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This article examines the relationship between the density of germinal centers in the thymic medulla in myasthenia gravis and other features of the disease. Specimens of thymus were obtained from twenty-three cases of myasthenia gravis, twenty from thymectomy and three from necropsy. The twenty-three patients, twenty females and three males, were aged 14-65 years at the time the thymus was obtained. The clinical data included sex and age of the patients and duration of symptoms of myasthenia gravis, serological findings, and density of medullary germinal centers. The serum of four often cases tested contained antibody to striations of skeletal muscle and thymic epithelial cells, the other six cases had neither antibody.

An overview of near-field optics is presented with a focus on the fundamental advances that have been made in the field since its inception 30 years ago. A focus is placed on the advancements that have been achieved in instrumentation. These advances have led to a greater generality of use with ultra-low mechanical and optical noise and the ultimate in force sensitivity with near-field optical probes. An emphasis is placed on the importance of fully integrating near-field optics with other imaging and spectroscopic modalities including Raman spectroscopy and electron/ion beam imaging. Important directions in probe design, force feedback methods and scanner flexibility are described. These developing avenues provide considerable optimism for an ever increasing incorporation of near-field optics to help resolve critical problems in fundamental and applied science.

One of the main hallmarks of Parkinson's disease (PD) pathology is the spread of the aggregate-prone protein α-synuclein (α-syn), which can be detected in the plasma and cerebrospinal fluid of patients as well as in the extracellular environment of neuronal cells. The secreted α-syn can exhibit "prion-like" behavior and transmission to naïve cells can promote conformational changes and pathology. The precise role of plasma membrane proteins in the pathologic process of α-syn is yet to be fully resolved. The TMEM16 family of lipid scramblases and ion channels has been recently associated with cancer and infectious diseases but is less known for its role in aging-related diseases. To elucidate the role of TMEM16F in α-syn spread, we transduced neurons derived from TMEM16F knockout mice with a reporter system that enables the distinction between donor and recipient neurons of pathologic α-synA53T. We found that the spread of α-synA53T was reduced in neurons derived from TMEM16F-knockout mice. These findings were recapitulated in vivo in a mouse model of PD, where attenuated α-synA53T spread was observed when TMEM16F was ablated. Moreover, we identified a single nucleotide polymorphism in TMEM16F of Ashkenazi Jewish PD patients resulting in a missense Ala703Ser mutation with enhanced lipid scramblase activity. This mutation is associated with altered regulation of α-synA53T extracellular secretion in cellular models of PD. Our study highlights TMEM16F as a novel regulator of α-syn spread and as a potential therapeutic target in synucleinopathies., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Alpha-synuclein (αS) aggregation is a widely regarded hallmark of Parkinson's disease (PD) and can be detected through synuclein amplification assays (SAA). This study investigated the association between cerebrospinal fluid (CSF) radiological measures in 41 PD patients (14 iPD, 14 GBA1-PD, 13 LRRK2-PD) and 14 age-and-sex-matched healthy controls. Quantitative measures including striatal binding ratios (SBR), whole-brain and deep gray matter volumes, neuromelanin-MRI (NM-MRI), functional connectivity (FC), and white matter (WM) diffusion-tensor imaging (DTI) were calculated. Nine LRRK2-PD patients were SAA-negative (PD-SAA-). PD-SAA+ patients showed lower whole-brain gray matter, putamenal, brainstem, and substantia nigra volumes, reduced FC in the left caudate, and lower fractional anisotropy in the left fronto-occipital fasciculus compared to PD-SAA-. Taken together, αS aggregation was observed in iPD, GBA1-PD, and 38% of LRRK2-PD patients, and this was associated with reduced regional brain volumes, altered caudal FC, and SBRs. These changes were less pronounced in PD-SAA-, possibly suggesting a milder neurodegenerative process., Competing Interests: Competing interests: AD is an Associate Editor for npj Parkinson’s Disease and receives honoria from Springer Nature. He was not involved in the journal’s review of, or decisions related to, this manuscript. AY-V, BC, NO, AB-S, MG-W, OG, and AO-U report no competing interests. KBF, OSM, and JCS are employees of and own stock in Biogen. RNA research is funded by the Michael J. Fox Foundation (MJFF) and the Parkinson’s Foundation. He received consultation fees from Genzyme/Sanofi, Takeda, and Gain Therapeutics. JMC is a former employee of Biogen, and reports no competing interests relevant to this work. NG has no competing interests pertaining to this work. He serves as a member of the editorial board for the Journal of Parkinson’s Disease. He serves as a consultant to Sionara, Accelmed, Teva, NeuroDerm, Intec Pharma, Pharma2B, Denali, and Abbvie. He received royalties from Lysosomal Therapeutics (LTI) and payment for lectures at Teva, UCB, Abbvie, Sanofi-Genzyme, Bial and Movement Disorder Society. He received research support from the Michael J Fox Foundation, the National Parkinson Foundation, the European Union 7th Framework Program, and the Israel Science Foundation, as well as from the Teva NNE program, Biogen, LTI, and Pfizer. AM reports no competing interests relevant to this work. AM is an Associate Editor for npj Parkinson’s Disease and receives Honoria from Springer Nature. She was not involved in the journal’s review of, or decisions related to, this manuscript. She reports serving as an advisor to Neuroderm. AT reports receiving honoraria from Abbvie, research funding from MJFF, and consultation fees from Capsida Inc. He reports no competing interests relevant to this work., (© 2025. The Author(s).)

