Attempted Depletion of Passenger Leukocytes by Irradiation in Pigs

Allograft/xenograft rejection is associated with “passenger leukocyte” migration from the organ into recipient lymph nodes. In Study 1, we attempted to deplete leukocytes from potential kidney “donor” pigs, using two regimens of total body irradiation. A dose of 700 cGy was administered, followed by either 800 cGy (“low-dose”) or 1,300 cGy (“high dose”) with the kidneys shielded. Neither regimen was entirely successful in depleting all leukocytes, although remaining T and 8 cell numbers were negligible. Study 2 was aimed at providing an indication of whether near-complete depletion of leukocytes had any major impact on kidney allograft survival. In non-immunosuppressed recipient pigs, survival of a kidney from a donor that received high-dose irradiation was compared with that of a kidney taken from a non-irradiated donor. Kidney graft survival was 9 and 7 days, respectively, suggesting that depletion had little impact on graft survival. The lack of effect may have been related to (i) inadequate depletion of passenger leukocytes, thus not preventing a direct T cell response, (ii) the presence of dead or dying leukocytes (antigens), thus not preventing an indirect T cell response, or (iii) constitutive expression of MHC class II and B7 molecules on the porcine vascular endothelium, activating recipient T cells

Genetically-Engineered Pig-to-Baboon Liver Xenotransplantation: Histopathology of Xenografts and Native Organs

Orthotopic liver transplantation was carried out in baboons using wild-type (WT, n = 1) or genetically-engineered pigs (α1,3-galactosyltransferase gene-knockout, GTKO), n = 1; GTKO pigs transgenic for human CD46, n = 7) and a clinically-acceptable immunosuppressive regimen. Biopsies were obtained from the WT pig liver pre-Tx and at 30 min, 1, 2, 3, 4 and 5 h post-transplantation. Biopsies of genetically-engineered livers were obtained pre-Tx, 2 h after reperfusion and at necropsy (4–7 days after transplantation). Tissues were examined by light, confocal, and electron microscopy. All major native organs were also examined. The WT pig liver underwent hyperacute rejection. After genetically-engineered pig liver transplantation, hyperacute rejection did not occur. Survival was limited to 4–7 days due to repeated spontaneous bleeding in the liver and native organs (as a result of profound thrombocytopenia) which necessitated euthanasia. At 2 h, graft histology was largely normal. At necropsy, genetically-engineered pig livers showed hemorrhagic necrosis, platelet aggregation, platelet-fibrin thrombi, monocyte/macrophage margination mainly in liver sinusoids, and vascular endothelial cell hypertrophy, confirmed by confocal and electron microscopy. Immunohistochemistry showed minimal deposition of IgM, and almost absence of IgG, C3, C4d, C5b-9, and of a cellular infiltrate, suggesting that neither antibody- nor cell-mediated rejection played a major role

Late onset of development of natural anti-nonGal antibodies in infant humans and baboons:implications for xenotransplantation in infants

If an ABO-incompatible heart is transplanted into an infant before natural antibodies have developed to the specific donor carbohydrate A/B antigen(s), then B-cell tolerance to the donor A/B antigen is achieved, and these antibodies never develop. Anti-carbohydrate antibodies play a role in the rejection of wild type (WT) and alpha1,3-galactosyltransferase gene-knockout (GT-KO) pig xenografts. We investigated development of these antibodies in infant baboons and humans. Serum samples from infant baboons (n = 42) and humans (n = 42) were tested by flow cytometry for immunoglobulin M and immunoglobulin G binding to peripheral blood mononuclear cells from WT and GT-KO pigs, and for complement-dependent cytotoxicity. The presence of anti-blood group antibodies was tested in baboon serum. In infant baboons and humans, cytotoxic anti-Galalpha1,3Gal antibodies develop during the first 3 months, and steadily increase with age, whereas cytotoxic anti-nonGal antibodies are either absent or minimal in the majority of cases throughout the first year of life. Anti-blood group antibodies were not detected before 16 weeks of age. Our data suggest GT-KO pig organ/cell transplants could be carried out in early infancy in the absence of preformed cytotoxic anti-nonGalalpha1,3Gal antibodies.</p

