry (IPMS) assay and compared to the reference standards of amyloid PET and CSF Aβ42/Aβ40., Results: In the combined cohort of 465 participants, plasma Aβ42/Aβ40 had good concordance with amyloid PET status (receiver operating characteristic area under the curve [AUC] 0.84, 95% confidence interval [CI] 0.80-0.87); concordance improved with the inclusion of APOE ε4 carrier status (AUC 0.88, 95% CI 0.85-0.91). The AUC of plasma Aβ42/Aβ40 with CSF amyloid status was 0.85 (95% CI 0.78-0.91) and improved to 0.93 (95% CI 0.89-0.97) with APOE ε4 status. These findings were consistent across the 3 cohorts, despite differences in protocols. The assay performed similarly in both cognitively unimpaired and impaired individuals., Discussion: Plasma Aβ42/Aβ40 is a robust measure for detecting amyloid plaques and can be utilized to aid in the diagnosis of AD, identify those at risk for future dementia due to AD, and improve the diversity of populations enrolled in AD research and clinical trials., Classification of Evidence: This study provides Class II evidence that plasma Aβ42/Aβ40, as measured by a high precision IPMS assay, accurately diagnoses brain amyloidosis in both cognitively unimpaired and impaired research participants., (© 2021 American Academy of Neurology.)

In recent years, atomic force spectroscopy (AFS) has been used to detect and characterize the endothelial glycocalyx (eGlx) in in vitro and ex vivo experiments. Several analysis methods were proposed, which differ not only in the numerical implementations, but also in physical models of glycocalyx description. Therefore, it is difficult to directly relate the experiments performed by different groups. In this work, we compared different models used for quantitative analysis of atomic force spectroscopy datasets recorded for eGlx. To capture glycocalyx at various structural conditions, we used basic enzymatic protocols for glycocalyx removal and restoration in human aortal endothelial cells (HAEC). Nanoindentation experiments for this model system were performed for (i) untreated cells, (ii) for cells after heparinase incubation, which enzymatically removes glycocalyx, (iii) for cells with successive heparin treatment, which partially restores the glycocalyx layer. Analysis of nanoindentation data was performed using different models: (a) a single-layer contact mechanics, (b) a double-layer model contact mechanics, (c) a polymer "brush" two-layer model based on the Alexander - de Gennes theory and (d) a simple single-layer "mechanical spring" model. Although different physical parameters are evaluated in methods (a-d), we show that all approaches revealed similar qualitative changes of the glycocalyx layer, which reflected the processes of glycocalyx degradation and its partial restoration. This paper may facilitate a direct comparison of past and future glycocalyx oriented AFS experiments that are analysed with different approaches., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Despite the progress made in recent years in the field of oncology, the results of glioblastoma treatment remain unsatisfactory. In this paper, cholesterol derivatives - oxysterols - have been investigated in the context of their anti-cancer activity. First, the influence of three oxysterols (7-K, 7β-OH and 25-OH), differing in their chemical structure, on the properties of a model membrane imitating glioblastoma multiforme (GBM) cells was investigated. For this purpose, the Langmuir monolayer technique was applied. The obtained results clearly show that oxysterols modify the structure of the membrane by its stiffening, with the 7-K effect being the most pronounced. Next, the influence of 7-K on the nanomechanical properties of glioblastoma cells (U-251 line) was verified with AFM. It has been shown that 7-K has a dose-dependent cytotoxic effect on glioblastoma cells leading to the induction of apoptosis as confirmed by viability tests. Interestingly, significant changes in membrane structure, characteristic for phospholipidosis, has also been observed. Based on our results we believe that oxysterol-induced apoptosis and phospholipidosis are related and may share common signaling pathways. Dysregulation of lipids in phospholipidosis inhibit cell proliferation and may play key roles in the induction of apoptosis by oxysterols. Moreover, anticancer activity of these compounds may be related to the immobilization of cancer cells as a result of stiffening effect caused by oxysterols. Therefore, we believe