Withaferin A Effectively Targets Soluble Vimentin in the Glaucoma Filtration Surgical Model of Fibrosis

Withaferin A (WFA) is a natural product that binds to soluble forms of the type III intermediate filament (IF) vimentin. Currently, it is unknown under what pathophysiological contexts vimentin is druggable, as cytoskeltal vimentin-IFs are abundantly expressed. To investigate druggability of vimentin, we exploited rabbit Tenon\u27s capsule fibroblast (RbTCF) cell cultures and the rabbit glaucoma filtration surgical (GFS) model of fibrosis. WFA potently caused G₀/G₁ cell cycle inhibition (IC₅₀ 25 nM) in RbTCFs, downregulating ubiquitin E3 ligase skp2 and inducing p27(Kip1) expression. Transforming growth factor (TGF)-ß-induced myofibroblast transformation caused development of cell spheroids with numerous elongated invadopodia, which WFA blocked potently by downregulating soluble vimentin and α-smooth muscle actin (SMA) expression. In the pilot proof-of-concept study using the GFS model, subconjunctival injections of a low WFA dose reduced skp2 expression in Tenon\u27s capsule and increased p27(Kip1) expression without significant alteration to vimentin-IFs. This treatment maintains significant nanomolar WFA concentrations in anterior segment tissues that correspond to WFA\u27s cell cycle targeting activity. A ten-fold higher WFA dose caused potent downregulation of soluble vimentin and skp2 expression, but as found in cell cultures, no further increase in p27(Kip1) expression was observed. Instead, this high WFA dose potently induced vimentin-IF disruption and downregulated α-SMA expression that mimicked WFA activity in TGF-ß-treated RbTCFs that blocked cell contractile activity at submicromolar concentrations. These findings illuminate that localized WFA injection to ocular tissues exerts pharmacological control over the skp2-p27(Kip1) pathway by targeting of soluble vimentin in a model of surgical fibrosis

Reproductive Ecology of Male and Female Strobili and Mating System in Two Different Populations of Pinus roxburghii

We studied several flowering traits, namely, male-female cone phenology, male-female cone production per tree, mating system, sex ratio, air-borne pollen grains and pollen migration, over four successive years in two different natural populations of P. roxburghii from Garhwal Himalaya, India. Assessment of each trait mentioned except pollen dispersion was done by selecting five representative trees randomly in each population. The pollen migration was studied on naturally isolated source trees. The pollen trapping was done in all directions up to 2.5 km. The average reproductive period in P. roxburghii was 36 days with 3–5 days protandry. There were significant year and population effects for male and female cone output and pollen grains production per tree. In mass production year (1999), an average production of pollen cone per tree was estimated as 42.44 ± 8.32 × 103 at lower altitude and 28.1 ± 0.89 × 103 at higher altitude. The controlled pollination results in high level of outcrossing with 90% seed setting. We conclude that the high male-female ratio and tremendous pollen production capacity in P. roxburghii indicate high male competition among trees within populations. The isolation strip of 600 m is considered minimal for the management of seed orchard

Reformulating Constraints for Compilability and Efficiency

KBSDE is a knowledge compiler that uses a classification-based approach to map solution constraints in a task specification onto particular search algorithm components that will be responsible for satisfying those constraints (e.g., local constraints are incorporated in generators; global constraints are incorporated in either testers or hillclimbing patchers). Associated with each type of search algorithm component is a subcompiler that specializes in mapping constraints into components of that type. Each of these subcompilers in turn uses a classification-based approach, matching a constraint passed to it against one of several schemas, and applying a compilation technique associated with that schema. While much progress has occurred in our research since we first laid out our classification-based approach [Ton91], we focus in this paper on our reformulation research. Two important reformulation issues that arise out of the choice of a schema-based approach are: (1) compilability-- Can a constraint that does not directly match any of a particular subcompiler's schemas be reformulated into one that does? and (2) Efficiency-- If the efficiency of the compiled search algorithm depends on the compiler's performance, and the compiler's performance depends on the form in which the constraint was expressed, can we find forms for constraints which compile better, or reformulate constraints whose forms can be recognized as ones that compile poorly? In this paper, we describe a set of techniques we are developing for partially addressing these issues