Background: Glucocerebrosidase 1 (GBA1) mutations are associated with reduced survival in Parkinson's disease but their effect on survival in dementia with Lewy bodies (DLB) is unclear., Objective: To assess the impact of GBA1 mutations on survival among Ashkenazi Jews with DLB, while controlling for APOE status., Methods: One hundred and forty participants from Tel Aviv Medical Center, Israel were genotyped for GBA1 mutations and APOE polymorphisms. Survival rates and follow-up cognitive screening scores were analyzed., Results: GBA1 mutation carriers had a two-fold increased risk of death (HR = 1.999), while APOE status did not independently affect survival. In a subset of patients with available clinical data (N = 63), carriers of the APOE ε4 allele showed faster cognitive deterioration, while GBA1 mutation carriers also declined more rapidly albeit not significantly., Conclusion: Understanding the genetic effects on survival and progression is crucial for patient counseling and inclusion in clinical trials., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Stem cells are the foundation for cell therapy due to their ability to self-renew, differentiate into other cell types, and persist throughout the life of an organism. Stem cell isolation and transplantation have not yet been established in Hexacorallia, a cnidarian subclass containing stony corals and sea anemones. Here, we demonstrate that candidate stem cells in the hexacorallian Nematostella vectensis can be transplanted into adult animals. These cells exhibited the hallmarks of stem cell functional properties; they integrated into recipients' tissues and rescued them from lethal doses of chemotherapy. Additionally, these cells proliferated and survived serial transplantations. Notably, we showed that this cellular subpopulation can be enriched by sorting using species-non-specific cell markers and that similar subpopulations of cells can be isolated from other hexacorallians, including stony corals. This research establishes the basis for studying stem cell biology on a functional level in Hexacorallia., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The adaptive immune response has a role in Parkinson's disease (PD). Patients with LRRK2 or GBA1 mutations often exhibit distinct clinical characteristics., Objective: To evaluate the involvement of adaptive immune response genes in three PD groups: GBA1 -PD, LRRK2 -PD, and non-carrier (NC)-PD., Methods: Differentially expressed genes (DEGs) associated with PD were identified using four datasets. Of them, adaptive immune response genes were evaluated using whole-genome-sequencing of 201 unrelated Ashkenazi-Jewish (AJ) PD patients. Potential pathogenic variants were identified, and P2RX7 variants were assessed in 1200 AJ-PD patients. Burden analysis of rare variants (allele frequencies (AF) < 0.01) on disease risk, and association analyses of common variants (AF ≥ 0.01) with disease risk and age-at-onset (AAO) were conducted. AFs were compared to AJ-non-neuro cases reported in gnomAD. Variants associated with PD were further examined in an independent AJ cohort from AMP-PD., Results: Of the four adaptive immune DEGs identified, CD8B2, P2RX7 , IL27RA , and ZC3H12A , three common variants in P2RX7 were statistically significant: Tyr155His was associated with NC-PD (allelic OR = 1.15, p  = 0.015) ; Arg276His was associated with LRRK2 -PD (allelic OR = 2.10, p  = 0.037), while Glu496Ala was associated with earlier AAO in LRRK2 -PD ( p  = 0.014). Burden analysis showed no significant effect on PD-risk. In the AMP-PD cohort, odds ratios of the two risk variants were similar to the primary cohort, but did not reach significance, probably due to small control sample size (n = 263)., Conclusions: Common variants within P2RX7 are likely associated with PD-risk and earlier AAO. These findings further suggest P2RX7 's involvement in PD and its potential interplay with LRRK2 ., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Purpose: Subtle executive dysfunction is common in people newly diagnosed with Parkinson disease (PD), even when general cognitive abilities are intact. This study examined the Short Weekly Calendar Planning Activity (WCPA-10)'s known-group construct validity, comparing persons with PD to healthy controls (HCs) and nonmanifesting carriers of LRRK2 and GBA gene mutations to HCs. Additionally, convergent and ecological validity was examined., Methods: The study included 73 participants: 22 with idiopathic PD (iPD) who do not carry any of the founder GBA mutations or LRRK2-G2019S, 29 nonmanifesting carriers of the G2019S-LRRK2 (n = 14) and GBA (n = 15) mutations, and 22 HCs. Known-group validity was determined using the WCPA-10, convergent validity by also using the Montreal Cognitive Assessment (MoCA) and Color Trails Test (CTT), and ecological validity by using the WCPA-10, Schwab and England Activities of Daily Living Scale (SE ADL), and Physical Activity Scale for the Elderly (PASE)., Results: Known-group validity of the WCPA-10 was established for the iPD group only; they followed fewer rules (p = 0.020), were slower (p = 0.003) and less efficient (p = 0.001), used more strategies (p = 0.017) on the WCPA-10, and achieved significantly lower CTT scores (p < 0.001) than the HCs. The nonmanifesting carriers and HCs were similar on all cognitive tests. Convergent and ecological validity of the WCPA-10 were partially established, with few correlations between WCPA-10 outcome measures and the MoCA (r = 0.50, r = 0.41), CTT-2 (r = 0.43), SE ADL (r = 0.41), and PASE (r = 0.54, r = 0.46, r = 0.31)., Conclusions: This study affirms the known-group validity for most (four) WCPA-10 scores and partially confirms its convergent and ecological validity for PD., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: MRI is an important tool for disease diagnosis of Creutzfeldt-Jakob disease (CJD), yet its role in identifying preclinical stages of disease remains unclear. Here, we explored subtle white matter (WM) alterations in genetic CJD (gCJD) patients and in asymptomatic E200K mutation carriers using MRI, depending on total tau protein (t-tau) levels in CSF., Methods: