Gene therapy and cellular transplantation : towards a combination strategy for spinal cord injury repair.

The combination of viral mediated gene delivery, tissue engineering, and Schwann cell (SC) transplantation offer a promising strategy to enhance axonal regeneration and functional recovery following spinal cord injury (SCI). The rationale and feasibility of using such combination has been extensively reviewed in Chapter 1. The study presented in Chapter 2 showed that lentiviral vectors are most suitable in situations where stable long term transgene expression is needed, while adenovirus and retrovirus are more suited for transient gene delivery. Tissue engineering combined with Schwann cell (SC) transplantation is a promising method to enhance regeneration and remyelination of axons following a thoracic spinal cord injury (SCI). Previously, SCs in semi-permeable guidance channels made of polyacrylonitrile and polyvinylchloride (PAN/PVC) copolymers were shown to promote the growth of axons into the graft environment. In Chapter 3, we test whether different PAN/PVC mini-channel geometries affects axonal regeneration, we compared three types of channels, i.e. channels with smooth inner wall, channels with grooved inner wall, and channels filled with filaments using this model. Our results showed that grooving of the channel inner wall along the axis of the channel resulted in a significantly higher number (730.66±252.76) of myelinated axons at the channel mid-point, compared to the channels with smooth inner wall (539.4±287.63; p \u3c 0.01), indicating an enhancement of axonal regeneration when grooves are provided within the channel. In contrast, channels filled with filaments had a significantly lower number of myelinated axons (163.54±76.04) than both the grooved and smooth inner wall channels (p \u3c 0.001), indicating that densely-packed filaments prohibited axonal growth into the channel. This type of channels may need to be modified to incorporate growth-promoting molecules on filament surface and/or decrease the number of filaments inside the channel to provide attractiveness and/or space for more axons to grow. We conclude that the use of channels with grooved inner wall, combination with seeded SCs, is more suitable for axonal regeneration and myelination following SCI than the other two channel types. This combination can be used in further studies with the addition of regeneration enhancing factors such as neurotrophins. In Chapter 4, we examined axonal regeneration following transplantation of PAN/PVC mini-channel seeded with SCs that were infected with 3 viral vectors, i.e. retroviral, adenoviral, and lentiviral vectors. Although, animals in LZRS-DI5A SCs group had a significantly lower number of myelinated axons compared to lentiD15A group they showed significant improvement in grid walking test. We conclude that different patterns of transgene expression may enhance regeneration and myelination of different populations of regenerating axons following thoracic SCI. In conclusion, combination strategies for SCI using different transgene expression patterns and different channel inner wall geometry enhance axonal regeneration and myelination. Functional recovery however, may be the result of reorganization of spinal cord circuitry rather than successful axonal regeneration

Crosstalk and the Dynamical Modularity of Feed-Forward Loops in Transcriptional Regulatory Networks

Network motifs, such as the feed-forward loop (FFL), introduce a range of complex behaviors to transcriptional regulatory networks, yet such properties are typically determined from their isolated study. We characterize the effects of crosstalk on FFL dynamics by modeling the cross regulation between two different FFLs and evaluate the extent to which these patterns occur in vivo. Analytical modeling suggests that crosstalk should overwhelmingly affect individual protein-expression dynamics. Counter to this expectation we find that entire FFLs are more likely than expected to resist the effects of crosstalk (approximate to 20% for one crosstalk interaction) and remain dynamically modular. The likelihood that cross-linked FFLs are dynamically correlated increases monotonically with additional crosstalk, but is independent of the specific regulation type or connectivity of the interactions. Just one additional regulatory interaction is sufficient to drive the FFL dynamics to a statistically different state. Despite the potential for modularity between sparsely connected network motifs, Escherichia coli (E. coli) appears to favor crosstalk wherein at least one of the cross-linked FFLs remains modular. A gene ontology analysis reveals that stress response processes are significantly overrepresented in the cross-linked motifs found within E. coli. Although the daunting complexity of biological networks affects the dynamical properties of individual network motifs, some resist and remain modular, seemingly insulated from extrinsic perturbations-an intriguing possibility for nature to consistently and reliably provide certain network functionalities wherever the need arise

Identifying Parameters for Robust Network Growth using Attachment Kernels: A case study on directed and undirected networks

Network growing mechanisms are used to construct random networks that have structural behaviors similar to existing networks such as genetic networks, in efforts of understanding the evolution of complex topologies. Popular mechanisms, such as preferential attachment, are capable of preserving network features such as the degree distribution. However, little is known about such randomly grown structures regarding robustness to disturbances (e.g., edge deletions). Moreover, preferential attachment does not target optimizing the network\u27s functionality, such as information flow. Here, we consider a network to be optimal if it\u27s natural functionality is relatively high in addition to possessing some degree of robustness to disturbances. Specifically, a robust network would continue to (1) transmit information, (2) preserve it\u27s connectivity and (3) preserve internal clusters post failures. In efforts to pinpoint features that would possibly replace or collaborate with the degree of a node as criteria for preferential attachment, we present a case study on both; undirected and directed networks. For undirected networks, we make a case study on wireless sensor networks in which we outline a strategy using Support Vector Regression. For Directed networks, we formulate an Integer Linear Program to gauge the exact transcriptional regulatory network optimal structures, from there on we can identify variations in structural features post optimization