Automating Mission Scheduling for Space-Based Observatories

In this paper we describe the use of our planning and scheduling framework, HSTS, to reduce the complexity of science mission planning. This work is part of an overall project to enable a small team of scientists to control the operations of a spacecraft. The present process is highly labor intensive. Users (scientists and operators) rely on a non-codified understanding of the different spacecraft subsystems and of their operating constraints. They use a variety of software tools to support their decision making process. This paper considers the types of decision making that need to be supported/automated, the nature of the domain constraints and the capabilities needed to address them successfully, and the nature of external software systems with which the core planning/scheduling engine needs to interact. HSTS has been applied to science scheduling for EUVE and Cassini and is being adapted to support autonomous spacecraft operations in the New Millennium initiative

Butorphanol for Post-Operative Analgesia - A Comparative Clinical Study with Ketorolac

Introduction: Butorphanol, an opioid derivative has been shown to have, in addition to its analgesic properties, several other advantageous effects like antistressor, sedative and anti-shivering action. The efficacy and safety profile of ketorolac, yet another widely used post-operative analgesic is well documented. This study aims to compare the two analgesics. Aims and objectives: This study was conducted to compare the analgesic efficacy and other effects of butorphanol and ketorolac, administered intramuscularly, in post-operative patients who have undergone lower abdominal and pelvic surgeries. Materials and methods: 50 patients undergoing lower abdominal and pelvic surgeries under general or spinal anaesthesia were randomly divided into two Groups (25 each). At a particular level of post-operative pain, the patients Groups I and II were administered intramuscular ketorolac 30mg and butorphanol 2mg respectively. The analgesic effect was studied using Visual Analogue Scale (VAS) and the verbal category scale. Patients were monitored for the sedative action, respiratory status and other vital parameters for 300 minutes and for other adverse reactions over the next twelve hours. Observations: Butorphanol provided better analgesia within the first two hours of administration, while ketorolac was more effective at 4-5 hours. Better sedative action without any significant respiratory depressant effect was demonstrated with butorphanol. There were no clinically significant hemodynamic fluctuations or adverse reactions with butorphanol or ketorolac. Conclusions: Butorphanol provides better early analgesia as compared to ketorolac with a desirable and safe sedative effect in post-operative patients who have undergone lower abdominal and pelvic surgeries

DEVELOPMENT AND OPTIMIZATION OF ENZALUTAMIDE-LOADED SOLID LIPID NANOPARTICLES USING BOX–BEHNKEN DESIGN

Objective: The primary motive behind this investigation is to develop and optimize the solid lipid nanoparticles formulation of enzalutamide for the effective drug delivery. Materials and Methods: The formulation variables were optimized using design of experiments. Box–Behnken design was used for the study and the results were analyzed using response surface methodology. The prepared nanoformulation was characterized for particle size, zeta potential, surface morphology, X-ray diffractometry (XRD), in vitro drug release kinetics, and stability study. Results: The influence of formulation variables, drug-to-lipid ratio, concentration of phosphatidylcholine, and concentration of poloxamer 188 were evaluated by regression analysis. The optimized formulation (F3) was found to have the minimum particle size (253 nm) with maximum entrapment efficiency (89.72%) and drug loading (23.84%). From SEM studies, the data showed a spherical shape for enzalutamide nanoparticles with uniform and relatively narrow particle distribution. From XRD examines, it is demonstrative that the drug was not in crystalline form in nanoformulation when compared with pure drug. In vitro release studies disclosed that maximum cumulative drug release was attained by F3 (99.72%) in controlled manner. The optimized formulation of enzalutamide followed zero-order release kinetics with a strong correlation coefficient (R2 = 0.9994). Conclusion: The nanoformulation prepared under optimized conditions is in concurrence with the expected results. The SLN formulation can be used as a potential carrier for the effective delivery of enzalutamide