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Nooh, M. M., and S. W. Bahouth, "Visualization and quantification of GPCR trafficking in mammalian cells by confocal microscopy.", Methods in cell biology, vol. 142, pp. 67-78, 2017. Abstract

G protein-coupled receptors (GPCRs) are recognized as one of the most fruitful group of therapeutic targets, accounting for more than 40% of all approved pharmaceuticals on the market. Therefore, the search for selective agents that affect GPCR function is of major interest to the pharmaceutical industry. This chapter describes methods for measuring agonist-promoted GPCR trafficking, which involves the internalization of the GPCR and its subsequent recycling back to the plasma membrane or retention and eventual degradation. These pathways will be analyzed by confocal cellular imaging, using the β1-adrenergic receptor (β1-AR) as a primary model. A major problem encountered in studying GPCR trafficking is the unavailability of antibodies that would recognize the native receptor in cells or tissues. Therefore, wild-type, point mutants, and β1-AR chimeras are generated as epitope-tagged proteins, which are stably- or transiently expressed in mammalian cells. GPCR are labeled with a fluorophore-conjugated antibody directed against the N-terminal epitope tag. The trafficking of the fluorophore-tagged GPCR between divergent trafficking pathways that result in retention and eventual degradation or recycling and reinsertion into the plasma membrane can be followed by confocal immunofluorescence microscopy techniques outlined in this review.

Nooh, M. M., R. Kansal, C. David, and M. Kotb, "Evidence for a direct role of HLA class II allelic variation in potentiating susceptibility to severe invasive streptococcal infection", JOURNAL OF IMMUNOLOGY, vol. 176: AMER ASSOC IMMUNOLOGISTS 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA, pp. S236–S236, 2006. Abstract
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Nooh, M. M., S. Mancarella, and S. W. Bahouth, "Identification of novel transplantable GPCR recycling motif for drug discovery.", Biochemical pharmacology, vol. 120, pp. 22-32, 2016 Nov 15. Abstract

β1-Adrenergic receptor (β1-AR) agonists and antagonists are widely used in the treatment of major cardiovascular diseases such as heart failure and hypertension. The β1-AR like other G protein-coupled receptors (GPCRs) are endocytosed in response to intense agonist activation. Recycling of the agonist-internalized β1-AR is dependent on its carboxy-terminal type-1 PSD-95/DLG/ZO1 (PDZ) and on phospho-serine(312) in the third intracellular loop of the β1-AR. Progressive elongation of the β1-AR at its C-tail inactivated the PDZ-biding domain and inhibited the recycling of the β1-AR. However, fusing a twenty amino acid peptide derived from the multiple cloning region of the mammalian expression vector pCDNA3 to the C-tail of the β1-AR (β1-AR[+20]) produced a chimeric β1-AR that recycled rapidly and efficiently. The β1-AR[+20] recycled in a type-1 PDZ and phospho-Ser(312)-independent manner, indicating that this peptide provided a general GPCR recycling signal. Fusing the enhanced yellow fluorescent protein (EYFP) down-stream of β1-AR[+20] generated a β1-AR-EYFP chimera that was expressed on the membrane and recycled efficiently after agonist-induced internalization. This construct trafficked in a PDZ-SNX27/retromer-independent manner. We also fused EYFP to the N-terminus of the β1-AR to created EYFP-WT β1-AR. This construct recycled in PDZ and SNX27/retromer dependent manner. These β1-AR-EYFP constructs would be useful for high throughput screening (HTS) programs to identify new entities that would interfere with the recycling of agonist internalized GPCR that traffic in PDZ-dependent vs. PDZ-independent roadmaps.