Six symptomatic gCJD patients and N=60 healthy relatives of gCJD patients were included. Participants underwent genetic testing for the E200K mutation, MRI scans at 3T and a lumbar puncture (LP) for t-tau. Diffusion tensor imaging (DTI) metrics were calculated along WM tracts., Results: gCJD patients demonstrated higher mean diffusivity (MD), radial diffusivity (RD) and lower fractional anisotropy (FA) values compared with healthy relatives in several WM tracts (p<0.05). Out of the healthy relatives, 50% (N=30) were found to be carriers of the E200K mutation. T-tau levels in cerebrospinal fluid (CSF) were above the normal range (>290 pg/mL) in N=8 out of 23 carriers who underwent an LP. No significant differences in FA, MD, axial diffusivity (AD) and RD were detected between healthy mutation carriers (HMC) and healthy non-carriers within the WM tracts. Finally, significantly higher FA and lower MD, RD and AD along several WM tracts were found in HMC with elevated t-tau compared with HMC with normal t-tau (p<0.05)., Conclusions: DTI abnormalities along WM tracts were found in healthy E200K mutation carriers with elevated t-tau in CSF. Longer follow-up is required to determine whether these subtle WM alterations are predictive of future conversion to symptomatic gCJD., Trial Registration Number: NCT05746715., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Mild cognitive impairment (MCI) is common in Parkinson's disease (PD). We aimed to assess the incidence of MCI among patients with PD, carriers of mutations in LRRK2 and GBA1 genes, based on the movement disorder society (MDS) criteria for the diagnosis of MCI in early-stage PD., Methods: Patients with PD were included if they scored ≤2 on the Hoehn and Yahr and ≤6 years since motor symptom onset. A group of age and gender matched healthy adults served as controls. A neuropsychological cognitive battery was used covering five cognitive domains (executive functions, working memory, memory, visuospatial and language). MCI was explored while applying two methods (level I and II). Frequency of MCI was assessed in comparison between groups., Results: 70 patients with idiopathic PD (iPD) (68 % males), 42 patients with LRRK2-PD (61 % males), 83 patients with GBA1-PD (63 % males) and 132 age and gender matched controls (61 % males), participated in this study. PD groups were similar in clinical characteristics. Level I criteria were positive in 57.5 % of iPD, 43 % of LRRK2-PD and 63.4 % of the GBA1-PD (p = 0.071). Level II criteria was met by 39 % of iPD, 14 % LRRK2-PD and 41 % of GBA1-PD (p < 0.001), when using a 2 standard-deviation (SD) threshold. GBA1-PD and iPD showed impairments on multiple domains even in the more conservative 2 SD, reflecting MCI., Conclusions: The majority of our PD cohort was classified as MCI when assessed with strict criteria. GBA1-PD and iPD showed a more widespread pattern of MCI compared with LRRK2-PD., Competing Interests: Declaration of competing interest AT – Receiving research grants from MJFF, honoraria from AbbVie and consulting fees from Capsida. VL – nothing to report. ER – nothing to report. NO – nothing to report. AS – nothing to report. BC – nothing to report. NG – Received research grant support from The Michael J Fox Foundation, The National Parkinson Foundation, The European Union and The Israel Science Foundation, Biogen and Ionis. Receives support from The Sieratzki Family Foundation and The Aufzien Academic Center in Tel-Aviv University. Serves as a consultant to Sionara, NeuroDerm and Pharma2B. JCS – Employee of Biogen and holds company stocks. JMC – Reports having equity positions in VanquaBio and Immunobrain Checkpoint. MGW – nothing to report. OG – nothing to report. AO – Research support from the Michael J Fox Foundation and Biogen. RNA – Received research grant support from the MJFF, the Parkisnon's Foundation and the Silverstein Foundation. Received consultation fees from Sanofi, Takeda, Capsida, and Gain Therapeutics. RNA institution (TLVMC) has received research funds from Biogen. AM – Received research grant support from MJFF, The department of defense (DOD), JPND and the Israeli Ministry of Health. Received honoraria from Abbvie and Biogen., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction : MAPT locus is associated with Parkinson's disease (PD), which is located within a large inversion region of high linkage disequilibrium (LD). We aimed to determine whether the H2-haplotype protective effect and its effect size depends on the GBA1 or LRRK2 risk allele carrier status, and to further characterize genetic alterations that might contribute to its effect. Methods : LD analysis was performed using whole-genome sequencing data of 202 unrelated Ashkenazi Jewish (AJ) PDs. A haplotype-divergent variant was genotyped in a cohort of 1200 consecutively recruited AJ-PDs. The odd ratios were calculated using AJ-non-neuro cases from the gnomAD database as the controls in an un-stratified and a stratified manner according to the mutation carrier status, and the effect on the Age at Motor Symptom Onset (AMSO) was examined. Expression and splicing quantitative trait locus (eQTL and sQTL) analyses were carried out using brain tissues from a database. Results : The H2 haplotype exhibited significant association with PD protection, with a similar effect size in GBA1 carriers, LRRK2 -G2019S carriers, and non-carriers (OR = 0.77, 0.69, and 0.82, respectively), and there was no effect on AMSO. The LD interval was narrowed to approximately 1.2 Mb. The H2 haplotype carried potential variants in candidate genes ( MAPT and SPPL2C ); structural deletions and segmental duplication ( KANSL1 ); and variants affecting gene expression and intron excision ratio in brain tissues ( LRRC37A/2 ). Conclusions : Our results demonstrate that H2 is associated with PD and its protective effect is not influenced by the GBA1/LRRK2 risk allele carrier status. This effect may be genetically complex, resulting from different levels of variations such as missense mutations in relevant genes, structural variations, epigenetic modifications, and RNA expression changes, which may operate independently or in synergy.

