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Between January 2018 and June 2021, the Ezer Mizion recruited 223,960 donors. All donors were typed for their HLA class I and II alleles at high resolution by Next Generation Sequencing techniques. Comparison between the sequences obtained from these donors and those in the IPD-IMGT/HLA Database, revealed 122 Novel HLA alleles that were found in 133 donors. Most of the alleles, 94 (77%) were identified in the HLA class I genes (30, 35, and 29 in HLA-A, -B, and -C, respectively), and 28 (23%) were detected in the HLA class II genes (9 in HLA-DRB1 and -DQB1 and 10 in -DPB1). Most of these novel alleles, 106 (86.9%) comprised single nucleotide variation (SNV), 9 (7.4%) present multiple amino acids variation, 4 and 3 were generated because of deletions and insertions, respectively. Ten of these novel alleles were seen to be null alleles., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Soluble human leucocyte antigen (sHLA) molecules, released into the plasma, carry their original peptide cargo and provide insight into the protein synthesis and degradation schemes of their source cells and tissues. Other body fluids, such as pleural effusions, may also contain sHLA-peptide complexes, and can potentially serve as a source of tumor antigens since these fluids are drained from the tumor microenvironment. We explored this possibility by developing a methodology for purifying and analyzing large pleural effusion sHLA class I peptidomes of patients with malignancies or benign diseases., Methods: Cleared pleural fluids, cell pellets present in the pleural effusions, and the primary tumor cells cultured from cancer patients' effusions, were used for immunoaffinity purification of the HLA molecules. The recovered HLA peptides were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) and the resulting LC-MS/MS data were analyzed with the MaxQuant software tool. Selected tumor antigen peptides were tested for their immunogenicity potential with donor peripheral blood mononuclear cells (PBMCs) in an in vitro assay., Results: Mass spectrometry analysis of the pleural effusions revealed 39,669 peptides attributable to 11,305 source proteins. The majority of peptides identified from the pleural effusions were defined as HLA ligands that fit the patients' HLA consensus sequence motifs. The membranal and soluble HLA peptidomes of each individual patient correlated to each other. Additionally, soluble HLA peptidomes from the same patient, obtained at different visits to the clinic, were highly similar. Compared with benign effusions, the soluble HLA peptidomes of malignant pleural effusions were larger and included HLA peptides derived from known tumor-associated antigens, including cancer/testis antigens, lung-related proteins, and vascular endothelial growth factor pathway proteins. Selected tumor-associated antigens that were identified by the immunopeptidomics were able to successfully prime CD8 + T cells., Conclusions: Pleural effusions contain sHLA-peptide complexes, and the pleural effusion HLA peptidome of patients with malignant tumors can serve as a rich source of biomarkers for tumor diagnosis and potential candidates for personalized immunotherapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

HLA haplotypes were found to be associated with increased risk for viral infections or disease severity in various diseases, including SARS. Several genetic variants are associated with COVID-19 severity. Studies have proposed associations, based on a very small sample and a large number of tested HLA alleles, but no clear association between HLA and COVID-19 incidence or severity has been reported. We conducted a large-scale HLA analysis of Israeli individuals who tested positive for SARS-CoV-2 infection by PCR. Overall, 72,912 individuals with known HLA haplotypes were included in the study, of whom 6413 (8.8%) were found to have SARS-CoV-2 by PCR. A total of 20,937 subjects were of Ashkenazi origin (at least 2/4 grandparents). One hundred eighty-one patients (2.8% of the infected) were hospitalized due to the disease. None of the 66 most common HLA loci (within the five HLA subgroups: A, B, C, DQB1, DRB1) was found to be associated with SARS-CoV-2 infection or hospitalization in the general Israeli population. Similarly, no association was detected in the Ashkenazi Jewish subset. Moreover, no association was found between heterozygosity in any of the HLA loci and either infection or hospitalization. We conclude that HLA haplotypes are not a major risk/protecting factor among the Israeli population for SARS-CoV-2 infection or severity. Our results suggest that if any HLA association exists with the disease it is very weak, and of limited effect on the pandemic., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A catalog of common, intermediate and well-documented (CIWD) HLA-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5, -DQB1 and -DPB1 alleles has been compiled from over 8 million individuals using data from 20 unrelated hematopoietic stem cell volunteer donor registries. Individuals are divided into seven geographic/ancestral/ethnic groups and data are summarized for each group and for the total population. P (two-field) and G group assignments are divided into one of four frequency categories: common (≥1 in 10 000), intermediate (≥1 in 100 000), well-documented (≥5 occurrences) or not-CIWD. Overall 26% of alleles in IPD-IMGT/HLA version 3.31.0 at P group resolution fall into the three CIWD categories. The two-field catalog includes 18% (n = 545) common, 17% (n = 513) intermediate, and 65% (n = 1997) well-documented alleles. Full-field allele frequency data are provided but are limited in value by the variations in resolution used by the registries. A recommended CIWD list is based on the most frequent category in the total or any of the seven geographic/ancestral/ethnic groups. Data are also provided so users can compile a catalog specific to the population groups that they serve. Comparisons are made to three previous CWD reports representing more limited population groups. This catalog, CIWD version 3.0.0, is a step closer to the collection of global HLA frequencies and to a clearer view of HLA diversity in the human population as a whole., (© 2020 The Authors. HLA published by John Wiley & Sons Ltd.)

