Biology subjects

Eid, S.

Publications and source records attributed to Eid, S..

3 recordsLinked to original sources

bioRxiv2023

Emergence of the Novel Infectious bursal disease viruse Variant in Vaccinated Poultry Flocks in Egypt

Infectious bursal disease viruses (IBDVs) have a profound impact on poultry production worldwide, directly causing mortality rates of up to 100%, and indirectly through their immunosuppressive effects. Since the emergence of the antigenically modified very virulent IBDV (vvIBDV) in Egypt in late 1999, the country has experienced recurrent outbreaks with high mortality rates and typical vvIBDV gross lesions. However, a notable shift occurred in 2023, characterized by a substantial increase in reported subclinical IBDV cases exhibiting atrophied bursa and associated immunosuppression. To assess the field situation, we examined samples from 21 farms in 2023 and 18 farms from 2021 and 2022, all of which experienced IBD outbreaks based on clinical diagnosis. These samples were submitted to our laboratory for confirmatory testing and subsequently subjected to VP2-HVR sequencing. Phylogenetic analysis revealed that all samples collected in 2021 and 2022 clustered with classical virulent strains and very virulent IBDV. In 2023, one sample clustered with the Egyptian vvIBDV, while one sample clustered with classic virulent IBDV, and the remaining 2023 samples clustered with the Chinese novel variant IBDV (nVarIBDV). The alignment of deduced amino acid sequences for VP2 revealed that all Egyptian classic virulent strains were similar to the Winterfield or Leukert strains. In contrast, vvIBDV strains exhibited two out of the three typical residues found in Egyptian antigenically atypical vvIBDV, namely Y220F and G254S, but not A321T, and one sample was identical to the European vvIBDV (emerged in 1989). Meanwhile, all variant strains recognized in the present study exhibited typical residues found in variant IBDV, in addition to the three conserved amino acid residues found only in Chinese variant IBDVs. However, all Egyptian variant strains showed a mutation at position 321 (321V), which represents the most exposed part of the capsid and is known to have a massive impact on IBDV antigenicity, with the exception of one sample that had 318G instead. This report highlights the emergence of a new variant IBDV clustered with the Chinese new variant in Egypt, causing bursa atrophy and spreading subclinically in broiler farms over a wide geographic distance, resulting in massive economic losses due to immunosuppression.

microbiology↗

bioRxiv2022

Somatostatin slows Aβ plaque deposition in aged APPNL-F/NL-F mice by blocking Aβ aggregation in a neprilysin-independent manner

The molecular underpinnings that govern the endoproteolytic release of the amyloid beta peptide (A{beta}) from the amyloid precursor protein (APP) are now quite well understood. The same cannot be said for the events that precipitate the aggregation and amyloid deposition of A{beta} in Alzheimers disease (AD). The 14-amino-acid cyclic neuroendocrine peptide somatostatin (SST-14) has long been thought of as playing a role, foremost by controlling the expression of the A{beta} clearing enzyme neprilysin, and more recently by directly interacting with A{beta} oligomers. Missing have been in vivo data in a relevant A{beta} amyloidosis model. Here we addressed this shortcoming by crossing AppNL-F/NL-F mice with Sst-deficient mice of identical genetic background to assess if and how the presence of Sst influences key pathological hallmarks of A{beta} amyloidosis that develop in AppNL-F/NL-F mice after 10 months of age. Surprisingly, we found that Sst had no influence on whole brain neprilysin transcript, protein or activity levels, an observation that cannot be accounted for by a compensatory upregulation of the Sst paralog, cortistatin (Cort), that we observed in 15-month-old Sst-deficient mice. The absence of Sst did lead to a subtle but significant increase in the density of cortical A{beta} amyloid plaques. Follow-on western blot analyses of whole brain extracts indicated that Sst interferes with early steps of A{beta} assembly that manifest in Sst null brains through the appearance of SDS-stable smears of 55- 150 kDa. As expected, no effect of Sst on tau steady-state levels or its phosphorylation were observed. Results from this study are easier reconciled with an emerging body of data that point toward Sst affecting A{beta} amyloid plaque formation through direct interference with A{beta} aggregation rather than through its effects on neprilysin expression.

neuroscience↗

bioRxiv2022

Identification of a cardiac glycoside exhibiting favorable brain bioavailability and potency for reducing levels of the cellular prion protein

Several strands of investigation have established that a reduction in the levels of the cellular prion protein (PrPC) is a promising avenue for the treatment of prion diseases. We recently described an indirect approach for reducing PrPC levels that targets Na,K-ATPases (NKAs) with cardiac glycosides (CGs), causing cells to respond with the degradation of these pumps and nearby molecules, including PrPC. Because the therapeutic window of widely used CGs is narrow and their brain bioavailability is low, we set out to identify a CG with improved pharmacological properties for this indication. Starting with the CG known as oleandrin, we combined in silico modeling of CG binding poses within human NKA folds, CG structure-activity relationship (SAR) data, and predicted blood-brain barrier (BBB) penetrance scores to identify CG derivatives with improved characteristics. Focusing on C4-dehydro-oleandrin as a chemically accessible shortlisted CG derivative, we show that it reaches four times higher levels in the brain than in the heart one day after subcutaneous administration, exhibits promising pharmacological properties, and suppresses steady-state PrPC levels by 84% in immortalized human cells that have been differentiated to acquire neural or astrocytic characteristics. Finally, we validate that the mechanism of action of this approach for reducing cell surface PrPC levels requires C4-dehydro-oleandrin to engage with its cognate binding pocket within the NKA subunit. The improved brain bioavailability of C4-dehydro-oleandrin, combined with its relatively low toxicity, make this compound an attractive lead for brain CG indications and recommends its further exploration for the treatment of prion diseases. AUTHOR SUMMARYPrion diseases are fatal neurodegenerative diseases for which there is no effective treatment. An abundance of data indicates that reducing the levels of a specific protein, termed the cellular prion protein (PrPC), would not only be safe but would delay disease onset and extend prion disease survival. This project builds on our recent discovery that PrPC binds to NKAs, specific cellular transport proteins that use energy to electrify cellular membranes by pumping charged potassium and sodium metals in and out of cells. We showed that targeting NKAs with their natural inhibitors, cardiac glycosides (CGs), causes brain cells to internalize and degrade NKAs, and that PrPC, on account of residing next to NKAs, gets co-degraded. Natural CGs act primarily on the heart. Here, we used computational modeling to identify a CG, termed KDC203, that is predicted to have favorable characteristics for brain applications. We show that KDC203 reduces PrPC levels by 84% in immortalized human brain-like cells grown in the dish. Moreover, we show that KDC203 exhibits relatively low toxicity, predominantly targets the brain when subcutaneously injected into mice, and has other promising pharmacological characteristics that recommend it for further evaluation for the treatment of prion diseases.

neuroscience↗