Proposed therapy, developed in a Pcdh15-deficient mouse, for progressive loss of vision in human Usher Syndrome

Usher syndrome type I (USH1) is characterized by deafness, vestibular areflexia and progressive retinal degeneration. The protein-truncating p.Arg245* founder variant of PCDH15 (USH1F) has an ~2% carrier frequency amongst Ashkenazi Jews accountings for ~60% of their USH1 cases. Here, longitudinal phenotyping in thirteen USH1F individuals revealed progressive retinal degeneration, leading to severe vision loss with macular atrophy by the sixth decade. Half of the affected individuals were legally blind by their mid-fifties. The mouse Pcdh15R250X variant is equivalent to human p.Arg245*. Homozygous Pcdh15R250X mice also have visual deficits and aberrant light-dependent translocation of the phototransduction cascade proteins, arrestin and transducin. Retinal pigment epithelium- (RPE) specific retinoid cycle proteins, RPE65 and CRALBP, were also reduced in Pcdh15R250X mice, indicating a dual role for protocadherin-15 in photoreceptors and RPE. Exogenous 9-cis retinal improved ERG amplitudes in Pcdh15R250X mice, suggesting a basis for a clinical trial of FDA approved retinoids to preserve vision in USH1F patients.

Genetic and phylogeographic evidence for Jewish Holocaust victims at the Sobibór death camp

Six million Jews were killed by Nazi Germany and its collaborators during World War II. Archaeological excavations in the area of the death camp in Sobibór, Poland, revealed ten sets of human skeletal remains presumptively assigned to Polish victims of the totalitarian regimes. However, their genetic analyses indicate that the remains are of Ashkenazi Jews murdered as part of the mass extermination of European Jews by the Nazi regime and not of otherwise hypothesised non-Jewish partisan combatants. In accordance with traditional Jewish rite, the remains were reburied in the presence of a Rabbi at the place of their discovery.

Without a compass: Salonikan Jews in Nazi Concentration Camps and later

During the Holocaust, the largest Sephardi community in the world located in Saloniki was almost completely destroyed. Despite their limited number in comparison with that of Ashkenazi Jews, the Salonikan Jews, initially deported to Auschwitz Birkenau and Bergen Belsen, went through all the hardest experiences and were sent to many camps in occupied Poland, and in Germany. This article explores, using archival documents and the testimonies, the geographical directions of their deportations. It also analyses historical coordinates and the Salonikan Jews’ characteristics which affected their destinations and the itinerary with which they were forced to cope.

Potential therapy for progressive vision loss due to PCDH15-associated Usher syndrome developed in an orthologous Usher mouse

Usher syndrome type I (USH1) is characterized by congenital deafness, vestibular areflexia, and progressive retinal degeneration with age. The protein-truncating p.Arg245* founder variant of PCDH15 has an ~2% carrier frequency among Ashkenazi Jews, accounting for nearly 60% of their USH1 cases. Here, longitudinal ocular phenotyping in thirteen USH1F individuals harboring the p.Arg245* variant revealed progressive retinal degeneration, leading to severe loss of vision with macular atrophy by the sixth decade. Half of the affected individuals met either the visual acuity or visual field loss definition for legal blindness by the middle of their fifth decade of life. Mice homozygous for p.Arg250* (Pcdh15R250X; equivalent to human p.Arg245*) also have early visual deficits evaluated using electroretinography. Light-dependent translocation of phototransduction cascade proteins, arrestin and transducin, was found to be impaired in Pcdh15R250X mice. Retinal pigment epithelium- (RPE) specific visual retinoid cycle proteins, RPE65 which converts all-trans retinoids to 11-cis retinoids and CRALBP that transports retinoids, and key retinoid levels were also reduced in Pcdh15R250X mice, suggesting a dual role for protocadherin-15 in photoreceptors and RPE. Administration of exogenous 9-cis retinal, an analog of the naturally occurring 11-cis retinal, improved ERG amplitudes in these mutant mice, suggesting a basis for a clinical trial of exogenous FDA approved retinoids to preserve vision in USH1F patients.