Background: Retirement is a tipping point and a significant change in lifestyle for people who have worked for most of their lives. Life without work, a social framework, employment, content and a sense of necessity are a blow to the self-image and identity of a person who feels that retirement was imposed on him only because he reached a certain age specified in the law., Objectives: To examine the post-retirement tendency of physicians to continue working in various public frameworks., Methods: A qualitative study was conducted in which the data was collected through semi-structured in-depth interviews that enable the integration of pre-determined key questions along with flexibility and freedom to develop dialogue and raise additional questions. The study population included twenty doctors of various specialties who reached retirement age and continue to work. The interviewees were asked questions about their work, whether they had prepared themselves for retirement, if they had fears about retirement, why they decided to continue working, how long they thought they would continue to work, and more., Results: Many physicians have talked about the fact that in the field of medicine, experience is one of the most important resources. Retirement at the age of 67, at the physician's professional peak, is perceived as forced retirement. In addition, all physicians spoke about the fear of a drop in their standard of living and monthly income due to the low pension to which they are entitled. Moreover, since the profession of medicine is so demanding in terms of hours of work, many of them have no leisure pursuits or alternatives to work. Furthermore, since the medical profession is so central in their identity, retirement may be an affront to that very identity., Conclusions: Despite the great pressure that characterizes the work in hospitals, many doctors continue to work after retirement age, finding it hard to give up their professional identity, status, and especially their years of experience.

According to the Standards of the World Marrow Donor Association (WMDA), unrelated stem cell donor registries and donor centers are responsible for compliance of their collection and apheresis centers with these Standards. To ensure high stem cell product quality and high standards for safety and satisfaction of voluntary unrelated stem cell donors, we here present guidelines for audits of collection and apheresis centers that can be used by new and established donor registries, as well as by collection centers in preparation of audits. We define the general requirements and recommendations for collaboration with the collection and apheresis centers and define critical procedures for the collection of the stem cell product, such as information session, medical assessment, product collection, quality controls, product handover for transportation, and donor follow-up. The specific guidelines are accompanied by detailed checklists and forms that can be found in Supplementary Information and may be used during an initial or follow-up on-site or paper-based audit.

HLA haplotype frequencies in a volunteer bone marrow donor registry should reflect the frequencies of potential transplant recipients served by that registry, a challenge in a country with diverse subethnicities of immigrants from Eastern and Western cultures, such as Israel. We evaluated the likelihood of finding suitable donors for hypothetical patients drawn from defined subethnicities in the Ezer Mizion Bone Marrow Donor Registry (EM BMDR) from donors both within and outside the registry now and during the coming decade. On average, bioinformatics modeling predicts that, given current donor recruitment trends, 6/6 high-resolution HLA match rates for Israelis, which currently stand at 40% to 55% for most subethnicities, will rise by up to 1% per year over the next decade. Subethnicities with historically lower rates of interethnic admixture are less likely to find matches outside of their designated group but will benefit from expansion of the registry, whereas ethnically directed drives will enhance matching rates for currently underrepresented subethnicities. Donor searches for the same cohort using a large extramural registry was of only slight benefit for most of the 19 EM BMDR subethnicities evaluated, confirming that local donor registries that reflect the ethnic diversity of the community being served are best equipped to serve the needs of their respective communities. Contemporary trends of an increasingly multiethnic admixture in Israel may impact the effect of ethnic profiling in assessing future match rates for EM BMDR., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

We have recently reported that Entamoeba histolytica trophozoites can adapt to toxic levels of the nitric oxide (NO) donor, S-nitrosoglutathione (GSNO). Even if the consequences of this adaptation on the modulation of gene expression in NO-adapted trophozoites (NAT) have been previously explored, insight on S-nitrosylated (SNO) proteins in NAT is missing. Our study aims to fill this knowledge gap by performing a screening of SNO proteins in NAT. Employing SNO resin-assisted capture (RAC), we identified 242 putative SNO proteins with key functions in calcium binding, enzyme modulation, redox homeostasis, and actin cytoskeleton. Of the SNO proteins in NAT, proteins that are associated with actin family cytoskeleton protein are significantly enriched. Here we report that the formation of actin filaments (F-actin) is impaired in NAT. Consequently, the ability of NAT to ingest erythrocytes and their motility and their cytopathic activity are impaired. These phenotypes can be imitated by treating control parasite with cytochalasin D (CytD), a drug that binds to F-actin polymer and prevent polymerization of actin monomers. Removal of GSNO from the culture medium of NAT restored the sensitivity of the parasite to nitrosative stress (NS) and its ability to form F-actin formation and its virulence. These results establish the central role of NO in shaping the virulence of the parasite through its effect on F-actin formation and highlight the impressive ability of this parasite to adapt to NS.