Nooh, M. M., and S. W. Bahouth, "SAP97 Controls beta 1-Adrenergic Receptor Trafficking in a PDZ Dependent Manner", The FASEB Journal, vol. 25, pp. 628–6, 2011. Abstract
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Nooh, M. M., S. Nookala, R. Kansal, and M. Kotb, "Individual genetic variations directly effect polarization of cytokine responses to superantigens associated with streptococcal sepsis: implications for customized patient care", The Journal of Immunology, vol. 186, no. 5: Am Assoc Immnol, pp. 3156–3163, 2011. Abstract
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Nooh, M. M., and S. W. Bahouth, "Two barcodes encoded by the type-1 PDZ and by phospho-Ser(312) regulate retromer/WASH-mediated sorting of the ß1-adrenergic receptor from endosomes to the plasma membrane.", Cellular signalling, vol. 29, pp. 192-208, 2017 Jan. Abstract

Recycling of the majority of agonist-internalized GPCR is dependent on a type I-PDZ "barcode" in their C-tail. The recycling of wild-type (WT) ß1-AR is also dependent on its default "type-1 PDZ barcode", but trafficking of the ß1-AR is inhibited when PKA or its substrate serine at position 312 (Ser(312)) are inactivated. We tested the hypothesis that phospho-Ser(312) provided a second barcode for ß1-AR sorting from endosomes to the plasma membrane by determining the role of retromer/WASH complexes in ß1-AR trafficking. Recycling of WT ß1-AR or WT ß2-AR was dependent on targeting the retromer to endosomal membranes via SNX3 and rab7a, and on complexing the retromer to the WASH pentamer via the C-tail of FAM21 (FAM21C). These maneuvers however, did not inhibit the recycling of a phospho-Ser(312) ß1-AR mimic ((S312D) ß1-AR). Knockdown of the trans-acting PDZ protein sorting nexin27 (SNX27) inhibited the recycling of WT ß1-AR and WT ß2-AR, but had no effect on (S312D) ß1-AR∆PDZ or on phosphorylation of WT ß1-AR by PKA at Ser(312). However, depletion of FKBP15, a FAM21C-binding endosomal protein, selectively inhibited WT ß1-AR but not ß2-AR recycling, suggesting divergence might exist in GPCR trafficking roadmaps. These results indicate that two barcodes are involved in sorting WT ß1-AR out of early endosomes. The first and antecedent "barcode" was the "type-1 PDZ", followed by a second reversible "phospho-Ser(312)" verification "barcode". This organization allows tight regulation of ß1-AR density to signaling intensity in conditions associated with aberrant ß1-AR signaling such as in hypertension and heart failure.

Nooh, M. M., R. K. Aziz, M. Kotb, A. Eroshkin, W. - J. Chuang, T. Proft, and R. Kansal, "Streptococcal mitogenic exotoxin, SmeZ, is the most susceptible M1T1 streptococcal superantigen to degradation by the streptococcal cysteine protease, SpeB", Journal of Biological Chemistry, vol. 281, no. 46: American Society for Biochemistry and Molecular Biology, pp. 35281–35288, 2006. Abstract
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Nooh, M. M., M. M. Chumpia, T. B. Hamilton, and S. W. Bahouth, "Sorting of $\beta$1-adrenergic receptors is mediated by pathways that are either dependent on or independent of type I PDZ, protein kinase A (PKA), and SAP97", Journal of Biological Chemistry, vol. 289, no. 4: American Society for Biochemistry and Molecular Biology, pp. 2277–2294, 2014. Abstract
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Nooh, M. M., S. Mancarella, and S. W. Bahouth, "Novel Paradigms Governing -Adrenergic Receptor Trafficking in Primary Adult Rat Cardiac Myocytes.", Molecular pharmacology, vol. 94, issue 2, pp. 862-875, 2018 Aug. Abstract

The -adrenergic receptor (-AR) is a major cardiac G protein-coupled receptor, which mediates cardiac actions of catecholamines and is involved in genesis and treatment of numerous cardiovascular disorders. In mammalian cells, catecholamines induce the internalization of the -AR into endosomes and their removal promotes the recycling of the endosomal -AR back to the plasma membrane; however, whether these redistributive processes occur in terminally differentiated cells is unknown. Compartmentalization of the -AR in response to -agonists and antagonists was determined by confocal microscopy in primary adult rat ventricular myocytes (ARVMs), which are terminally differentiated myocytes with unique structures such as transverse tubules (T-tubules) and contractile sarcomeres. In unstimulated ARVMs, the fluorescently labeled -AR was expressed on the external membrane (the sarcolemma) of cardiomyocytes. Exposing ARVMs to isoproterenol redistributed surface -ARs into small (∼225-250 nm) regularly spaced internal punctate structures that overlapped with puncta stained by Di-8 ANEPPS, a membrane-impermeant T-tubule-specific dye. Replacing the -agonist with the -blocker alprenolol, induced the translocation of the wild-type -AR from these punctate structures back to the plasma membrane. This step was dependent on two barcodes, namely, the type-1 PDZ binding motif and serine at position 312 of the -AR, which is phosphorylated by a pool of cAMP-dependent protein kinases anchored at the type-1 PDZ of the -AR. These data show that redistribution of the -AR in ARVMs from internal structures back to the plasma membrane was mediated by a novel sorting mechanism, which might explain unique aspects of cardiac -AR signaling under normal or pathologic conditions.