Mutations in GBA and LRRK2 Are Not Associated with Increased Inflammatory Markers

Background: Inflammation is an integral part of neurodegeneration including in Parkinson’s disease (PD). Ashkenazi Jews have high rates of genetic PD with divergent phenotypes among GBA-PD and LRRK2-PD. The role of inflammation in the prodromal phase of PD and the association with disease phenotype has yet to be elucidated. Objective: To assess central and peripheral cytokines among PD patients with mutations in the LRRK2 and GBA genes and among non-manifesting carriers (NMC) of these mutations in order to determine the role of inflammation in genetic PD. Methods: The following cytokines were assessed from peripheral blood and cerebrospinal fluid (CSF): TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10 and INF- γ. A comprehensive intake including general medical conditions, use of anti-inflammatory treatments, motor and cognitive assessments and additional laboratory measures were recorded, enabling the construction of the MDS probable prodromal score. Results: Data from 362 participants was collected: 31 idiopathic PD (iPD), 30 LRRK2-PD, 77 GBA-PD, 3 homozygote GBA-PD, 3 GBA-LRRK2-PD, 67 LRRK2-NMC, 105 GBA-NMC, 14 LRRK2-GBA-NMC, and 32 healthy controls. No between-group differences in peripheral or CSF cytokines were detected. No correlation between disease characteristics or risk for prodromal PD could be associated with any inflammatory measure. Conclusion: In this study, we could not detect any evidence on dysregulated immune response among GBA and LRRK2 PD patients and non-manifesting mutation carriers.

Jewish branch of cultural text of the Crimean ethnic ornament

The subject of this research is the continuum of ethnic symbols of the ornament of the Crimean Jews. The object is the traditional decorative and applied art of the peoples of Crimea following Judaism: Ashkenazi Jews, Karaite and Krymchaks. The symbolism of ethnic art is viewed based on the analysis of traditional decor. The article employs the methods of comparative analysis, analysis of previous research, method of synthesis in conclusions pertinent to connotations of symbols. The author explores the morphology and semantics of visual symbols in decorative and applied art of the aforementioned people, as well as connotations of symbols. Special attention is given to aspects that characterize polyethnic cultural landscape of Crimea in the context of phylogenesis. The main conclusions are as follows:   1. Crimea is a polyethnic region with various cultural processes – from reception to inculturation and integration of ethnoses, which ultimately formed the Crimean cultural landscape. Its peculiarities are represented by ethnic ornament, such as decorated household items and ritual attributes   2. Symbolism of the elements of traditional art of Ashkenazi Crimean Jews, Karaite and Krymchaks has common connotations due to the Torah that underlies the religious confession of all three ethnoses, as well as similar morphology. The art of Karaite and Krymchaks are more identical to each other than to Jewish. The author’s special contribution lies in systematization of the morphology of visual symbols in the art of the three ethnoses. The scientific novelty consists in carrying out a comparative analysis of the art of three Crimean ethnoses, revealing foundations of the genesis and continuum of its elements, their similarities and differences.

Introduction

This chapter gives an extensive background of Jewish folk medicine. It explains that the aim of writing this book is to bring to light the wealth of notions connected with the folk medicine of Ashkenazi Jews living in eastern Europe around 1900s. Folk medicine is long tarred by the derogatory description 'superstition.' The term 'folk medicine' is usually used to describe remedies and treatment methods specific to traditional culture and which do not fall within the contemporary dominant biomedical model. Magic practices are one area of activity often categorized as 'folklore'. They tend to be perceived as bizarre and mysterious, and are commonly associated with bats, garlic, and arcane incantations. Folk medicine was a complex system which comprised both natural and magic elements of highly diverse provenance.