Objectives: VPS35 and VPS13 have been associated with Parkinson's disease (PD), and their shared phenotype in yeast when reduced in function is abnormal vacuolar transport. We aim to test if additional potentially deleterious variants in other genes that share this phenotype can modify the risk for PD., Methods: 77 VPS and VPS-related genes were analyzed using whole-genome-sequencing data from 202 PD patients of Ashkenazi Jewish (AJ) ancestry. Filtering was done based on quality and functionality scores. Ten variants in nine genes were further genotyped in 1200 consecutively recruited unrelated AJ-PD patients, and allele frequencies and odds ratio calculated compared to gnomAD-AJ-non-neuro database, in un-stratified (n = 1200) and stratified manner (LRRK2-G2019S-PD patients (n = 145), GBA-PD patients (n = 235), and non-carriers of these mutations (NC, n = 787))., Results: Five variants in PIK3C3, VPS11, AP1G2, HGS and VPS13D were significantly associated with PD-risk. PIK3C3-R768W showed a significant association in an un-stratified (all PDs) analysis, as well as in stratified (LRRK2, GBA, and NC) analyses (Odds ratios = 2.71, 5.32, 3.26. and 2.19 with p = 0.0015, 0.002, 0.0287, and 0.0447, respectively). AP1G2-R563W was significantly associated in LRRK2-carriers (OR = 3.69, p = 0.006) while VPS13D-D2932N was significantly associated in GBA-carriers (OR = 5.45, p = 0.0027). VPS11-C846G and HGS-S243Y were significantly associated in NC (OR = 2.48 and 2.06, with p = 0.022 and 0.0163, respectively)., Conclusions: Variants in genes involved in vesicle-mediated protein transport and recycling pathways, including autophagy and mitophagy, may differentially modify PD-risk in LRRK2-carriers, GBA carriers, or NC. Specifically, PIK3C3-R768W is a PD-risk allele, with the highest effect size in LRRK2-G2019S carriers. These results suggest oligogenic effect that may depends on the genetic background of the patient. An unbiased burden of mutations approach in these genes should be evaluated in additional PD and control groups. The mechanisms by which these novel variants interact and increase PD-risk should be researched in depth for better tailoring therapeutic intervention for PD prevention or slowing disease progression., Competing Interests: Declaration of Competing Interest OG, MGW, SB, VN, ABS, AT, TG, AM, NG, RNA, and AOU have no conflict of interest regarding this manuscript., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Recent studies found an association between Parkinson's disease (PD) and alterations in the innate immune system. However, whether the involvement of this system in two of the known genetic forms of PD, GBA-PD and LRRK2-PD, and in patients who do not carry these mutations is different, is yet to be determined. We aimed to test if genetic variations in the innate immune genes are differentially associated with PD in these subgroups., Methods: Innate immune genes were identified and classified into sub-lists according to Reactome pathways. Whole-genome-sequencing (WGS) was performed on 201 unrelated Ashkenazi-Jewish (AJ) PD patients including 104 GBA-PD, 32 LRRK2-PD, and 65 non-carriers-PD (NC-PD). To identify genes with different burden between these subgroups of PD, gene-based Sequence kernel association optimal unified test (SKAT-O) analysis was performed on innate immune pathways. Candidate variants within the significant genes were further genotyped in a cohort of 1200 unrelated, consecutively recruited, AJ-PD patients, and to evaluate their association with PD-risk their allele frequencies were compared to AJ-non-neuro cases in gnomAD database, in a stratified and un-stratified manner., Results: SKAT-O analysis showed significantly different burden for PSMB9 (GBA-PD versus NC-PD) and FGR (GBA-PD versus LRRK2-PD). Two candidate variants in PSMB9 showed an association with GBA-PD-risk and NC-PD-risk while one FGR variant showed an association with LRRK2-PD-risk., Conclusion: Our data supports differential involvement of innate immunity risk alleles in PD and emphasizes the differences between the GBA- and LRRK2-PD subgroups., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Creutzfeldt-Jakob Disease (CJD) is the most common prion disease in humans causing a rapidly progressive neurological decline and dementia and is invariably fatal. The familial forms (genetic CJD, gCJD) are caused by mutations in the PRNP gene encoding for the prion protein (PrP). In Israel, there is a large cluster of gCJD cases, carriers of an E200K mutation in the PRNP gene, and therefore the largest population of at-risk individuals in the world. The mutation is not necessarily sufficient for the formation and accumulation of the pathological prion protein (PrP sc ), suggesting that other, genetic and non-genetic factors affect the age at symptoms onset. Here we present the protocol of a cross-sectional and longitudinal natural history study of gCJD patients and first-degree relatives of gCJD patients, aiming to identify biological markers of preclinical CJD and risk factors for phenoconversion., Methods: The study has two groups: Patients diagnosed with gCJD, and first-degree healthy relatives (HR) (both carriers and non-carriers of the E200K mutation in the PRNP gene) of patients diagnosed with gCJD. At baseline, and at the end of every year, healthy participants are invited for an "in-depth" visit, which includes a clinical evaluation, blood and urine collection, gait assessment, brain MRI, lumbar puncture (LP), and Polysomnography (PSG). At 6 months from baseline, and then halfway through each year, participants are invited for a "brief" visit, which includes a clinical evaluation, short cognitive assessment, and blood and urine collection. gCJD patients will be invited for one "in-depth" visit, similar to the baseline visit of healthy relatives., Discussion: This continuous follow-up of the participants and the frequent assessments will allow early identification and diagnosis in case of conversion into disease. The knowledge generated from this study is likely to advance the understanding of the underlying clinicopathological processes that occur at the very beginning of CJD, as well as potential genetic and environmental risk factors for the development of the disease, therefore advancing the development of safe and efficient interventions., Trial Registration: The study is an observational study. It has registered retrospectively in https://clinicaltrials.gov/ and has been assigned an identification number NCT05746715., (© 2023. The Author(s).)

