The role of caspases in Parkinson’s Disease pathogenesis: a brief look at the mitochondrial pathway

Parkinson’s disease (PD) is a neurodegenerative disorder characterised by tremor, rigidity, Bradykinesia and reduced facial expression. Development of PD is considered to be the result of deficiency of the neurotransmitter dopamine, which is due to death of Dopamine-Containing Neurons (DCNs) that produce dopamine in the pars compacta region of the substantia nigra. Although the concentrated efforts of the scientific community over the last decades, the etiology of the death of DCN is yet to be understood. Oxidative stress has been considered as one of the causes of defects in the mitochondria leading to the dopaminergic cell damage [1]. Levodopa therapy is a well-known treatment for the symptoms of PD, however long term use of L-dopa causes side effects including further enhancement of oxidative stress [2]. The elevated levels of Reactive Oxidative Species (ROS) such as hydrogen peroxide, superoxide and hydroxyl ions, induce stimulation to the Permeability Transition Pore (mPTP) of the mitochondria leading to the collapse of the mitochondrial membrane potential and the release of cytochrome C. Furthermore, increased ROS activity promote nitric oxide binding to superoxide producing peroxynitrate enhancing oxidative and nitrosative stress, which results in DNA damage, chromosomal mutations, lipid peroxidation and enzyme defects [3]. Mutation of E3 ligase caused by peroxynitrate damage leads to impairment of ubiquitin-proteasome system, resulting in high levels of defective proteins, which accumulate in the Endoplasmic Reticulum (ER) promoting ER stress and ultimately cell death. Moreover, the apoptotic neuron triggers injury signals that activate microglia and promote release of cytokines such as interleukins-6 and -8. Subsequently, interleukins trigger Caspase activation along with inducible NO synthase, which further elevates formation of nitric oxide. Exposure to excessive reactive nitrite species along with enhanced production of ROS and peroxynitrate lead to dysfunction of complex-IV and complex-I activities of the mitochondria and promote mitochondrialmediated apoptosis through Caspase activation [4,5]

Four wave mixing nonlinearity effect in wavelength division multiplexing radio over fiber system

The integration of wireless and optical networks is a potential solution for the increasing capacity and mobility as well as decreasing costs in the access networks. Optical networks are fast, robust and error free, however, there are nonlinearity obstacles preventing them from being perfect media. The performance of wavelength division multiplexing (WDM) in radio over fiber (RoF) systems is found to be strongly influenced by nonlinearity characteristics in side the fiber. The effect of four wave mixing (FWM) as one of the influential factors in the WDM for RoF has been studied here using Optisystem and Matlab. From the results obtained, it is found that the FWM effects have become significant at high optical power levels and have become even more significant when the capacity of the optical transmission line is increased, which has been done by either increasing the channel bit rate, and decreasing the channel spacing, or by the combination of both process. It is found that when the channel spacing is 0.1 nm, 0.2 nm and 0.5 nm the FWM power is respectively, becomes about -59 dBm, -61 dBm and -79 dBm. This result confirms that the fiber nonlinearities play decisive role in the WDM for RoF system. The simulation results obtained here are in reasonable agreement as compared with other numerical simulation results obtained, elsewhere, using different simulation tools

Investigation of antitumor properties of semi-synthetic flavonoid derivatives on gynecological cancer cell lines