Nooh, M. M., A. P. Naren, S. - J. Kim, Y. K. Xiang, and S. W. Bahouth, "SAP97 Controls the Trafficking and Resensitization of the Beta-1-Adrenergic Receptor through Its PDZ2 and I3 Domains", PloS one, vol. 8, no. 5: Public Library of Science, pp. e63379, 2013. Abstract
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Nooh, M. M., N. El-Gengehi, R. Kansal, C. S. David, and M. Kotb, "HLA transgenic mice provide evidence for a direct and dominant role of HLA class II variation in modulating the severity of streptococcal sepsis", The Journal of Immunology, vol. 178, no. 5: Am Assoc Immnol, pp. 3076–3083, 2007. Abstract
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Nooh, M. M., R. G. Kansal, C. S. David, and M. Y. Kotb, "146-P: HLA class II plays a key role in modulating the severity of invasive streptococcal infections: In vivo and in vitro studies using HLA transgenic mice", Human Immunology, vol. 67: Elsevier, pp. S146, 2006. Abstract
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Nooh, M. M., and S. W. Bahouth, "Characterizing the Structural Elements Involved in $\beta$1-Adrenergic Receptor Interaction with SAP97", The FASEB Journal, vol. 27, pp. 882–8, 2013. Abstract
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Nooh, M. M., S. M. Rizk, N. M. Saied, and S. M. Abdelazim, "Carnosine Remedial Effect on Fertility of Male Rats Receiving Cyclophosphamide, Hydroxydaunomycin, Oncovin and Prednisone (CHOP).", Andrologia, vol. 53, issue 11, pp. e14233, 2021. Abstract

Chemotherapeutic agents can impair gonadal function triggering infertility. Here, we probed the properties of carnosine as an antioxidant in reproductive disorders caused by the combination of cyclophosphamide, hydroxydaunomycin (doxorubicin), oncovin (vincristine) and prednisone (CHOP); this combination is mostly used in treating non-Hodgkin lymphoma. Animals were distributed into four groups: Group I was the control. Group II received carnosine (250mg kg day , i.p.); Group III received CHOP: cyclophosphamide (27 mg/kg/cycle), doxorubicin (1.8 mg/kg/cycle) and vincristine (0.05 mg/kg /cycle) by i.p. plus oral prednisone (1.47 mg kg  day /cycle) for five days. Group IV received carnosine plus CHOP. The study involved 4 cycles each of 3 weeks. Also, we explored the effect of combining carnosine with CHOP on the development of solid Ehrlich carcinoma in mice. CHOP lowered genitals weight, sperm count and motility, testicular function marker enzymes, serum testosterone level and gene expression of 3β-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase and steroidogenic acute regulatory protein. Furthermore, CHOP elevated testicular oxidative stress, serum follicle-stimulating hormone, luteinising hormone and triggered DNA damage. Morphometric and histopathological examinations of testicular tissues buttressed the biochemical results. Importantly, administration of carnosine ameliorated CHOP-induced alterations without diminishing CHOP's antineoplastic action. These results indicated that carnosine may ameliorate reproductive disorders induced by CHOP.

