TOM-1/tomosyn acts with the UNC-6/netrin receptor UNC-5 to inhibit growth cone protrusion in Caenorhabditis elegans

In the polarity/protrusion model of growth cone repulsion from UNC-6/netrin, UNC-6 first polarizes the growth cone of the VD motor neuron axon via the UNC-5 receptor, and then regulates protrusion asymmetrically across the growth cone based on this polarity. UNC-6 stimulates protrusion dorsally through the UNC-40/DCC receptor, and inhibits protrusion ventrally through UNC-5, resulting in net dorsal growth. Previous studies showed that UNC-5 inhibits growth cone protrusion via the flavin monooxygenases and potential destabilization of F-actin, and via UNC-33/CRMP and restriction of microtubule plus-end entry into the growth cone. We show that UNC-5 inhibits protrusion through a third mechanism involving TOM-1/tomosyn. A short isoform of TOM-1 inhibited protrusion downstream of UNC-5, and a long isoform had a pro-protrusive role. TOM-1/tomosyn inhibits formation of the SNARE complex. We show that UNC-64/syntaxin is required for growth cone protrusion, consistent with a role of TOM-1 in inhibiting vesicle fusion. Our results are consistent with a model whereby UNC-5 utilizes TOM-1 to inhibit vesicle fusion, resulting in inhibited growth cone protrusion, possibly by preventing the growth cone plasma membrane addition required for protrusion

Solution of the distributional equation and Green’s functions for scattering problems

AbstractA general method is described to obtain Green’s functions involved in nuclear scattering theory problems. By imposing specified boundary conditions on the general solution to the distribution equation, one can readily obtain the Green’s function for the radial Schrödinger equation

THERMOSENSITIVE IN SITU GEL OF TINIDAZOLE IN TREATMENT OF BACTERIAL VAGINOSIS: FORMULATION AND EVALUATION

Bacterial Vaginosis (BV) is the leading cause of vaginal discharge. Because of its big surface area, wealthy blood supply, avoidance of the first-pass effect and high permeability to many drugs, the vagina offers a promising location for local impact as well as systemic drug delivery. In situ gels give several benefits, such as ease of administration in the respective body cavities, elevated spreadability at certain temperatures, reduced administration frequency, improved patient compliance and comfort compared to standard dosage forms. Tinidazole (TNZ) can give effective treatment over the BV. In situ gel of TNZ containing polaxomer 407 and HPMC E100 or carbopol 941NF was optimized on the basis of various evaluation parameters. Gelation temperature (Tgel) and pH of all batches was found in range of 36.6 to 38.0 ºC and 4.20 to 5.03, viscosity was found in range of 1100-2050 cps at 25ºC and 4800-6530 cps at 37ºC. The Spredability was found in range of 16-20 cm. From these evaluation parameters we selected best combination for the mucoadhesive property, antimicrobial study, in vitro drug release and for HET CAM irritation study. The optimized formulation gives satisfactory results. In this study we also compare the performance of two mucoadhesive polymer. Based on maximum desirability and cost effectiveness, in situ vaginal gel containing 20% polaxomer and 0.5% HPMC E100 could be considered as a highly promising treatment for bacterial vaginosis

Polymer-drug conjugates as nano-sized multi-targeting systems for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive, neurodegenerative condition. There are clear markers for the presence and progression of the disease, including β-amyloid (Aβ) plaques and Tau tangles, with many potential causes debated in the scientific community. Most existing treatments only provide symptomatic solutions. Due to poor aqueous solubility and possibly limited uptake across the blood–brain barrier (BBB), medications targeting the hallmarks of AD are still under study despite enormous efforts. Recently, nanoparticle-based drug delivery systems have demonstrated remarkable promise as precision medicines that may effectively increase bioavailability, permeate the BBB, and improve the targeting ability of a variety of pharmaceuticals. Polymer therapeutics have made tremendous progress in recent years, particularly in cancer treatment. Polymer–drug conjugates (PDCs) typically have a longer half-life, higher stability, and enhanced water solubility. Polymers serve as carriers for the administration of drugs, proteins, targeting moieties, and imaging agents in polymeric and macromolecular prodrugs. Numerous commercially viable PDCs for the treatment of various diseases have already proved their potential. This paper focuses mainly on the rationale for the design, synthesis, and potential use of PDCs as a multi-target treatment for neurodegenerative diseases

A short isoform of the UNC-6/Netrin receptor UNC-5 is required for growth cone polarity and robust growth cone protrusion in Caenorhabditis elegans

