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"Morrow, John A"
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عهود النبي محمد صلى الله عليه وسلم لمسيحيي العالم
كتاب (عهود النبي محمد صلى الله عليه وسلم لمسيحيي العالم) في السيرة النبوية يتمحور موضوعه حول علاقة الإسلام بأهل الكتاب عموما والمسيحيين خصوصاً ويدعو إلى إعادة النظرة إلى العلاقات بين هذه الأديان وقد عرض الكتاب كيفية تعامل النبي صلى الله عليه وسلم مع المسيحيين في مختلف بقاع العالم والمنهج الحسن الذي اتبعه معهم وعهوده لهم.
BOOK
Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases
Mutations in Park8, encoding for the multidomain Leucine-rich repeat kinase 2 (LRRK2) protein, comprise the predominant genetic cause of Parkinson's disease (PD). G2019S, the most common amino acid substitution activates the kinase two- to threefold. This has motivated the development of LRRK2 kinase inhibitors; however, poor consensus on physiological LRRK2 substrates has hampered clinical development of such therapeutics. We employ a combination of phosphoproteomics, genetics, and pharmacology to unambiguously identify a subset of Rab GTPases as key LRRK2 substrates. LRRK2 directly phosphorylates these both in vivo and in vitro on an evolutionary conserved residue in the switch II domain. Pathogenic LRRK2 variants mapping to different functional domains increase phosphorylation of Rabs and this strongly decreases their affinity to regulatory proteins including Rab GDP dissociation inhibitors (GDIs). Our findings uncover a key class of bona-fide LRRK2 substrates and a novel regulatory mechanism of Rabs that connects them to PD. Parkinson’s disease is a degenerative disorder of the nervous system that affects approximately 1% of the elderly population. Mutations in the gene that encodes an enzyme known as LRRK2 are the most common causes of the inherited form of the disease. Such mutations generally increase the activity of LRRK2 and so drug companies have developed drugs that inhibit LRRK2 to prevent or delay the progression of Parkinson’s disease. However, it was not known what role LRRK2 plays in cells, and why its over-activation is harmful. Steger et al. used a 'proteomics' approach to find other proteins that are regulated by LRRK2. The experiments tested a set of newly developed LRRK2 inhibitors in cells and brain tissue from mice. The mice had mutations in the gene encoding LRRK2 that are often found in human patients with Parkinson’s disease. The experiments show that LRRK2 targets some proteins belonging to the Rab GTPase family, which are involved in transporting molecules and other 'cargoes' around cells. Several Rab GTPases are less active in the mutant mice, which interferes with the ability of these proteins to correctly direct the movement of cargo around the cell. Steger et al.’s findings will help to advance the development of new therapies for Parkinson’s disease. The next challenges are to identify how altering the activity of Rab GTPases leads to degeneration of the nervous system and how LRRK2 inhibitors may slow down these processes.
Journal Article
Finding W.D. Fard : unveiling the identity of the founder of the Nation of Islam
Since his arrival in Detroit on July 4, 1930, W.D. Fard, known also as Wallace Fard Muhammad and over 50 other aliases, has elicited an enormous amount of curiosity. Who was this man who claimed that he was both the Messiah and the Mahdi, and who was identified as God in Person by his disciple, Elijah Muhammad, whom he reportedly appointed as his Final Messenger? The people who actually met him, and the scholars who have studied him, have suggested that he was variously an African American, an Arab from Syria, Lebanon, Algeria, Morocco or Saudi Arabia, a Jamaican, a Turk, an Afghan, an Indo-Pakistani, an Iranian, an Azeri, a white American, a Bosnian, a Mexican, a Greek or even a Jew. In an attempt to determine the origins of W.D. Fard, most scholars have relied on his teachings as passed down, and perhaps modified, by Elijah Muhammad.