that oxysterols are good candidates as new therapeutic molecules as an alternative to the aggressive treatment of GBM currently in use., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Blood-based assays to measure brain amyloid beta (Aβ) deposition are an attractive alternative to the cerebrospinal fluid (CSF)-based assays currently used in clinical settings. In this study, we examined different blood-based assays to measure Aβ and how they compare among centers and assays., Methods: Aliquots from 81 plasma samples were distributed to 10 participating centers. Seven immunological assays and four mass-spectrometric methods were used to measure plasma Aβ concentrations., Results: Correlations were weak for Aβ42 while Aβ40 correlations were stronger. The ratio Aβ42/Aβ40 did not improve the correlations and showed weak correlations., Discussion: The poor correlations for Aβ42 in plasma might have several potential explanations, such as the high levels of plasma proteins (compared to CSF), sensitivity to pre-analytical sample handling and specificity, and cross-reactivity of different antibodies. Different methods might also measure different pools of plasma Aβ42. We, however, hypothesize that greater correlations might be seen in future studies because many of the methods have been refined during completion of this study., Competing Interests: OH has acquired research support (for the institution) from Avid Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Alzpath, Biogen, Cerveau, and Roche. SP is a full‐time employee of Roche Diagnostics GmbH and holds shares in Roche. TB is a full‐time employee of and owns stock in F. Hoffmann‐La Roche Ltd. KB has served as a consultant, on advisory boards, or on data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. HZ has served on scientific advisory boards for Alector, Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies and CogRx. JLD is an employee and stockholder of Eli Lilly and Company. ELECSYS is a trademark of Roche. E Stoops and KM are full‐time paid employees of ADx NeuroSciences. JMS has received research funding from Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly and Company); has consulted for Roche Pharmaceuticals, Biogen, Merck, and Eli Lilly; given educational lectures sponsored by GE Healthcare, Eli Lilly, and Biogen; and serves on a Data Safety Monitoring Committee for Axon Neuroscience SE. RJB cofounded C2N Diagnostics. Washington University and Dr. Bateman have equity ownership interest in C2N Diagnostics and receive royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. He receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with RJB as co‐inventor, has submitted the US provisional patent application “Plasma Based Methods for Detecting CNS Amyloid Deposition.” He has received consultant fees from Roche, C2N Diagnostics, Genentech, AbbVie, Pfizer, Boehringer‐Ingelheim, Eisai, AC Immune, Janssen, and Merck. He serves as principal investigator of the DIAN‐TU, which is supported by the Alzheimer's Association, GHR Foundation, Eisai, an anonymous organization ,and the DIAN‐TU Pharma Consortium. HV is a founder of Biomarkable and a co‐founder of ADx NeuroSciences. RY and NK are full‐time employees of Shimadzu Corporation. NK holds stock in Shimadzu Corporation and has received payment for manuscript writing from Rinshohoushasen. CET has a collaboration contract with ADx Neurosciences and Quanterix; performed contract research or received grants from AC‐Immune, Axon Neurosciences, Biogen, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, PeopleBio, Roche, Toyama, Vivoryon; received honoraria from Medidact Neurologie. LMS has received honorarium from Biogen for teaching. LS and JA have submitted patents for “Methods for quantification of amyloid beta peptides in plasma by mass spectrometry.” AN received honoraria from The Educational Program for Dementia Experts in Hokuriku (NINPRO), The Japan Society for the Promotion of Science (JSPS), Translational Research Center for Medical Innovation (TRI), Eisai Co. Ltd. SY is an employee and shareholder of MagQu Co., Ltd. KGM, VO, and JB have submitted patent application “Plasma Based Methods for Detecting CNS Amyloid Deposition” and may receive royalties based on blood plasma assay technology licensed to C2N Diagnostics. ES has received payment (to institution) from Roche Diagnostics for medical writing., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Alzheimer's disease (AD) is the most common form of dementia