Nooh, M. M., A. Kale, and S. W. Bahouth, "Involvement of PDZ-SAP97 interactions in regulating AQP2 translocation in response to vasopressin in LLC-PK cells.", American journal of physiology. Renal physiology, vol. 317, issue 2, pp. F375-F387, 2019 Aug 01. Abstract

Arginine-vasopressin (AVP)-mediated translocation of aquaporin-2 (AQP2) protein-forming water channels from storage vesicles to the membrane of renal collecting ducts is critical for the renal conservation of water. The type-1 PDZ-binding motif (PBM) in AQP2, "GTKA," is a critical barcode for its translocation, but its precise role and that of its interacting protein partners in this process remain obscure. We determined that synapse-associated protein-97 (SAP97), a membrane-associated guanylate kinase protein involved in establishing epithelial cell polarity, was an avid binding partner to the PBM of AQP2. The role of PBM and SAP97 on AQP2 redistribution in response to AVP was assessed in LLC-PK renal collecting cells by confocal microscopy and cell surface biotinylation techniques. These experiments indicated that distribution of AQP2 and SAP97 overlapped in the kidneys and LLC-PK cells and that knockdown of SAP97 inhibited the translocation of AQP2 in response to AVP. Binding between AQP2 and SAP97 was mediated by specific interactions between the second PDZ of SAP97 and PBM of AQP2. Mechanistically, inactivation of the PBM of AQP2, global delocalization of PKA, or knockdown of SAP97 inhibited AQP2 translocation as well as AVP- and forskolin-mediated phosphorylation of Ser in AQP2, which serves as the major translocation barcode of AQP2. These results suggest that the targeting of PKA to the microdomain of AQP2 via SAP97-AQP2 interactions in association with cross-talk between two barcodes in AQP2, namely, the PBM and phospho-Ser, plays an important role in the translocation of AQP2 in the kidney.

Nooh, H. A., M. S. Abdellateif, L. Refaat, E. Z. Kandeel, A. Bayoumi, M. Samra, and medhat khafagy, "The role of inflammatory indices in the outcome of COVID-19 cancer patients.", Medical oncology (Northwood, London, England), vol. 39, issue 1, pp. 6, 2022. Abstract

To assess the prognostic role of different inflammatory indices on the outcome of cancer patients with COVID-19. Sixty-two adults and 22 pediatric cancer patients with COVID-19 infection were assessed for the prognostic value of certain inflammatory indices including the neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), platelet to lymphocyte ratio (PLR), derived NLR (dNLR), systemic inflammation index (SII), mean platelet volume to platelet ratio (MPR), C-reactive protein to lymphocyte ratio (CRP/L), aggregate index of systemic inflammation (AISI), systemic inflammation response index (SIRI), and neutrophil to lymphocyte, platelet ratio (NLPR). Data were correlated to patients' outcome regarding ICU admission, and incidence of mortality. Increased CRP/L ratio in adult COVID-19 cancer patients was significantly associated with inferior survival [152 (19-2253) in non-survivors, compared to 27.4 (0.8-681) in survivors (P = 0.033)]. It achieved a sensitivity (60%) and a specificity (90.2%) at a cut-off 152, while it achieved a sensitivity of 60% and specificity 95.1% at a cut-off 252 (AUC 0.795, P = 0.033). When combining both CRP/L and NLPR for the prediction of poor outcome in adult cancer patients with COVID19, the sensitivity increased to 80% and the specificity was 70.7% (AUC 0.805, P = 0.027). Increased incidence of ICU admission in pediatric cancer patients associated significantly with the severity of covid19 infection, decreased mean corpuscular hemoglobin (MCH) < 28.3, increased red cell distribution width (RDW) > 16, lymphopenia < 1.04, pseudo Pelger-Huet appearance, and PLR < 196.4 (P = 0.004, P = 0.040, P = 0.029, P = 0. 0.039, P = 0.050, and P = 0.040; respectively). The mean corpuscular volume (MCV), MCH, and RDW could be useful prognostic markers for poor outcome in COVID-19 pediatric cancer patients (P < 0.05 for all). Increased both CRP/L and NLPR associated significantly with poor survival in adult COVID-19 cancer patients, while PLR associated significantly with ICU admission in pediatric COVID-19 cancer patients.