The present PhD work aimed to contribute to the knowledge available on the antitumor properties of flavonoids through the in vitro evaluation of the bioactivity of some uncommon semi-synthetic derivatives against a panel of breast and cervical cancer cell lines that are well-established models for certain types of gynecological cancer. The work included the semi-synthetic preparation of seven naringenin oxime and oxime ether derivatives prior to their bioactivity testing, and the in vitro evaluation of nine protoflavone-chalcone hybrid compounds and their reference fragments against breast (hormone-dependent MCF-7 and triple-negative MDA-MB-231), and cervical (SiHa & HeLa) cancer cell lines in addition to human HL-60 leukemia cells and non-cancerous mouse embryonic fibroblasts (NIH/3T3). The work included cytotoxicity, cell cycle distribution, caspase-3 activity, and antioxidant activity evaluations. Further, the cytotoxic activity of the hybrid compounds was evaluated in comparison with that of their corresponding fragments in a virtual and experimental combination study. In summary, our work led to the following results. Two naringenin oxime isomers and five oxime ether derivatives were synthesized, purified and characterized. Four of these compounds, such as the minor product naringenin Z-oxime, and the ethyl, allyl, and tert-butyl ethers of naringenin E-oxime were prepared as new compounds. When evaluating the in vitro cytotoxicity of the prepared derivatives of naringenin, tert-butyl oxime ether (6) showed the most potent effects on different gynecological cancer cells, with significant activity against MCF-7 and HeLa cells. The flow cytometric analysis of compound (6) on gynecological cancer cells revealed significant accumulation of cells in the hypodiploid (subG1) phase in HeLa & SiHa cell lines, indicating the apoptosis induction effect, and induced cycle suppression at G2/M stage in MCF-7 cancer cells. Further, the proapoptotic activity of this compound was confirmed in HeLa cells by detecting the increased activity of caspase-3. To our surprise, naringenin methyl oxime ether was more potent in the ORAC assay than its parent compound, while all other analogs were up to an order of magnitude less active. This suggests good peroxyl radical scavenging capacity for this compound. There was no apparent correlation between the in vitro cytotoxic and antioxidant activities of the tested compounds, suggesting that their anticancer effects are likely not related to their antioxidant properties. Four protoflavone hybrid compounds were identified as promising antitumor lead compounds based on their prominent in vitro cytotoxic effects and their selectivity on different breast and cervical cancer cells with antiproliferative effects better than cisplatin. The most potent compounds have an intense proapoptotic effect on TNBC, as evidenced by flow cytometric investigation and caspase-3 activity. It was shown that compound 10c induces a considerable expansion in caspase-3 activity in a concentration-time dependent manner with a significant increase in the sub G1 phase. A novel approach was used to evaluate the bioactivity of the hybrid compounds in comparison with that of their corresponding fragments. A virtual combination study was performed by using the Chou-Talalay method as a mathematical tool, and results were compared to the corresponding experimental combinations of the cells with non-coupled fragments. This gave valuable extra information as virtual combination index values and confirmed that the studied hybrid compounds are much more potent than what would be expected by a mathematical sum of the bioactivity of their fragments. Based on the above, we demonstrated the use of a novel approach to evaluate the bioactivity of hybrid compounds in general, and suggested an extension of the applicability of the Chou-Talalay method, one of the currently available most popular platforms for drug-drug combination studies. Altogether, our present study provided valuable information about the antitumor potential of two series of unusual semi-synthetic flavonoid derivatives, and made a significant contribution to identifying a set of highly potent hybrid lead compounds obtained through fragment-based drug design. Further, by providing a novel use for an existing convenient and very widely used mathematical platform, we believe our study may have contributed to the research of hybrid compounds also in a more general manner

Role of the Immune System and Bioactive Lipids in Trafficking Bone Marrow-Derived Stem Cells in Patients with Ischemic Heart Disease

Acute myocardial infarction (AMI) triggers the mobilization of stem/progenitor cells from bone marrow (BMSPCs) into peripheral blood (PB). The underlying mechanisms orchestrating this mobilization and subsequent homing of BMSPCs to the myocardium are poorly understood. While the role of traditional chemokines in the mobilization and homing of hematopoietic stem cell (HSCs) to BM niches is undisputed, their role in directing BMSPCs to the highly proteolytic environment of the ischemic myocardium is debatable and other redundant mechanism may exist. Based on our observation that bioactive lipids, such as sphingosine-1 phosphate (S1P) and ceramide-1 phosphate (C1P), play an important role in regulating trafficking of HSCs; we explored if they also direct trafficking of BMSPCs in the setting of myocardial ischemia. While BMSPCs expressed S1P receptors regardless of the source, the expression of S1P receptor 1 (S1PR1) and receptor 3 (S1PR3), which are responsible for migration and chemotaxis, was elevated in BMSPCs in naïve BM cells and was reduced following mobilization. This expression correlated to differential response of BMSPCs to S1P in chemotaxis assays. By employing flow cytometry analyses, we observed an increase in circulating PB CD34+, CD133+ and CXCR4+ lineage negative (Lin-)/CD45- cells that are enriched in non-HSCs (P \u3c 0.05 vs. controls). This corroborated our mass spectrometry studies showing a temporal increase in S1P and C1P plasma levels. At the same time, plasma obtained in the early phases following AMI strongly chemoattracted human BM-derived CD34+/Lin- and CXCR4+/Lin- cells in Transwell chemotaxis assays in an S1P dependent fashion. We examined other mechanisms that may contribute to the homing of BMSPCs to the infarcted myocardium due to the reduction of S1PRs upon mobilization. We observed that hypoxia induced higher expression of cathelicidins in cardiac tissues. Indeed, PB cells isolated from patients with AMI migrated more efficiently to low, yet physiological, gradient of SDF-1 in Transwell migration assays compared to SDF-1 alone. Together, these observations suggest that while elevated S1P plasma levels early in the course of AMI may trigger mobilization of non-HSCs into PB, cathelicidins appear to play an important role in their homing to ischemic and damaged myocardium

Evaluation of the antimicrobial (antibacterial and antifungal) activity of ethanolic extracts of some medical plants.