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Insoluble dietary fibers: structure, metabolism, interactions with human microbiome, and role in gut homeostasis

Consumption of food rich in dietary fibers (DFs) has been long recognized to exert an overall beneficial effect on human health. This review aims to provide a holistic overview on how IDFs impact human gut health either directly, or through modulation of the gut microbiome. Several databases were searched for collecting papers such as PubMed, Google Scholar, Web of Science, Scopus and Reaxys from 2000 till 2022. Firstly, an overview of the chemical structure of the various IDFs and the pathways employed by gut microbiota for their degradation is provided. The impact of IDFs on microbial community structure and pathogens colonization inside the human gut was discussed. Finally, the impact of IDFs on gut homeostasis and systemic effects at the cellular level, as well as the overall immunological benefits of IDFs consumption were analyzed. IDFs ., cellulose, hemicellulose, resistant starch, and lignin found enriched in food are discussed for these effects. IDFs were found to induce gut immunity, improve intestinal integrity and mucosal proliferation, and favor adhesion of probiotics and hence improve human health. Also, IDFs were concluded to improve the bioavailability of plant polyphenols and improve their health-related functional roles. Ultimately, dietary fibers processing by modification shows potential to enhance fibers-based functional food production, in addition to increase the economic value and usage of food-rich fibers and their by-products

Seismicity characteristics of the Gulf of Aqaba seismogenic zone and their hazard implications in northwestern Saudi Arabia

The seismogenic characteristics of the Gulf of Aqaba zone have been assessed using the maximum likelihood method to estimate various earthquake recurrence parameters. These parameters encompass the β-value, annual recurrence rate (λ), and maximum probable magnitude (Mmax). This assessment has identified three sub-seismogenic zones, each corresponding to specific structural faults within the Gulf. These zones are associated with the Aragonese, Arnona and Aqaba faults, delineating pull-apart basin structures in the Gulf of Aqaba. An updated earthquake catalogue has been compiled using a unified moment magnitude (Mw) scale to improve the analysis, established by developing two empirical relationships. According to the findings of this study, there is a possibility that the Aragonese seismogenic zone could experience an earthquake with a maximum magnitude of 7.7, highlighting a significant seismic hazard in the region. While acknowledging the inherent uncertainties in this assessment, a probabilistic seismic hazard was calculated for hard rock conditions within a spatial area divided into elementary cells, each measuring 0.1°×0.1°. The highest peak ground acceleration (PGA) is associated with a spectral frequency of 5.0 to 10.0 Hz and could significantly impact building codes in the region. The spatial distribution variations of seismic hazard corresponding to the proposed sub-seismogenic zones indicate a high degree of crustal heterogeneity and seismotectonic complexity. This comprehensive assessment contributes to understanding seismic hazards that may import from the Gulf of Aqaba seismogenic zone

Integration of local soil effect into the assessment of seismic hazard at the Kharga Oasis, Western Desert, Egypt

The effect of local soil is integrated into the assessment of seismic hazard at the Kharga Oasis, Western Desert, Egypt. The work is done by adopting the probabilistic approach of seismic hazard assessment and the site response analysis. The probabilistic approach was utilized based on a homogenous earthquake catalogue, a reasonable seismic source model, and selective ground-motion prediction equations. The site response analysis is performed to describe the interaction between ground motion time series that are well-matched with the results of the probabilistic analysis and the dynamic soil properties defined from the seismic survey. The outputs are presented in terms of the site-specific seismic hazard maps which includes the amplification maps and maps for the expected values of the ground motion at the surface. The amplification maps show that the northern part of the area has the lowest amplification while the middle part of the area has the highest amplification. The maps for peak ground acceleration and spectral acceleration for the return periods of 475 years show that the maximum expected peak ground acceleration for this return period is 100.6 cm/s2. It has the values of 135 cm/s2 at 0.1 s spectral acceleration