Yes

Knowledge can be dangerous. As neuroscience delves more deeply into our organ of thought and its complex soup of neurotransmitters - could it also be exploited for malign purposes? Is the brain the next target of terrorism? Pharmaceutically enhanced soldiers, chemical torture, incapacitants, neurological weaponry... The possibilities are frightening and progress rapid. Two leading researchers into biological weapons present their concerns, and argue scientists need to take action now. But are we at risk of paranoia?

Yes

Yes

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Cell biology is a branch of science with a seemingly infinite abundance of interesting phenomena which are essential to our understanding of life and which may potentially drive the development of technology that improves our lives. Among the open ended questions within the field, an understanding of how gene networks are affected by limited cellular components is both broad and rich with interest. Common to all cellular systems are enzymes which perform many tasks within cells without which organisms could not remain healthy. Here are presented several explorations of enzymatic processing as well as a tool constructed for this purpose. More specifically, these works consider the effect of coupling of gene networks via competition for enzymes found within the cell. It is shown that a limitation on the number of available enzymes permits the formation of bottlenecks which drastically affect molecular dynamics within cells. These effects potentially afford cell behaviors that in part explain the impressive robustness of life to constantly fluctuating environments. / Ph. D.

Benign masseter hypertrophy causes swelling at the angulus mandibulae and may be associated with masticatory myofascial pain due to hyperfunction from bruxism. The aim of this research was to use the systematic review process to investigate the true or reliable scientific evidence contained in four major databases pertaining to the efficacy and safety of intra-muscular injections of botulinum toxin A (BTX-A) for the treatment of masticatory myofascial pain and benign masseter hypertrophy associated with bruxism, compared with placebo or other traditional treatments prescribed for bruxism such as occlusal splints, pharmacotherapy, or lifestyle modification. Using the PICO format, a research question was formulated, MeSH terms were derived, and an electronic literature search was conducted in PubMed, Embase, Web of Science, and Cochrane. This sequence was followed by a screening and selection of articles by two independent reviewers according to defined inclusion and exclusion criteria. The selected studies were then evaluated and assessed based on study quality and identification of biases, and the results were summarized and reported. This review highlighted the lack of well-designed, randomized controlled trials to evaluate the efficacy and safety of botulinum toxin A for reducing the size/volume of the masseter muscles and for improving masticatory myofascial pain in patients who present with bruxism. Thus, the results were inconclusive.

Chronic migraines are a neurological disorder, which can be debilitating to patients and result in increased healthcare costs and disability-affected life years. Botox and CGRP antagonists are two drugs used as prophylactic treatments for chronic migraine patients who have failed other medications in the past. However, there are currently no studies that have directly compared the two drugs and existing research indirectly comparing them has had conflicting conclusions regarding efficacy. This double-blind, prospective clinical study aims to determine whether there is a clinically significant difference in efficacy between the two drugs defined as percent reduction in headache days per month. Patients will be recruited and divided into three groups: those who will receive Botox injections, those who will receive Emgality injections, and placebo. The results of this study will be analyzed with ANOVA to determine whether there is a statistically significant difference among the groups, then further analyzed with paired T-tests to determine if one treatment is superior to the other. These results could be used for further research into migraine treatments, as well as to help determine which treatment to trial first in patients with migraines refractory to other medications.

Toxins produced by the Gram-positive bacteria Clostridium botulinum cause transient chemodenervation of mammalian muscle. The toxin binds to specific proteins within cholinergic presynaptic nerve terminals which regulate the release of acetylcholine in the synaptic space resulting is loss of muscle activation and function. Local injections with botulinum toxins are currently used in humans for the treatment of disorders that benefit from prolonged neuromuscular blockade such as strabismus, blepharospasm, focal dystonias, spasticity, tremors, and anal fissures. Injections with botulinum toxin type A into the internal or external anal sphincter cause relaxation of the anal canal and allow healing of chronic anal fissures. Perineal lacerations in mares, which occur during foaling often dehisce after surgical repair due to the high pressure across the incision resulting from accumulation of feces in the rectum. We hypothesized local injections of Clostridium botulinum type B toxin into the external anal sphincter could cause a decrease in anal pressures, thus reducing the incidence of dehiscence if used before surgical repair of perineal laceration in mares. The purpose of this project was to determine the effects of BTB injection in the external anal sphincter in normal horses. Our hypothesis was that local injection of BTB would result in transient reduction of anal tone without causing clinical side effects. Peak and resting anal sphincter pressures of horses were measured with a custom made rectal probe connected to a pressure transducer. Pressures were measured before treatment and after injection with Clostridium botulinum type B toxin (BTB) or saline. Dose titration with 500, 1000, 1500 and 2500 units of BTB was completed. The horses' physical changes, behavior, and anal pressure were recorded. Injection of 1000 units of BTB produced significant reduction in peak anal pressure from days 2 to 84 when compared to control animals (P<0.05). Maximal effect of the toxin was observed within the first 15 days after injections followed by a slow return to baseline over 168 days. Injection in the anal sphincter with 2500 units of BTB in one horse produced signs of depression, generalized weakness, and dysphagia for 14 days. Clinical side effects were not observed in horses after injections with 500, 1000, or 1500 units of BTB. In summary, local injections of botulinum toxin type-B in the external anal sphincter of horses caused transient relaxation of the anus and reduction of peak anal pressures. Systemic side effects were observed in one horse, which suggested a narrow dosage range to avoid toxicity. Further research to test the effects of botulinum toxin in clinical cases is needed to determine the full potential of this treatment modality. / Master of Science

Bordetella pertussis is an important human pathogen that causes an infection disease called whooping cough. This gram-negative bacterium produces an adenylate cyclase toxin (CyaA) that recognizes an integrin receptor CD11b/CD18 present on the surface of myeloid phagocytes and delivers an adenylate cyclase (AC) domain into the cell cytosol. This thesis deals with the endocytic machinery of CyaA and its potential use as a specific marker for endocytosis of the CD11b/CD18 receptor molecule. Detoxified mutant of CyaA, CyaA-AC- , that has the capacity to promote calcium influx as well the potassium efflux, was shown to trigger activation of the integrin receptor CD11b/CD18 followed with endocytic uptake by clathrin-dependent pathway. On the other side, the inactive mutant CyaA-KP-AC- that is unable to provoke integrin activation was endocytosed by clathrin-independent pathway. These results suggest that the various endocytic pathways of the CD11b/CD18 are determined by different conformational states of the receptor molecule.