eBook
The relationship between glycine transporter 1 occupancy and the effects of the glycine transporter 1 inhibitor RG1678 or ORG25935 on object retrieval performance in scopolamine impaired rhesus monkey
Reduced NMDA receptor functioning is hypothesized to underlie the cognitive and negative symptoms associated with schizophrenia. However, because direct activation of the NMDA receptor is accompanied by neurotoxicity, mechanisms that activate the glycine co-agonist site on the NMDA receptor could carry greater therapeutic potential. In the current study, the effects of two glycine transporter 1 (GlyT1) inhibitors, RG1678 and ORG25935, were characterized in the object-retrieval detour (ORD) task in scopolamine-impaired rhesus monkeys and, using positron emission tomography (PET), the GlyT1 occupancy to efficacy relationship of each compound was established. Scopolamine exerted a significant decrease in accuracy in the ORD task. Lower doses of RG1678 (0.3 and 1.0 mg/kg, p.o.) significantly attenuated the impact of scopolamine, whereas the highest dose tested (1.8 mg/kg) did not. The predicted GlyT1 occupancies of RG1678 at the effective doses were ~10 and 30 %. ORG25935 (0.1, 0.3, and 1 mg/kg, p.o.) also significantly attenuated the impact of scopolamine on the ORD task, whereas 3 mg/kg did not. The predicted GlyT1 occupancies of ORG25935 at the effective doses ranged from 16 to 80 %. These data suggest that GlyT1 inhibitors have the potential to improve performance on prefrontal cortex-dependent tests such as the ORD task, but that efficacy is lost when higher occupancies are achieved. Importantly, recent Ph2B data published by Roche suggests that low but not high doses of RG1678 improved negative symptoms in patients with schizophrenia, highlighting the potential translational nature of the current preclinical findings.
Journal Article
Comparison of Alterations in c-fos and Egr-1 (zif268) Expression Throughout the Rat Brain Following Acute Administration of Different Classes of Antidepressant Compounds
The majority of immediate-early gene (IEG) studies focus on a few key brain regions associated with the class of psychoactive compound being studied. Recently, using a meta-analysis of the c-fos literature, we demonstrated the utility of c-fos profiling to classify such compounds. The present study examined acute delivery of a range of antidepressant classes; fluoxetine, imipramine, LiCl, and mirtazapine. The dual aims were to study the IEG profiles of these varying classes of antidepressants throughout the rat brain and to compare the utility of c-fos or Egr-1 as IEGs to classify clinically efficacious antidepressants. All antidepressants increased c-fos mRNA in the central amygdala, as previously shown, while c-fos was also increased in the anterior insular cortex and significantly decreased within the septum. Although acute antidepressant administration altered c-fos expression in a number of brain regions, Egr-1 expression was only significantly altered in the central amygdala, suggesting that Egr-1 may not be as useful a marker to investigate acute antidepressant treatment. The fact that these drugs, including the previously unclassified antidepressant mirtazapine, share a number of common loci of activation, which are implicated by human and animal studies in depression, adds further support to the use of IEG mapping to classify psychoactive compounds.
Journal Article
Vaccinology
\"This book addresses a profound deficiency in the field of vaccine research and development, namely the lack of a single volume describing the design and construction of vaccine strategies from first principles to implementation. This is an authoritative textbook that details a comprehensive and systematic approach to the science of vaccinology focusing on not only basic science, but the many stages required to commercialize and navigate the regulatory requirements for human application both in the United States and Europe. The book has broad appeal to clinicians, scientific and medical researchers alike, and graduate students\"--Provided by publisher.
eBook
Comparison of Alterations in c-fos and Egr-1 (zif268) Expression Throughout the Rat Brain Following Acute Administration of Different Classes of Antidepressant Compounds
The majority of immediate-early gene (IEG) studies focus on a few key brain regions associated with the class of psychoactive compound being studied. Recently, using a meta-analysis of the
c-fos
literature, we demonstrated the utility of
c-fos
profiling to classify such compounds. The present study examined acute delivery of a range of antidepressant classes; fluoxetine, imipramine, LiCl, and mirtazapine. The dual aims were to study the IEG profiles of these varying classes of antidepressants throughout the rat brain and to compare the utility of
c-fos
or Egr-1 as IEGs to classify clinically efficacious antidepressants. All antidepressants increased
c-fos
mRNA in the central amygdala, as previously shown, while
c-fos
was also increased in the anterior insular cortex and significantly decreased within the septum. Although acute antidepressant administration altered
c-fos
expression in a number of brain regions, Egr-1 expression was only significantly altered in the central amygdala, suggesting that Egr-1 may not be as useful a marker to investigate acute antidepressant treatment. The fact that these drugs, including the previously unclassified antidepressant mirtazapine, share a number of common loci of activation, which are implicated by human and animal studies in depression, adds further support to the use of IEG mapping to classify psychoactive compounds.
Journal Article
AMPA Receptor Positive Modulators
This chapter contains sections titled:
Introduction
AMPA Receptor Structure and Function
AMPA Receptor Modulation and the Glutamate Hypothesis of Schizophrenia
AMPA Receptor Positive Modulators: Chemistry and Pharmacology
Preclinical Evidence for the Use of AMPA Receptor Modulators in Schizophrenia: Tests Predictive of Antipsychotic‐Like Activity
Targeting Cognition in Schizophrenia
Clinical Studies with AMPA Receptor Modulators
Conclusion
References
Book Chapter