Semikarbazon – svestrani farmakofor u dizajniranju antikonvulziva

During the last fifteen years semicarbazones have been extensively investigated for their anticonvulsant properties. 4-(4-Flurophenoxy) benzaldehyde semicarbazone (C0102862, V102862) has been discovered as a lead molecule and is being developed as a potent antiepileptic drug, with maximal electroskock (MES) ED50 (i.p. 12.9 mg kg1). In MES (oral screen), this compound has protective index (PI = TD50/ED50 >315) higher than carbamazepine (PI 101), phenytoin (PI >21.6) and valproate (PI 2.17). This compound is a potent sodium channel blocker. Other semicarbazones have demonstrated activity in various chemoshock screens, like subcutaneous pentylenetetrazole (ScPTZ), subcutaneous strychnine (ScSTY), subcutaneous picrotoxine (ScPIC) and subcutaneous bicculline (ScBIC). Semicarbazones are also GABA-transaminase inhibitors. Extensive structure-activity relationship has demonstrated that F, Cl, Br and NO2 substitutents in the arylhydrophobic pocket and a hydrogen bonding domain (HBD) are generally found in active anticonvulsant agents.Tijekom posljednjih petnaest godina intenzivno su istraživana antikonvulzivna svojstva semikarbazona. 4-(4-Flurofenoksi)benzaldehid semikarbazon (C0102862, V102862) otkriven je kao vodeći spoj iz kojeg je razvijen antiepileptik s maksimalnom elektrošok aktivnošću (MES) ED50 12,9 mg kg1 (i.p.) i zaštitnim indeksom (PI = TD50/ED50 > 315) većim od karbamazepina (PI 101), fenitoina (PI > 21,6) i valproata (PI 2,17). Spoj je snažni blokator natrijevih kanala. Drugi su se semikarbazoni pokazali učinkovitima u različitim kemo-šok testovima, kao što su supkutana primjena pentilentetrazola, strihnina, pikrotoksina i bikukulina. Semikarbazoni su također inhibitori GABA-transaminaze. Opširne studije odnosa strukture i djelovanja pokazale su da je za antikonvulzivno djelovanje bitna prisutnost F, Cl, Br i NO2 supstituenata u arilhidrofobnom džepu i domena za vezanje vodikovim vezama (HBD)

Anomalous spectral evolution with bulk sensitivity in BiPd

We investigate the electronic structure of a noncentrosymmetric superconductor, BiPd using photoemission spectroscopy with multiple photon energies ranging from ultraviolet to hard x-ray. Experimental data exhibit interesting difference in the surface and bulk electronic structures of this system. While the surface Bi core level peaks appear at lower binding energies, the surface valence band features are found at the higher binding energy side of the bulk valence band; valence band is primarily constituted by the Pd 4d states. These changes in the electronic structure cannot be explained by the change in ionicity of the constituent elements via charge transfer. Analysis of the experimental data indicates that the Bi-Pd hybridization physics plays the key role in deriving the anomalous spectral evolution and the electronic properties of this system.Comment: Proceedings of DAE SSPS 201

Comparing the effects of sun exposure and vitamin D supplementation on vitamin D insufficiency, and immune and cardio-metabolic function: the Sun Exposure and Vitamin D Supplementation (SEDS) Study

BACKGROUND Adults living in the sunny Australian climate are at high risk of skin cancer, but vitamin D deficiency (defined here as a serum 25-hydroxyvitamin D (25(OH)D) concentration of less than 50 nmol/L) is also common. Vitamin D deficiency may be a risk factor for a range of diseases. However, the optimal strategies to achieve and maintain vitamin D adequacy (sun exposure, vitamin D supplementation or both), and whether sun exposure itself has benefits over and above initiating synthesis of vitamin D, remain unclear. The Sun Exposure and Vitamin D Supplementation (SEDS) Study aims to compare the effectiveness of sun exposure and vitamin D supplementation for the management of vitamin D insufficiency, and to test whether these management strategies differentially affect markers of immune and cardio-metabolic function. METHODS/DESIGN The SEDS Study is a multi-centre, randomised controlled trial of two different daily doses of vitamin D supplementation, and placebo, in conjunction with guidance on two different patterns of sun exposure. Participants recruited from across Australia are aged 18-64 years and have a recent vitamin D test result showing a serum 25(OH)D level of 40-60 nmol/L. DISCUSSION This paper discusses the rationale behind the study design, and considers the challenges but necessity of data collection within a non-institutionalised adult population, in order to address the study aims. We also discuss the challenges of participant recruitment and retention, ongoing engagement of referring medical practitioners and address issues of compliance and participant retention. TRIAL REGISTRATION Australia New Zealand Clinical Trials Registry: ACTRN12613000290796 Registered 14 March 2013

