Discovery of new mutually orthogonal bioorthogonal cycloaddition pairs through computational screening.

Density functional theory (DFT) calculations and experiments in tandem led to discoveries of new reactivities and selectivities involving bioorthogonal sydnone cycloadditions. Dibenzocyclooctyne derivatives (DIBAC and BARAC) were identified to be especially reactive dipolarophiles, which undergo the (3+2) cycloadditions with N-phenyl sydnone with the rate constant of up to 1.46 M-1 s-1. Most signifcantly, the sydnone-dibenzocyclooctyne and norbornene-tetrazine cycloadditions were predicted to be mutually orthogonal. This was validated experimentally and used for highly selective fluorescence labeling of two proteins simultaneously

Functional Imaging of Autonomic Regulation: Methods and Key Findings.

Central nervous system processing of autonomic function involves a network of regions throughout the brain which can be visualized and measured with neuroimaging techniques, notably functional magnetic resonance imaging (fMRI). The development of fMRI procedures has both confirmed and extended earlier findings from animal models, and human stroke and lesion studies. Assessments with fMRI can elucidate interactions between different central sites in regulating normal autonomic patterning, and demonstrate how disturbed systems can interact to produce aberrant regulation during autonomic challenges. Understanding autonomic dysfunction in various illnesses reveals mechanisms that potentially lead to interventions in the impairments. The objectives here are to: (1) describe the fMRI neuroimaging methodology for assessment of autonomic neural control, (2) outline the widespread, lateralized distribution of function in autonomic sites in the normal brain which includes structures from the neocortex through the medulla and cerebellum, (3) illustrate the importance of the time course of neural changes when coordinating responses, and how those patterns are impacted in conditions of sleep-disordered breathing, and (4) highlight opportunities for future research studies with emerging methodologies. Methodological considerations specific to autonomic testing include timing of challenges relative to the underlying fMRI signal, spatial resolution sufficient to identify autonomic brainstem nuclei, blood pressure, and blood oxygenation influences on the fMRI signal, and the sustained timing, often measured in minutes of challenge periods and recovery. Key findings include the lateralized nature of autonomic organization, which is reminiscent of asymmetric motor, sensory, and language pathways. Testing brain function during autonomic challenges demonstrate closely-integrated timing of responses in connected brain areas during autonomic challenges, and the involvement with brain regions mediating postural and motoric actions, including respiration, and cardiac output. The study of pathological processes associated with autonomic disruption shows susceptibilities of different brain structures to altered timing of neural function, notably in sleep disordered breathing, such as obstructive sleep apnea and congenital central hypoventilation syndrome. The cerebellum, in particular, serves coordination roles for vestibular stimuli and blood pressure changes, and shows both injury and substantially altered timing of responses to pressor challenges in sleep-disordered breathing conditions. The insights into central autonomic processing provided by neuroimaging have assisted understanding of such regulation, and may lead to new treatment options for conditions with disrupted autonomic function

SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME NOVEL SCHIFF BASES OF 2-QUINOLONES

A series of novel substituted 3-acetyl-1-(benzylideneamino) quinolin-2(1H)-one (1-12) have been synthesized by condensing different substituted 3-acetyl-1-amino-quinolin-2-one and aromatic aldehydes in alcohol medium. 3-acetyl-1-amino-quinolin-2-one were synthesized from substituted 3-acetyl coumarin upon refluxing with hydrazine hydrate and ethanol. The structures of the final synthesized compounds were confirmed by IR, 1H NMR and mass spectra.The synthesized compounds were screened for their antimicrobial, antioxidant and cytotoxicity activities. The test compounds were screened for their antibacterial and antifungal activity against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans, Aspergillus niger respectively by cup plate method. Compounds 2, 3, 5, 6, 7, 11 and 12 showed good antibacterial activity compared to the standard drug amoxicillin. Compounds 1, 2, 4, 5, 6, 8, 9, 10 and 12 showed moderate antifungal activity compared to the standard drug fluconazole.The antioxidant activity of the synthesised test compounds was done using DPPH radical scavenging method. Compounds 2 and 6 showed values at 85.78 and 13.41 respectively when compared to that of ascorbic acid at IC50 value of 3.69µg/ml and showed inhibitory concentration for 50% inhibition below 100 µg/ml. The final synthesized compounds were screened for their in vitro cytotoxicity activity against Ehrlich Ascites Carcinoma cells (EAC) by Trypan blue exclusion method. Compounds 2, 6 and 7 induced the greatest effect on EAC cells with an activity more than 60% at a concentration of 250µg/ml. Hence novel schiff bases synthesized from 2-quinolones are found to be interesting lead molecules as antimicrobial, antioxidant and cytotoxicity agents

Ionizing Radiation in Glioblastoma Initiating Cells

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a median survival of 12–15 months with treatment consisting of surgical resection followed by ionizing radiation (IR) and chemotherapy. Even aggressive treatment is often palliative due to near universal recurrence. Therapeutic resistance has been linked to a subpopulation of GBM cells with stem cell-like properties termed GBM initiating cells (GICs). Recent efforts have focused on elucidating resistance mechanisms activated in GICs in response to IR. Among these, GICs preferentially activate the DNA damage response (DDR) to result in a faster rate of double-strand break (DSB) repair induced by IR as compared to the bulk tumor cells. IR also activates NOTCH and the hepatic growth factor (HGF) receptor, c-MET, signaling cascades that play critical roles in promoting proliferation, invasion, and resistance to apoptosis. These pathways are preferentially activated in GICs and represent targets for pharmacologic intervention. While IR provides the benefit of improved survival, it paradoxically promotes selection of more malignant cellular phenotypes of GBM. As reviewed here, finding effective combinations of radiation and molecular inhibitors to target GICs and non-GICs is essential for the development of more effective therapies

Colonoscopy: Advanced and Emerging Techniques-A Review of Colonoscopic Approaches to Colorectal Conditions.

A complete colonoscopy is key in the diagnostic and therapeutic approaches to a variety of colorectal diseases. Major challenges are incomplete polyp removal and missed polyps, particularly in the setting of a difficult colonoscopy. There are a variety of both well-established and newer techniques that have been developed to optimize polyp detection, perform complete polypectomy, and endoscopically treat various complications and conditions such as strictures and perforations. The objective of this article is to familiarize the colorectal surgeon with techniques utilized by advanced endoscopists

Autonomous space processor for orbital debris

The development of an Autonomous Space Processor for Orbital Debris (ASPOD) was the goal. The nature of this craft, which will process, in situ, orbital debris using resources available in low Earth orbit (LEO) is explained. The serious problem of orbital debris is briefly described and the nature of the large debris population is outlined. The focus was on the development of a versatile robotic manipulator to augment an existing robotic arm, the incorporation of remote operation of the robotic arms, and the formulation of optimal (time and energy) trajectory planning algorithms for coordinated robotic arms. The mechanical design of the new arm is described in detail. The work envelope is explained showing the flexibility of the new design. Several telemetry communication systems are described which will enable the remote operation of the robotic arms. The trajectory planning algorithms are fully developed for both the time optimal and energy optimal problems. The time optimal problem is solved using phase plane techniques while the energy optimal problem is solved using dynamic programming