Introduction: UNC-6/Netrin is a conserved bi-functional guidance cue which regulates dorsal-ventral axon guidance in C. elegans. In the Polarity/Protrusion model of UNC-6/Netrin mediated dorsal growth away from UNC-6/Netrin, The UNC-5 receptor first polarizes the VD growth cone such that filopodial protrusions are biased dorsally. Based on this polarity, the UNC-40/DCC receptor stimulates growth cone lamellipodial and filopodial protrusion dorsally. The UNC-5 receptor maintains dorsal polarity of protrusion, and inhibits growth cone protrusion ventrally, resulting in net dorsal growth cone advance.Methods: Growth cone imaging in mutants, combined with Cas9 genome editing and genetic analysis, were used to analyze the role of a novel short isoform on unc-5 in growth cone polarity and protrusion.Results: Work presented here demonstrates a novel role of a previously undescribed, conserved short isoform of UNC-5 (UNC-5B). UNC-5B lacks the cytoplasmic domains of UNC-5 long, including the DEATH domain, the UPA/DB domain, and most of the ZU5 domain. Mutations that specifically affect only the unc-5 long isoforms were hypomorphic, suggesting a role of unc-5B short. A mutation specifically affecting unc-5B caused loss of dorsal polarity of protrusion and reduced growth cone filopodial protrusion, the opposite of unc-5 long mutations. Transgenic expression of unc-5B partially rescued unc-5 axon guidance defects, and resulted in large growth cones. Tyrosine 482 (Y482) in the cytoplasmic juxtamembrane region has been shown to be important for UNC-5 function, and is present in both UNC-5 long and UNC-5B short. Results reported here show that Y482 is required for the function of UNC-5 long and for some functions of UNC-5B short. Finally, genetic interactions with unc-40 and unc-6 suggest that UNC-5B short acts in parallel to UNC-6/Netrin to ensure robust growth cone lamellipodial protrusion.Discussion: These results demonstrate a previously-undescribed role for the UNC-5B short isoform, which is required for dorsal polarity of growth cone filopodial protrusion and to stimulate growth cone protrusion, in contrast to the previously-described role of UNC-5 long in inhibiting growth cone protrusion

Anti-inflammatory and analgesic activity of different fractions of Boswellia serrata

The study was designed to investigate the anti-inflammatory and analgesic effect of different fractions of Boswellia serrata. The effect of different fractions of Boswellia serrata were studied using carrageenan induced paw edema, acetic acid induced writhing response, formalin induced pain, hot plate and tail flick method for studying anti-inflammatory and analgesic activity, respectively. The different fractions of B. serrata, essential oil (10 ml/kg), gum (100 mg/kg, resin (100 mg/kg) oleo-resin (100 mg/kg) and oleo-gum-resin (100 mg/kg) significantly reduces carrageenan induced inflammation in rats and shows analgesic activity, as determined by acetic acid induced writhing response, formalin induced pain, hot plate and tail flick method. The different fractions of B. serrata showed prompt anti-inflammatory and analgesic activity due to the inhibition of 5-lipoxygenase enzyme.Keywords: Analgesic; Boswellia serrata; Inflammation; 5- lipoxygenase; Burseraceae

Coupon scale Z-pinned IM7/8552 delamination tests under dynamic loading

Dynamic impact onto laminated composite structures can lead to large-scale delamination. This can be mitigated by the introduction of through-thickness reinforcement, such as z-pins. Here, mode I & II and mixed-mode delamination tests have been designed and conducted at high loading rate, for both unpinned and Z-pinned coupons to study the effect of rate of loading. It was found that the Z-pins were not effective in delaying the dynamic crack initiation or resisting the dynamic propagation of delaminations shorter than 5 mm. However, the further growth of cracks was substantially delayed by Z-pinning, especially for the pure mode I and mode I dominated failure modes. On the other hand, the effectiveness of Z-pins in shear tests was relatively modest. The mode I dominated delamination resistance of Z-pinned laminates was found to be sensitive to the loading rate

Zero Order Spectrophotometric Method for Estimation of Escitalopram Oxalate in Tablet Formulations

A new, simple, fast and reliable zero order spectrophotometric method has been developed for determination of Escitalopram Oxalate in bulk and tablet dosage forms. The quantitative determination of drug was carried out using the zero order values (absorbance) measured at 238 nm. Calibration graph constructed at 238 nm was linear in concentration range of 2-20 µg/ml with correlation coefficient 0.9999. The method was found to be precise, accurate, specific, and validated as per ICH guidelines and can be used for determination of Escitalopram Oxalate in tablet formulations