affecting 60%-70% of people afflicted with this disease. Accurate antemortem diagnosis is urgently needed for early detection of AD to enable reliable estimation of prognosis, intervention, and monitoring of the disease. The National Institute on Aging/Alzheimer's Association sponsored the 'Research Framework: towards a biological definition of AD', which recommends using different biomarkers in living persons for a biomarker-based definition of AD regardless of clinical status. Fluid biomarkers represent one of key groups of them. Since cerebrospinal fluid (CSF) is in direct contact with brain and many proteins present in the brain can be detected in CSF, this fluid has been regarded as the best biofluid in which to measure AD biomarkers. Recently, technological advancements in protein detection made possible the effective study of plasma AD biomarkers despite their significantly lower concentrations versus to that in CSF. This and other challenges that face plasma-based biomarker measurements can be overcome by using mass spectrometry. In this review, we discuss AD biomarkers which can be reliably measured in CSF and plasma using targeted mass spectrometry coupled to liquid chromatography (LC/MS/MS). We describe progress in LC/MS/MS methods' development, emphasize the challenges, and summarize major findings. We also highlight the role of mass spectrometry and progress made in the process of global standardization of the measurement of Aβ42/Aβ40. Finally, we briefly describe exploratory proteomics which seek to identify new biomarkers that can contribute to detection of co-pathological processes that are common in sporadic AD., (© 2021 International Society for Neurochemistry.)

Endothelial cells (ECs) play a crucial role in the development and propagation of the severe COVID-19 stage as well as multiorgan dysfunction. It remains, however, controversial whether COVID-19-induced endothelial injury is caused directly by the infection of ECs with SARS-CoV-2 or via indirect mechanisms. One of the major concerns is raised by the contradictory data supporting or denying the presence of ACE2, the SARS-CoV-2 binding receptor, on the EC surface. Here, we show that primary human pulmonary artery ECs possess ACE2 capable of interaction with the viral Spike protein (S-protein) and demonstrate the crucial role of the endothelial glycocalyx in the regulation of the S-protein binding to ACE2 on ECs. Using force spectroscopy method, we directly measured ACE2- and glycocalyx-dependent adhesive forces between S-protein and ECs and characterized the nanomechanical parameters of the cells exposed to S-protein. We revealed that the intact glycocalyx strongly binds S-protein but screens its interaction with ACE2. Reduction of glycocalyx layer exposes ACE2 receptors and promotes their interaction with S-protein. These results indicate that the susceptibility of ECs to COVID-19 infection may depend on the glycocalyx condition.

Objective: To determine whether treatment with escitalopram compared with placebo would lower CSF β-amyloid 42 (Aβ 42 ) levels., Rationale: Serotonin signaling suppresses Aβ 42 in animal models of Alzheimer disease (AD) and young healthy humans. In a prospective study in older adults, we examined dose and treatment duration effects of escitalopram., Methods: Using lumbar punctures to sample CSF levels before and after a course of escitalopram treatment, cognitively normal older adults (n = 114) were assigned to placebo, 20 mg escitalopram × 2 weeks, 20 mg escitalopram × 8 weeks, or 30 mg escitalopram × 8 weeks; CSF sampled pretreatment and posttreatment and within-subject percent change in Aβ 42 was used as the primary outcome in subsequent analyses., Results: An overall 9.4% greater reduction in CSF Aβ 42 was found in escitalopram-treated compared with placebo-treated groups ( p < 0.001, 95% confidence interval [CI] 4.9%-14.2%, d = 0.81). Positive baseline Aβ status (CSF Aβ 42 levels <250 pg/mL) was associated with smaller Aβ 42 reduction ( p = 0.006, 95% CI -16.7% to 0.5%, d = -0.52) compared with negative baseline amyloid status (CSF Aβ 42 levels >250 pg/mL)., Conclusions: Short-term longitudinal doses of escitalopram decreased CSF Aβ 42 in cognitively normal older adults, the target group for AD prevention., Clinicaltrialsgov Identifier: NCT02161458., Classification of Evidence: This study provides Class II evidence that for cognitively normal older adults, escitalopram decreases CSF Aβ 42 ., (© 2020 American Academy of Neurology.)