Background: Mood disorders have emerged as major non-motor comorbidities in Parkinson's disease (PD) even at the prodromal stage of the disease. Mutations in the LRRK2 and GBA genes are common among Ashkenazi Jews, with more severe phenotype reported for GBA -PD., Objective: To explore the association between genetic status and mood related disorders before and after diagnosis of PD and the association between mood-related medications, phenotype, and genetic status., Methods: Participants were genotyped for mutations in the LRRK2 and GBA genes. State of depression, anxiety and non-motor features were evaluated using validated questionnaires. History of mood disorders prior to diagnosis of PD and use of mood-related medications were assessed., Results: The study included 105 idiopathic PD (iPD), 55 LRRK2 -PD and 94 GBA -PD. Scores on mood related questionnaires and frequency of depression and anxiety before diagnosis were similar between the groups ( p >0.05). However, more GBA -PD patients used mood related medications before PD diagnosis than LRRK2 -PD and iPD (16.5% vs 7.1% and 8.2%, p =0.044). LRRK2 -PD and GBA -PD receiving mood-related medications at time of assessment had worse motor and non-motor phenotype compared to those that did not ( p <0.05). LRRK2 -PD receiving mood related-medications at time of assessment, scored higher on mood-related questionnaires compared to LRRK2 -PD not receiving such medications ( p <0.04)., Conclusions: Prodromal GBA -PD are more frequently treated with mood related-medications despite equal rates of reported mood-related disorders, while LRRK2 -PD with mood-related disorders experience high rates of anxiety and depression despite treatment, attesting to the need of more precise assessment and treatment of these genetic subgroups., (© 2023 International Parkinson and Movement Disorder Society.)

Acute Myeloid Leukemia (AML) is a severe disease with a very high relapse rate. AML relapse may be attributable to leukemic stem cells (LSC). Notably, the "cancer stem cell" theory, which relates to LSCs, is controversial and criticized due to the technical peculiarities of the xenotransplant of human cells into mice. In this study, we searched for possible LSCs in an immunocompetent synergetic mice model. First, we found phenotypic heterogeneity in the ML23 leukemia line. We prospectively isolated a sub-population using the surface markers cKit + CD9 - CD48 + Mac1 -/low , which have the potency to relapse the disease. Importantly, this sub-population can pass in syngeneic hosts and retrieve the heterogeneity of the parental ML23 leukemia line. The LSC sub-population resides in various organs. We present a unique gene expression signature of the LSC in the ML23 model compared to the other sub-populations. Interestingly, the ML23 LSC sub-population expresses therapeutic targeted genes such as CD47 and CD93. Taken together, we present the identification and molecular characterization of LSCs in a syngeneic murine model.

