Muhammad (SAW) in the Near-Contemporaneous Non-Muslim Sources: An Appraisal of Robert Spencer’s Views

Muhammad’s (SAW life is fully reserved and recorded in history. It has been established beyond a shadow of doubt that not only the major and significant events of his life but even the minutest details of his life are also painstakingly preserved by the Muslims. In spite of the availability of abundant authentic documents concerning Muhammad’s (SAW) life, sayings and deeds, some critics of Islam stubbornly refuse to believe in his historicity. Robert Spencer is one such critic who maintains that Muhammad’s (SAW) value is nothing more than a fictional or mythological figure. This article is an attempt to prove the existence of Muhammad (SAW) in contemporary non-Muslims sources. The article is divided into three major parts: the first part of the paper throws light on how much emphasis Muslims lay on historical authenticity of Muhammad (SAW), in the second part of the paper views and doubts of prominent like orientalists Spencer concerning Muhammad’s (SAW) historical authenticity have been summarized, whereas the third part presents Robert Spencer’s views in the same connection and endeavors to refute his views and approach drawing on contemporary non-Muslim Sources.  

Modelling of Tlr4 and Jak/Stat Signalling Pathways and Protein-Protein Interaction Studies to Examine the Pathophysiology of Sepsis

In this thesis, the medical condition of sepsis is considered at molecular level (signalling pathways) using computational systems-level approaches in order to get insights into the mechanism of disease progression. Sepsis is the pathological condition provoked due to the presence of bacterial endotoxin in the bloodstream. Subsequently Toll like receptors (TLR)4 and JAK/STAT signalling pathways attempt to reduce the pathogen burden by inducing pro- and anti-inflammatory innate immune responses. However, in some instances, an overwhelmed immune system could not properly regulate the balance between infection and inflammation that may ultimately lead to organ damage and consequently to death. In recent years, there has been an increasing amount of literature on the pattern of pro- and anti-inflammatory response elicited during sepsis, though; there has been a little agreement on the roles of pro- and antiinflammatory cytokines (AiCyts) in sepsis. This study mainly aims to address the controversy behind roles of pro- and anti-inflammatory cytokines in sepsis by modelling the signalling pathway of TLR4 and one of the connected signalling cascades of JAK/STAT using qualitative modelling approach introduced by René Thomas’. The possible system dynamics of TLR4-JAK/STAT signalling pathways are produced for two medical conditions i.e. non-sepsis (type of infections that generally do not cause sepsis) and sepsis along with perturbations in these two cases. As a result, recurrent induction and inactivation of pro-inflammatory cytokines is found as the basic feature associated with sepsis. Besides AiCyts, IFN-β and SOCS-1 are found to mediate down-regulation of pro-inflammatory cytokines at different stages of signalling which cause variation of pro-inflammatory cytokines levels. It is observed that intervention in IFN-β mediated down-regulation of pro-inflammatory cytokines at earlier stages of system dynamics, while intervening the SOCS-1 mediated down-regulation of proinflammatory cytokines at later stages ensures hyper-inflammatory condition. On the other hand, interventions in TLR4, NFκB (transcription factor involved in the TLR4 1 Abstract signalling pathway) and JAK/STAT signalling are good choices for supporting the anti-inflammatory immune responses. Thus only possible protein-protein interactions involved in the initial downstream interactions of TLR4 signalling are studied in order to predict a more appropriate target in these interactions. Previous studies indicated that MyD88 adaptor-like protein (MAL) is an endogenous adaptor protein recognized as an important protein involved in the induction of TLR4 mediated downstream signalling pathway. Moreover, it has also been demonstrated that BTK and PKCδ phosphorylate MAL (positions Tyr86 and Tyr106) which ultimately activates MAL. Thus the modelling of PKCδ and protein-protein interactions of both BTK and PKCδ with MAL is performed in order to explore their competitive interaction. Molecular docking and physicochemical analysis reveals that PKCδ may phosphorylate only Tyr106 of MAL, while BTK may phosphorylate MAL at both positions. Interestingly, the charge and hydrophobicity at interfaces of PKCδ and BTK are found different in nature yet well-compatible with the individual positions of Tyr86 and Tyr106 of MAL. The most prominent findings emerged from this analysis is that position Tyr86 of MAL may explicitly be phosphorylated by BTK, while position Tyr106 of MAL may be phosphorylated by the competing interest of both PKCδ and BTK. In conclusion, this thesis will enhance our understanding about the signalling and protein-protein interactions involved in sepsis which will contribute to the development of drugs and vaccines against the medical condition of sepsis.