The aim of the study was to evaluate the antimicrobial activity ethanolic extracts of Nigella sativa (N.sativa), Zingiber officinal (Ginger), and Trigonella foenum graecum (Fenugreek), in three concentration (50mg/ml, 100mg/ml, and 200mg/ml).The antimicrobial activities have been evaluated against two gram positive bacteria: Staphylococcus aureus, Streptococcus sp., and two gram negative bacteria: Escherichia coli, Proteus sp. And two pathogenic fungi: Candida albicans, Sacromysis sp. Ethanolic extract of Ginger showed the maximum antimicrobial against gram positive bacteria and Candida  albicans fungi while Fenugreek extract give the potent effect against gram negative bacteria and Sacromysis fungi. On the other hand N. sativa extract showed the minimum antimicrobial effects. The results indicate the efficacy of the plants as a potent antimicrobial agents. Key words: Antibacterial, Antifungal, Ethanolic extract, Nigella sativa, Ginger, Fenugreek

Jobs satisfaction mediates relationship between facets of job and citizenship behavior: a study of female employees of banking sector of Pakistan

Several articles have reported and discussed the job satisfaction and dissatisfaction of female workers in miscellaneous organizations. However, very few empirically-supported explanations have been given to explain how job satisfaction mediates the relationship between facets of job and citizenship behavior in banking sector of Pakistan and specially focusing on female employees. Probes into the explanations of determining how job satisfaction mediates the relationship between facets of job and citizenship behavior, the data were collected from female employees of banking sector of Pakistan. Total 200 self-administered questionnaires were distributed among the female staff of different banks. 188 completed questionnaire were received back with response rate of 94%. The participation in survey was voluntary and confidentiality of responses was ensured. Statistical analysis reveals that there exists significant relationship between facets of job (pay, promotion, supervisor’s behavior and coworker’s behavior) and dependent variables (organizational citizenship behavior); likewise, job satisfaction mediates the relationship between facets of job and citizenship behavior. Limitations and future implementations of this research are also discussed

Aeroelastic Investigation of Long Span Suspension Bridge Decks by Numerical CFD and FSI Analyses

CFD (Computational Fluid Dynamics) simulations appear to be strong competitor of the wind tunnel test which required scaled model and it is really expensive and time consuming tool in designing bridges therefore there is a strong claim to replace them with CFD. Analyses carried out for different deck cross sections by secondary development of commercial computational fluid dynamics software ANSYS FLUENT, establishing two dimensional bending and torsional fluid-structure interaction (FSI) numerical model to calculate flutter critical wind speed. The flutter motion belongs to a sharp growth of amplitude (heave or rotation) as a function of the wind speed can be detected by performing the FSI at different wind speeds set in FLUENT model as a velocity inlet. By using the two neighboring wind speeds the critical wind speed can be obtained once a decay motion oscillation observed. Steady and unsteady simulations have been computed in order to judge the feasibility of CFD simulations in the early design stage of long span bridges. Additionally realizable (κ-ε) model with enhanced wall treatment and (κ-ω SST) turbulence models have been considered to verify their performance in bridge aerodynamics problems. It has been found that static aerodynamic coefficients have been correctly modeled using a steady simulation, while flutter critical wind speed is judged from time histories of unsteady simulations for stationary deck sections. The validity of the simulation method was verified by comparison of simulation results with the work done by other researchers. Keywords: CFD, critical flutter wind speed, bridge aeroelasticity, suspension bridges

Study of MAC Protocols for Mobile Wireless Body Sensor Networks

Wireless Body Area Networks (WBAN) also referred to as a body sensor network (BSN), is a wireless network of wearable computing devices. It has emerged as a key technology to provide real-time health monitoring of a patient and diagnose many life threatening diseases. WBAN operates in close vicinity to, on, or inside a human body and supports a variety of medical and non-medical applications. The design of a medium access control is a challenge due to the characteristics of wireless channel and the need to fulfill both requirements of mobility support and energy efficiency.  This paper presents a comparative study of IEEE 802.15.6, IEEE 804.15.4 and T-MAC in order to analyze the performance of each standard in terms of delay, throughput and energy consumption. Keywords: Biomedical, IEEE 802.15.6; T-MAC, IEEE 802.15.4, mobility, low-power communication, wireless body sensor networks, implantable sensors, healthcare applications, biosensors