Transcriptional network growing models using motif-based preferential attachment

Understanding relationships between architectural properties of gene-regulatory networks (GRNs) has been one of the major goals in systems biology and bioinformatics, as it can provide insights into, e.g., disease dynamics and drug development. Such GRNs are characterized by their scale-free degree distributions and existence of network motifs – i.e., small-node subgraphs that occur more abundantly in GRNs than expected from chance alone. Because these transcriptional modules represent “building blocks” of complex networks and exhibit a wide range of functional and dynamical properties, they may contribute to the remarkable robustness and dynamical stability associated with the whole of GRNs. Here, we developed network-construction models to better understand this relationship, which produce randomized GRNs by using transcriptional motifs as the fundamental growth unit in contrast to other methods that construct similar networks on a node-by-node basis. Because this model produces networks with a prescribed lower bound on the number of choice transcriptional motifs (e.g., downlinks, feed-forward loops), its fidelity to the motif distributions observed in model organisms represents an improvement over existing methods, which we validated by contrasting their resultant motif and degree distributions against existing network-growth models and data from the model organism of the bacteriumEscherichia coli. These models may therefore serve as novel testbeds for further elucidating relationships between the topology of transcriptional motifs and network-wide dynamical properties

Effect of Intravenous Dexmedetomidine Infusion on Interleukin-6 (IL-6) and Plasma Cortisol in Open Heart Surgery

Aim of the work: to evaluate the effect of intravenous dexmedetomidine infusion on patients undergoing open heart surgery regarding stress response markers as plasma interleukin-6 and plasma cortisol. Patents and Methods: Fifty consecutive patients aged 18-70years, scheduled for elective open heart surgery using CPB technique were enrolled in this study at the Cardiothoracic Surgery Unit, Luxor international hospital, from July 2018 to May 2019. Patients randomly assigned using closed envelope technique into two equal groups according to the drug infused intraoperatively: 1st group (25 patients):- Dexmedetomidine group (Group D); received loading dose of intravenous dexmedetomidine infusion of 1 μg/kg IV dissolved in 20ml normal saline over 10 minutes followed by maintenance dose of 0.5 μg/kg/hr. till the end of surgery where 0.5 μg /kg/h was calculated for each patient and dissolved in 12.5 ml normal saline 2nd group ( 25 patients):- placebo group (Group P); receive 20ml intravenous infusion of normal saline 0.9 % over 10 minutes followed by continuous infusion of 12.5 ml of normal saline till the end of surgery. Results: Our study revealed that HR and MAP wasn’t significantly different between the two groups at the baseline, but significantly lowered in Dex. group after induction, during CPB, post CPB, and postoperative.Dexometomedine suppress the intraoperative and postoperative rise of IL-6 which was significantly higher in placebo group relative to Dex. group. Also dexometomedine has effect on stress hormone as serum cortisol and serum glucose decease in Dex. group relative to placebo group. None of studied cases revealed bradycardia or hypotention and there are no significant difference between groups regarding side effect drowsiness, nausea and vomiting Conclusion: This study demonstrated that the continuous administration of dexmedetomidine during open heart surgery with CPB suppressed intraoperative and post-operative cytokine secretion, and improved post-operative inflammatory response indices in the present study. Also it stabilize blood pressure and heart rate and blunt cardiovascular response to CPB. These results could be attributed to the anti-inflammatory effects of dexmedetomidine

Effect of Spraying Some Nutrients on Fruiting of Sewy Date palm (Phoenix dactylifera L.) Under New Valley Conditions

This study was carried out during two successive seasons of 2019 and 2020. To evaluate the effect of some nutrients spray on yield and fruit quality of Sewy date palm cultivar grown under El-Kharga Oasis , New Valley conditions. The experiment was set up in a complete randomized block design with ten treatments, using five replicates, bunch each. The data revealed that:- Mega phosphor, omega potas and omega cal-mag spray significantly increased the fruit retention and bunch weight compared to the untreated ones. Omega potas application was more effective compared with omega cal-mag or mega phosphor. - Spraying either mega phosphor, omega potas or omega cal-mag at any studied concentration was accompanied by improving fruit quality in terms of a significant increase in fruit weight, total soluble solids, sugars contents, NPK and beta carotene and significantly decreased in total acidity tannins and phenols compared to control. - The best results were obtained when using 4cm3/L of omega potas or 4cm3/L of omega cal-mag or 4cm3/L of mega phosphor, respectively. Also, no significant differences were found between spraying the two concentrations (2cm3 or 4cm3 of mega phosphor, omega potas and omega cal-mag.Therefore, from the results of the study, it could be concluded that must be sprayed the date bunches with 2 cm3/L of omega potas or 2cm3/L of omega cal-mag to obtain a high yield with good properties, hence, high value marketing

SocialTrove: A Self-summarizing Storage Service for Social Sensing

The increasing availability of smartphones, cameras, and wearables with instant data sharing capabilities, and the exploitation of social networks for information broadcast, heralds a future of real-time information overload. With the growing excess of worldwide streaming data, such as images, geotags, text annotations, and sensory measurements, an increasingly common service will become one of data summarization. The objective of such a service will be to obtain a representative sampling of large data streams at a configurable granularity, in real-time, for subsequent consumption by a range of data-centric applications. This paper describes a general-purpose self-summarizing storage service, called SocialTrove, for social sensing applications. The service summarizes data streams from human sources, or sensors in their possession, by hierarchically clustering received information in accordance with an application-specific distance metric. It then serves a sampling of produced clusters at a configurable granularity in response to application queries. While SocialTrove is a general service, we illustrate its functionality and evaluate it in the specific context of workloads collected from Twitter. Results show that SocialTrove supports a high query throughput, while maintaining a low access latency to the produced real-time application-specific data summaries. As a specific application case-study, we implement a fact-finding service on top of SocialTrove.Army Research Laboratory, Cooperative Agreement W911NF-09-2-0053DTRA grant HDTRA1-10-1-0120NSF grants CNS 13-29886, CNS 09-58314, CNS 10-35736Ope