Objective: To compare event-related oscillations in patients with dementia with Lewy bodies (DLB) who are carriers and non-carriers of glucocerebrosidase (GBA) mutations., Methods: EEG was recorded during a visual oddball task in eight Ashkenazi Jewish DLB patients with the N370S mutation in theGBAgene (GBA-DLB) and eleven DLB non-carriers. The time-frequency power and inter-trial phase clustering were calculated from the Morlet wavelet convolution for the midline electrodes., Results: Task performance and cognitive assessments were comparable between groups. While the within-non-GBA-DLB group analysis revealed delta-band power synchronization relative to the baseline (p = 0.01, Cohen's d = 1.0), the within-GBA-DLB-group analysis detected no event-related changes in power. Both groups showed an increase relative to the baseline in the delta and theta bands inter-trial phase clustering (all p < 0.03, d > 1.3). The between-group analysis revealed that event-related power - but not clustering - was lower in GBA-DLB compared to non-carriers in the delta band at Fz and Cz (p = 0.04, d = -0.9)., Conclusions: GBA-DLB patients showed decreased delta-band power compared to non-carriers despite the similar cognitive performance, whereas inter-trial phase clustering was comparable in both groups., Significance: Preserved inter-trial phase clustering possibly compensates for the impaired power by eliciting the appropriate functional configuration needed for stimulus processing and task performance., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background and Objectives: Amyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neuron degeneration, with juvenile ALS (jALS) defined as disease with age at onset (AAO) before 25 years. We aimed to identify the genetic basis of 2 unrelated patients with jALS with very rapid deterioration and early age intellectual disability (ID) and to assess association of genetic findings with both phenotypes in a large cohort of patients with ALS and controls, and in the literature., Methods: Exome sequencing was performed in 2 unrelated probands and their parents. Trio analyses included de novo, rare homozygosity, and compound heterozygosity analyses. A TaqMan genotyping assay was used to genotype ALS cohorts. A systematic literature review was conducted and additional information from authors obtained to assess prevalence of fused in sarcoma ( FUS )-ALS associated with ID., Results: A de novo mutation FUS -P525L was identified in both patients. Additional variations were identified in other genes related to intellectual disabilities. Among 8 additional unrelated juvenile patients, one carried the same FUS mutation and had a similar medical history of mild ID and fulminant ALS, whereas the others did not carry any FUS coding mutations and had no reported learning or intellectual disabilities ( p = 0.0083). In addition, 486 patients with ALS with AAO ≥25 years were negative for this mutation. An extensive literature review showed that among all patients with FUS -related ALS with full phenotype reports, 10.3% exhibited additional learning/intellectual disabilities., Discussion: FUS -P525L mutation was identified in 3 among 10 patients with jALS (30%) in our clinical cohort, all with a very aggressive disease course and ID. Together with literature reports, these results support a novel association between mutations in FUS and early life ID. Additional variations identified in genes related to ID and brain development in our patients ( GPT2 , DNAH10 , and SCUBE2 ) may suggest a complex oligogenic inheritance for this phenotype. We propose that this mutation should be screened in patients with ALS with very early AAO, aggressive disease course, and sporadic occurrence, especially when ALS is accompanied by ID., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Diabetic foot is a well-known problem among patients suffering from peripheral arterial diseases (PAD). This article presents an optical sensor for contactless measurement of the anatomical site based on laser speckle techniques. The sensor illuminates the inspected tissue and analyzes the captured back-reflected light from the time-changing speckle patterns. An occlusion test was implemented to provide a statistical parameter to differentiate between a low perfused and a healthy foot. A clinical study of 15 subjects was conducted. The video was analyzed by two methods: dynamic laser speckle (DLS) and laser speckle contrast analysis (LASCA). Data analysis included several classification models, where the KNN model exhibited maximum performance. These findings suggest that a simple and inexpensive system for PAD monitoring can be designed for home use and/or in community clinics.

Multiple Myeloma (MM) is a devastating malignancy that evades immune destruction using multiple mechanisms. The NKp44 receptor interacts with PCNA (Proliferating Cell Nuclear Antigen) and may inhibit NK cells' functions. Here we studied in vitro the expression and function of PCNA on MM cells. First, we show that PCNA is present on the cell membrane of five out of six MM cell lines, using novel anti-PCNA mAb developed to recognize membrane-associated PCNA. Next, we stained primary bone marrow (BM) mononuclear cells from MM patients and showed significant staining of membrane-associated PCNA in the fraction of CD38 + CD138 + BM cells that contain the MM cells. Importantly, blocking of the membrane PCNA on MM cells enhanced the activity of NK cells, including IFN-γ-secretion and degranulation. Our results highlight the possible blocking of the NKp44-PCNA immune checkpoint by the mAb 14-25-9 antibody to enhance NK cell responses against MM, providing a novel treatment option.

In many machine learning applications, we are faced with incomplete datasets. In the literature, missing data imputation techniques have been mostly concerned with filling missing values. However, the existence of missing values is synonymous with uncertainties not only over the distribution of missing values but also over target class assignments that require careful consideration. In this paper, we propose a simple and effective method for imputing missing features and estimating the distribution of target assignments given incomplete data. In order to make imputations, we train a simple and effective generator network to generate imputations that a discriminator network is tasked to distinguish. Following this, a predictor network is trained using the imputed samples from the generator network to capture the classification uncertainties and make predictions accordingly. The proposed method is evaluated on CIFAR-10 and MNIST image datasets as well as five real-world tabular classification datasets, under different missingness rates and structures. Our experimental results show the effectiveness of the proposed method in generating imputations as well as providing estimates for the class uncertainties in a classification task when faced with missing values.