Circuit-level design of a Four-pole Microstrip Bandpass Filter

This thesis describes a simple, circuit-level method for creating a compact four-pole hairpin microstrip band-pass filter. It begins with the basic Chebyshev low-pass prototype and shows how that ideal design is converted into U-shaped resonators and coupling gaps on a PCB substrate. Using AWR Microwave Office for lumped-element modeling and AXIEM for quick electromagnetic checks, the filter layout is refined until the simulated response meets the design goals. The finalized pattern is then etched onto a Rogers board, fitted with standard connectors, and measured on a calibrated network analyzer to confirm that real-world behavior follows the circuit-level predictions. By blending theory, circuit-level simulation and straightforward fabrication and testing, this work offers a hands-on guide for engineers and students. It demonstrates how to achieve high-performance microstrip filter designs without relying on early, full-wave layouts

Histologic and phenotypic factors and MC1R status associated with BRAF(V600E), BRAF(V600K), and NRAS mutations in a community-based sample of 414 cutaneous melanomas

Cutaneous melanomas arise through causal pathways involving interplay between exposure to UV radiation and host factors, resulting in characteristic patterns of driver mutations in BRAF, NRAS, and other genes. To gain clearer insights into the factors contributing to somatic mutation genotypes in melanoma, we collected clinical and epidemiologic data, performed skin examinations, and collected saliva and tumor samples from a community-based series of 414 patients aged 18 to 79, newly diagnosed with cutaneous melanoma. We assessed constitutional DNA for nine common polymorphisms in melanocortin-1 receptor gene (MC1R). Tumor DNA was assessed for somatic mutations in 25 different genes. We observed mutually exclusive mutations in BRAF (26%), BRAF (8%), BRAF (5%), and NRAS (9%). Compared to patients with BRAF wild-type melanomas, those with BRAF mutants were significantly younger, had more nevi but fewer actinic keratoses, were more likely to report a family history of melanoma, and had tumors that were more likely to harbor neval remnants. BRAF mutations were also associated with high nevus counts. Both BRAF and NRAS mutants were associated with older age but not with high sun exposure. We also found no association between MC1R status and any somatic mutations in this community sample of cutaneous melanomas, contrary to earlier reports

Variable Selection in Accelerated Failure Time (AFT) Frailty Models: An Application of Penalized Quasi-Likelihood

Variable selection is one of the standard ways of selecting models in large scale datasets. It has applications in many fields of research study, especially in large multi-center clinical trials. One of the prominent methods in variable selection is the penalized likelihood, which is both consistent and efficient. However, the penalized selection is significantly challenging under the influence of random (frailty) covariates. It is even more complicated when there is involvement of censoring as it may not have a closed-form solution for the marginal log-likelihood. Therefore, we applied the penalized quasi-likelihood (PQL) approach that approximates the solution for such a likelihood. In addition, we introduce an adaptive penalty function that makes the selection on both fixed and frailty effects in a left-censored dataset for a parametric AFT frailty model. We also compared our penalty function with other established procedures via their performance on accurately choosing the significant coefficients and shrinking the non-significant coefficients to zero

The Absurdity of Hinduism: Gandhi’s Ideas on Religion and Truth

This paper seeks to provide a renewed meaning to the idea of truth by enclosing it within Gandhi’s rhetorical use of the term religion. The religion that he seeks to present to us as Hinduism is absurd on all fronts, it is argued here. It is through such absurdity that he infuses notions of validity and obeyance on his own terms to take us to profuse criticisms of not only colonial but civilizational modernity as well. Further a newer meaning is given to Hinduism in a rather unexpected manner even in the context of the Indian national movement. The point about political conservatism, the element of exoticism and God takes us to adventures around truth by a thinker-activist speaking as a colonial subject.  &nbsp