Mild Phenotype of Wolfram Syndrome Associated With a Common Pathogenic Variant Is Predicted by a Structural Model of Wolframin

ObjectiveTo describe the WFS1 c.1672C>T; p.R558C missense variant, found in 1.34% of Ashkenazi Jews, that has a relatively mild phenotype and to use computational normal mode analysis (NMA) to explain the genotype-phenotype relationship.MethodsThe clinical, laboratory, and genetic features of 8 homozygotes were collected. A model of the wolframin protein was constructed, and NMA was used to simulate the effect of the variant on protein thermodynamics.ResultsMean age at Wolfram syndrome (WS) diagnosis among homozygotes was 30 years; diabetes (7/8) was diagnosed at mean age 19 years (15–21 years), and bilateral optic atrophy (with MRI evidence of optic/chiasm atrophy) (6/8) at mean age 29 years (15–48 years). The oldest patient (62 years) also had gait difficulties, memory problems, parietal and cerebellar atrophy, and white matter hyperintense lesions. All retained functional vision with independent ambulation and self-care; none had diabetes insipidus or hearing loss. The p.R558C variant caused less impairment of protein entropy than WFS1 variants associated with a more severe phenotype.ConclusionsThe p.R558C variant causes a milder, late-onset phenotype of WS. We report a structural model of wolframin protein based on empirical functional studies and use NMA modeling to show a genotype-phenotype correlation across all homozygotes. Clinicians should be alert to this condition in patients with juvenile diabetes and patients of any age with a combination of diabetes and optic atrophy. Computational NMA has potential benefit for prediction of the genotype-phenotype relationship.

Co-Option and Erasure

Much of the rhetoric around racism and racialized discrimination in Israel centers on Israeli Jewish treatment of Palestinians. However, an examination of the experience of Mizrahi Jews can also be instructive as to the ways that racism and white supremacy function within Israel—through a privileging of Ashkenazi Jews, whose experiences are used to define the contemporary Israeli Jewish experience. For example, Israeli Jewish artist of Yemeni descent Leor Grady’s work addresses the marginalization, erasure, and exile of Yemeni Mizrahi Jews in Israel. In his video work Eye and Heart, Grady highlights how, in its absorption into Israeli folk dance, traditional Yemeni dance has been uprooted from its site of origination and “whitewashed.” Through a discussion of this work and others alongside which it was shown in the exhibition Natural Worker, I argue that Grady’s articulation of the co-option of Yemeni culture by the dominant Ashkenazi (white) Israeli mainstream demonstrates how racialization plays out in the cultural realm of Israel. This method of privileging whiteness can be seen in the Israeli co-option of other Mizrahi and Palestinian cultural elements, such as couscous, hummus, and Arabic words such as “yalla.” This examination of Grady’s work allows for an understanding of how this privileging of whiteness functions within the Jewish Israeli context.

The Effect of GBA Mutations and APOE Polymorphisms on Dementia with Lewy Bodies in Ashkenazi Jews

Background: Glucocerebrosidase (GBA) gene mutations and APOE polymorphisms are common in dementia with Lewy bodies (DLB), however their clinical impact is only partially elucidated. Objective: To explore the clinical impact of mutations in the GBA gene and APOE polymorphisms separately and in combination, in a cohort of Ashkenazi Jewish (AJ) patients with DLB. Methods: One hundred consecutively recruited AJ patients with clinically diagnosed DLB underwent genotyping for GBA mutations and APOE polymorphisms, and performed cognitive and motor clinical assessments. Results: Thirty-two (32%) patients with DLB were carriers of GBA mutations and 33 (33%) carried an APOE ɛ4 allele. GBA mutation carriers had a younger age of onset (mean [SD] age, 67.2 years [8.9] versus 71.97 [5.91]; p = 0.03), poorer cognition as assessed by the Mini-Mental State Examination (21.41 [6.9] versus 23.97 [5.18]; p < 0.005), and more severe parkinsonism as assessed with the Unified Parkinson’s Disease Rating Scale motor part III (34.41 [13.49] versus 28.38 [11.21]; p = 0.01) compared to non-carriers. There were statistically significant interactions between the two genetic factors, so that patients who carried both a mild GBA mutation and the APOE ɛ4 allele (n = 9) had more severe cognitive (p = 0.048) and motor dysfunction (p = 0.037). Conclusion: We found a high frequency of both GBA mutations and the APOE ɛ4 allele among AJ patients with DLB, both of which have distinct effects on the clinical disease phenotype, separately and in combination.