Nooh, M. M., S. M. Rizk, N. M. Saied, and S. M. Abdelazim, "Carnosine Remedial Effect on Fertility of Male Rats Receiving Cyclophosphamide, Hydroxydaunomycin, Oncovin and Prednisone (CHOP)", Andrologia , vol. 53, issue 11, pp. e14233, 2021.
Nono, J. K., H. Ndlovu, N. A. Aziz, T. Mpotje, L. Hlaka, and F. Brombacher, "Host regulation of liver fibroproliferative pathology during experimental schistosomiasis via interleukin-4 receptor alpha.", PLoS neglected tropical diseases, vol. 11, issue 8, pp. e0005861, 2017 Aug. Abstract

Interleukin-4 receptor (IL-4Rα) is critical for the initiation of type-2 immune responses and implicated in the pathogenesis of experimental schistosomiasis. IL-4Rα mediated type-2 responses are critical for the control of pathology during acute schistosomiasis. However, type-2 responses tightly associate with fibrogranulomatous inflammation that drives host pathology during chronic schistosomiasis. To address such controversy on the role of IL-4Rα, we generated a novel inducible IL-4Rα-deficient mouse model that allows for temporal knockdown of il-4rα gene after oral administration of Tamoxifen. Interrupting IL-4Rα mediated signaling during the acute phase impaired the development of protective type-2 immune responses, leading to rapid weight loss and premature death, confirming a protective role of IL-4Rα during acute schistosomiasis. Conversely, IL-4Rα removal at the chronic phase of schistosomiasis ameliorated the pathological fibro-granulomatous pathology and reversed liver scarification without affecting the host fitness. This amelioration of the morbidity was accompanied by a reduced Th2 response and increased frequencies of FoxP3+ Tregs and CD1dhiCD5+ Bregs. Collectively, these data demonstrate that IL-4Rα mediated signaling has two opposing functions during experimental schistosomiasis depending on the stage of advancement of the disease and indicate that interrupting IL-4Rα mediated signaling is a viable therapeutic strategy to ameliorate liver fibroproliferative pathology in diseases like chronic schistosomiasis.

Nono, J. K., H. Ndlovu, N. A. Aziz, T. Mpotje, L. Hlaka, and F. Brombacher, "Interleukin-4 receptor alpha is still required after Th2 polarization for the maintenance and the recall of protective immunity to Nematode infection.", PLoS neglected tropical diseases, vol. 11, issue 6, pp. e0005675, 2017 Jun. Abstract

There is currently no vaccine against parasitic nematodes and the knowledge on the mechanisms by which protective immunity against this class of parasites is achieved is continuously expanding. Nematode parasites trigger a host protective type 2 immune response via interleukin-4 receptor alpha (IL-4Rα). Despite this central role, it is not known whether IL-4Rα has a role in maintaining host type 2 immune responses following polarization. To determine the role of IL-4Rα after polarization, we used a recently established strain of rosaCreERT2-/+IL-4Rα-/Lox mice where il4rα gene deletion can be temporally controlled. We show that sustained expression of IL-4Rα is required for the maintenance of type 2 immune responses and protective immunity following interruption after polarization with Nippostrongylus brasiliensis primary infection. Moreover, we show by temporal deletion of IL-4Rα prior to secondary infection with N. brasiliensis that signaling via this receptor drives more efficient recall of type 2 immune responses and clearance of the parasites. Together, this study demonstrates that sustained IL-4Rα mediated signaling is required for the maintenance of anti-nematode type 2 immune responses, describing a novel function for IL-4Rα that is distinct from its role in immune polarization.

Nomer, H. A. A., K. A. Alnowibet, A. Elsayed, and A. W. Mohamed, "Neural Knapsack: A Neural Network Based Solver for the Knapsack Problem", IEEE Access, vol. 8, pp. 224200 - 224210, 2020. Abstract
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Nomenyo, K., A. - S. Gadallah, S. Kostcheev, D. J. Rogers, and G. Lérondel, "Enhanced stimulated emission in ZnO thin films using microdisk top-down structuring", Applied Physics Letters, vol. 104, no. 18: AIP Publishing, pp. 181104, 2014. Abstract
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Noman, S., S. M. Shamsuddin, and A. E. Hassanien, "Hybrid learning enhancement of RBF network with particle swarm optimization", Foundations of Computational, Intelligence Volume 1: Springer Berlin Heidelberg, pp. 381–397, 2009. Abstract
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Noman, S., S. M. Shamsuddin, and A. E. Hassanien, "Hybrid learning enhancement of RBF network with particle swarm optimization", Foundations of Computational, Intelligence Volume 1: Springer Berlin Heidelberg, pp. 381–397, 2009. Abstract
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