We have investigated HLA population alleles and haplotype frequencies for the ethnicities that comprise the contemporary population of Israel, using a large data set from the Ezer Mizion Bone Barrow Donor Registry. We genotyped 275,699 individuals at the HLA-A, -B and -DRB1 loci using HLA genotyping methods. HLA A∼B∼DRB1 haplotype frequencies were estimated from 19 sub-ethnic Jewish populations and other non-Jewish minorities using the maximum likelihood model, which accommodates typing ambiguities. We present overall and sub-ethnicity specific HLA diversity results of the registry, which will help guide a data-driven strategy for future registry expansion., (Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Many eukaryotes encode multiple isoforms of the cap-binding translation initiation factor (eIF4E). Leishmanias and other trypanosomatids encode four paralogs of this protein, but none can complement the eIF4E function in a yeast mutant. A low conservation is observed between the four paralogs, suggesting they assist these organisms survive a multitude of conditions encountered throughout the life cycle. Earlier attempts to decipher their function led to identification of LeishIF4E-4 as the canonical translation initiation factor. LeishIF4E-1 appears to function during thermal stress, via a mechanism not yet understood. LeishIF4E-3 hardly binds cap-4 and is, therefore, less likely to serve as a typical initiation factor. Although it interacts with an eIF4G homolog, LeishIF4G-4, the two polypeptides do not co-migrate on sucrose gradients. While LeishIF4E-3 enters large particles that increase in size during nutritional stress, LeishIF4G-4 is found only in the top fractions. Confocal microscopy localized LeishIF4E-3 (but not LeishIF4G-4) within nutritional stress-induced granules. Accordingly, interaction between the two proteins reduced upon starvation. We therefore propose that under normal conditions, LeishIF4G-4 sequesters LeishIF4E-3 in the cytoplasm. During a nutritional stress, LeishIF4E-3 is modified and released from LeishIF4G-4 to enter stress granules, where inactive mRNAs are stored. Binding of LeishIF4G-4 to LeishIF4E-3 requires a short peptide within the LeishIF4G-4 N-terminus, which bears no similarity to the consensus 4E-binding peptide, YXXXXLΦ. Mutational analysis combined with structure prediction indicates that this interaction is based on an obligatory, conserved α helix in LeishIF4G-4. These features further highlight the uniqueness of LeishIF4E-3 and how it interacts with its binding partners.

Polarization sensitivity provides animals with information not available in the intensity or spectral domains. We examined the polarotaxis reactions in the epiplanktonic copepod Pontella karachiensis. Polarotaxis reactions were intensity dependent. At intensities corresponding to ambient daylight, P. karachiensis showed an attraction to a polarized light field; while at low intensities, corresponding to nighttime illumination, it showed negative polarotaxis. P. karachiensis's eye contained two classes of photoreceptors, each class with microvilli at orthogonal orientation to the other. P. karachiensis' eye structure can provide information regarding the polarization percentage but is not sufficient to calculate the exact e-vector orientation. The threshold for polarotoxisis response was 20-30%. Animals responded similarly to horizontal and vertical polarization; and also showed negative phototaxis, affected by light polarization. Results suggest that P. karachiensis responds to polarized light analogously to changes in brightness. The dynamic pattern of polarotaxis responses suggests that polarization sensitivity may enable P. karachiensis to detect other planktonic animals.

Cryptic hepatitis C virus (HCV) infection relates to patients infected chronically with HCV that are seronegative but have HCV-RNA. These patients are not identified by the standard serological tests for HCV, which are based on detection of antibodies to core, NS3 and NS5 antigens. They will, therefore, be wrongly diagnosed as non-infected, and are considered as a potential risk for others. Cryptic HCV infection in dialysis units occurs frequently and, due to medical procedures, is a major factor for contracting the virus when unrecognised. This study was conducted in order to assess the humoral immune responses to E2-antigen in sera of patients infected chronically with HCV. Recombinant E2 protein in enzyme linked immunosorbent assay (ELISA) and Western blot (WB) were used to test the occurrence of anti-E2 antibodies in the sera of patients from the liver clinic and of dialysis patients. The presence of E2 antibodies was found to be correlated with the presence of HCV-RNA and with viral load. Antibodies to the E2 protein could be detected in as many as 30% of the sera from dialysis patients with cryptic HCV infection (HCV-RNA only). The results suggest that detection of anti-E2 antibodies may enhance significantly HCV serological standard testing; especially among patients on dialysis, and that antibodies to envelope E2 protein appear to depend on and correlate with the presence of HCV particles., (Copyright 2004 Wiley-Liss, Inc.)