Aims: Atrial fibrillation (AF) is a major cause of morbidity and mortality. Current guidelines support performing electrocardiogram (ECG) screenings to spot AF in high-risk patients. The purpose of this study was to validate a new algorithm aimed to identify AF in patients measured with a recent FDA-cleared contact-free optical device., Methods and Results: Study participants were measured simultaneously using two devices: a contact-free optical system that measures chest motion vibrations (investigational device, 'Gili') and a standard reference bed-side ECG monitor (Mindray ® ). Each reference ECG was evaluated by two board certified cardiologists that defined each trace as: regular rhythm, AF, other irregular rhythm or indecipherable/missing. A total of 3582, 30-s intervals, pertaining to 444 patients (41.9% with a history of AF) were made available for analysis. Distribution of patients with active AF, other irregular rhythm, and regular rhythm was 16.9%, 29.5%, and 53.6% respectively. Following application of cross-validated machine learning approach, the observed sensitivity and specificity were 0.92 [95% confidence interval (CI): 0.91-0.93] and 0.96 (95% CI: 0.95-0.96), respectively., Conclusion: This study demonstrates for the first time the efficacy of a contact-free optical device for detecting AF., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Immune cells are generated from hematopoietic stem cells (HSCs) in the bone marrow (BM). Immune stimulation can rapidly activate HSCs out of their quiescent state to accelerate the generation of immune cells. HSCs' activation follows various viral or bacterial stimuli, and we sought to investigate the hypersensitivity immune response. Surprisingly, the Ova-induced hypersensitivity peritonitis model finds no significant changes in BM HSCs. HSC markers cKIT, SCA1, CD48, CD150, and the Fgd5-mCherry reporter showed no significant difference from control. Functionally, hypersensitivity did not alter HSCs' potency, as assayed by transplantation. We further characterized the possible impact of hypersensitivity using RNA-sequencing of HSCs, finding minor changes at the transcriptome level. Moreover, hypersensitivity induced no significant change in the proliferative state of HSCs. Therefore, this study suggests that, in contrast to other immune stimuli, hypersensitivity has no impact on HSCs., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Understanding the mechanisms that sustain immunological nonreactivity is essential for maintaining tissue in syngeneic and allogeneic settings, such as transplantation and pregnancy tolerance. While most transplantation rejections occur due to the adaptive immune response, the proinflammatory response of innate immunity is necessary for the activation of adaptive immunity. Botryllus schlosseri , a colonial tunicate, which is the nearest invertebrate group to the vertebrates, is devoid of T- and B-cell-based adaptive immunity. It has unique characteristics that make it a valuable model system for studying innate immunity mechanisms: (i) a natural allogeneic transplantation phenomenon that results in either fusion or rejection; (ii) whole animal regeneration and noninflammatory resorption on a weekly basis; (iii) allogeneic resorption which is comparable to human chronic rejection. Recent studies in B. schlosseri have led to the recognition of a molecular and cellular framework underlying the innate immunity loss of tolerance to allogeneic tissues. Additionally, B. schlosseri was developed as a model for studying hematopoietic stem cell (HSC) transplantation, and it provides further insights into the similarities between the HSC niches of human and B. schlosseri . In this review, we discuss why studying the molecular and cellular pathways that direct successful innate immune tolerance in B. schlosseri can provide novel insights into and potential modulations of these immune processes in humans.

Pathogenic C9orf72 -G 4 C 2 repeat expansions are associated with ALS/FTD, but not with Parkinson's disease (PD); yet the possible link between intermediate repeat lengths and PD remains inconclusive. We aim to study the potential involvement of these repeats in PD. The number of C9orf72 -repeats were determined by flanking and repeat-primed PCR assays, and the risk-haplotype was determined by SNP-array. Their association with PD was assessed in a stratified manner: in PD-patients-carriers of mutations in LRRK2 , GBA , or SMPD1 genes ( n = 388), and in PD-non-carriers (NC, n = 718). Allelic distribution was significantly different only in PD-NC compared to 600 controls when looking both at the allele with higher repeat's size ( p = 0.034) and at the combined number of repeats from both alleles ( p = 0.023). Intermediate repeats (20-60 repeats) were associated with PD in PD-NC patients ( p = 0.041; OR = 3.684 (CI 1.05-13.0)) but not in PD-carriers ( p = 0.684). The C9orf72 risk-haplotype, determined in a subgroup of 588 PDs and 126 controls, was observed in higher frequency in PD-NC (dominant model, OR = 1.71, CI 1.04-2.81, p = 0.0356). All 19 alleles within the risk-haplotype were associated with higher C9orf72 RNA levels according to the GTEx database. Based on our data, we suggest a model in which intermediate repeats are a risk factor for PD in non-carriers, driven not only by the number of repeats but also by the variants' genotypes within the risk-haplotype. Further studies are needed to elucidate this possible role of C9orf72 in PD pathogenesis.

Introduction the: GBA -N370S mutation is one of the most frequent risk factors for dementia with Lewy bodies (DLB) and Parkinson's disease (PD). We looked for genetic variations that contribute to the outcome in N370S-carriers, whether PD or DLB., Methods: Whole-genome sequencing of 95 Ashkenazi-N370S-carriers affected with either DLB (n = 19) or PD (n = 76) was performed, and 564 genes related to dementia and PD analyzed., Results: We identified enrichment of linked alleles in PINK1 locus in DLB patients (false discovery rate P  = .0412). Haplotype analysis delineated 1.8 Mb interval encompassing 29 genes and 87 unique variants, of them, KIF17 -R869C received the highest functional prediction score (Combined Annotation Dependent Depletion = 34). Its frequency was significantly higher in 26 DLB-N370S-carriers compared to 140 PD-N370S-carriers (odds ratio [OR] = 33.4 P  = .001, and OR = 70.2 when only heterozygotes were included)., Discussion: Because KIF17 was shown to be important for learning and memory in mice, our data further suggest, for the first time, its involvement in DLB, and possibly in human dementia., Competing Interests: O.G., M.G.W., T.S., R.A., Y.M., and A.B.S. declare no conflicts of interest. Y.Y.W. is an employee of NRGene Ltd. A.T. has received honoraria from AbbVie Inc. and research grants from the Michael J. Fox Foundation. T.G. reports advisory board membership with honoraria to her and to her institution from AbbVie Israel, Neuroderm Ltd., and Allergan; research support from Phonetica Ltd., Israeli Innovation Authority, Sagol School of Neuroscience (Brain Boost), and the Parkinson's Foundation; and travel support for herself and her team from Abbvie, Allergan, Medisson, Medronic. A.M. has received consulting fees from NeuroDerm and research grants from the Michael J. Fox Foundation, the Israeli Science Foundation, and the US Department of Defense. N.G. serves as a consultant to Intec Pharma, NeuroDerm, Denali, Abbvie, Sanofi‐Genzyme, Biogen, Vibrant, BOL, LTI, Idorsia, and Pharma2B; receives payment for lectures at Abbvie, Sanofi‐Genzyme, Movement Disorder Society, Bial, and UCB; received research support from the Michael J. Fox Foundation, the National Parkinson Foundation, and the Israel Science Foundation as well as from Teva NNE program, Biogen; serves on the advisory board of LTI, NeuroDerm, Sionara, Sanofi‐Genzyme, Biogen, Denali, Intec Pharma, Idorsia; owns stocks in Lysosomal Therapeutic Ltd, Vibrant, BOL; and serves as a member of the Editorial Board for the Journal of Parkinson's Disease. A.O.U. has received research support from the Michael J. Fox Foundation and Chaya Charitable Fund and has received honoraria from Sanofi Genzyme., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

GBA variations are common risk factors for Parkinson's disease (PD), and are found in 21.7% of Ashkenazi PD patients (AJ-PD), 4.23% of them carry an allele, 370Rec, which is different from the common GBA-N370S allele. Using whole-genome-sequencing of 370Rec carriers, N370S carriers, and non-carriers, we characterize the unique 370Rec haplotype in AJ-PDs, and show that it harbors a missense variant replacing the highly conserved methionine-27 with valine in the transmembrane domain of the mitochondrial SLC25A44., Competing Interests: Declaration of Competing Interest Authors OG, MGW, RA, TS, and ABS declare no conflicts of interest; Author AT has received honoraria from AbbVie Inc. and research grants from Michael J Fox Foundation; Author AM has received consulting fees from NeuroDerm and research grants from Michal J Fox Foundation, the Israeli Science Foundation and the US Department of Defense. Author NG serves as consultant to Intec Pharma, NeuroDerm, Denali, Abbvie, Sanofi-Genzyme, Biogen, Vibrant, BOL, LTI, Idorsia and Neuron23, Pharma2B, receives payment for lectures at Abbvie, Sanofi-Genzyme and Movement Disorder Society, received research support from the Michael J Fox Foundation, the National Parkinson Foundation, and the Israel Science Foundation as well as from Teva NNE program, Biogen, The Aufzien Center and the Sieratzki family Foundation at Tel-Aviv University, serves on the advisory board of LTI, NeuroDerm, Sionara, Sanofi-Genzyme, Biogen, Denali, Intec Pharma, Idorsia, and own stocks in Lysosomal Therapeutic Ltd., Vibrant, BOL, and serves as a member of the Editorial Board for the Journal of Parkinson's Disease; Author AOU has received research support from Michael J Fox Foundation and Chaya Charitable Fund and has received honoraria from Sanofi Genzyme., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Social media networks provide an abundance of diverse information that can be leveraged for data-driven applications across various social and physical sciences. One opportunity to utilize such data exists in the public health domain, where data collection is often constrained by organizational funding and limited user adoption. Furthermore, the efficacy of health interventions is often based on self-reported data, which are not always reliable. Health-promotion strategies for communities facing multiple vulnerabilities, such as men who have sex with men, can benefit from an automated system that not only determines health behavior risk but also suggests appropriate intervention targets., Objective: This study aims to determine the value of leveraging social media messages to identify health risk behavior for men who have sex with men., Methods: The Gay Social Networking Analysis Program was created as a preliminary framework for intelligent web-based health-promotion intervention. The program consisted of a data collection system that automatically gathered social media data, health questionnaires, and clinical results for sexually transmitted diseases and drug tests across 51 participants over 3 months. Machine learning techniques were utilized to assess the relationship between social media messages and participants' offline sexual health and substance use biological outcomes. The F1 score, a weighted average of precision and recall, was used to evaluate each algorithm. Natural language processing techniques were employed to create health behavior risk scores from participant messages., Results: Offline HIV, amphetamine, and methamphetamine use were correctly identified using only social media data, with machine learning models obtaining F1 scores of 82.6%, 85.9%, and 85.3%, respectively. Additionally, constructed risk scores were found to be reasonably comparable to risk scores adapted from the Center for Disease Control., Conclusions: To our knowledge, our study is the first empirical evaluation of a social media-based public health intervention framework for men who have sex with men. We found that social media data were correlated with offline sexual health and substance use, verified through biological testing. The proof of concept and initial results validate that public health interventions can indeed use social media-based systems to successfully determine offline health risk behaviors. The findings demonstrate the promise of deploying a social media-based just-in-time adaptive intervention to target substance use and HIV risk behavior., (©Anaelia Ovalle, Orpaz Goldstein, Mohammad Kachuee, Elizabeth S C Wu, Chenglin Hong, Ian W Holloway, Majid Sarrafzadeh. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 26.04.2021.)