Design, synthesis and evaluation of benzothiazole derivatives as multifunctional agents

Oxidative stress is the product or aetiology of various multifactorial diseases; on the other hand, the development of multifunctional compounds is a recognized strategy for the control of complex diseases. To this end, a series of benzothiazole derivatives was synthesized and evaluated for their multifunctional effectiveness as antioxidant, sunscreen (filter), antifungal and antiproliferative agents. Compounds were easily synthesized via condensation reaction between 2-aminothiophenols and different benzaldehydes. SAR study, particularly in position 2 and 6 of benzothiazoles, led to the identification of 4g and 4k as very interesting potential compounds for the design of multifunctional drugs. In particular, compound 4g is the best blocker of hERG potassium channels expressed in HEK 293 cells exhibiting 60.32% inhibition with IC50 = 4.79 μM

Segmented lordotic angles to assess lumbosacral transitional vertebra on EOS

Purpose: To test the vertical posterior vertebral angles (VPVA) of the most caudal lumbar segments measured on EOS to identify and classify the lumbosacral transitional vertebra (LSTV). Methods: We reviewed the EOS examinations of 906 patients to measure the VPVA at the most caudal lumbar segment (cVPVA) and at the immediately proximal segment (pVPVA), with dVPVA being the result of their difference. Mann\u2013Whitney, Chi-square, and ROC curve statistics were used. Results: 172/906 patients (19%) had LSTV (112 females, mean age: 43 \ub1 21 years), and 89/172 had type I LSTV (52%), 42/172 type II (24%), 33/172 type III (19%), and 8/172 type IV (5%). The cVPVA and dVPVA in non-articulated patients were significantly higher than those of patients with LSTV, patients with only accessory articulations, and patients with only bony fusion (all p <.001). The cVPVA and dVPVA in L5 sacralization were significantly higher than in S1 lumbarization (p <.001). The following optimal cutoff was found: cVPVA of 28.2\ub0 (AUC = 0.797) and dVPVA of 11.1\ub0 (AUC = 0.782) to identify LSTV; cVPVA of 28.2\ub0 (AUC = 0.665) and dVPVA of 8\ub0 (AUC = 0.718) to identify type II LSTV; cVPVA of 25.5\ub0 (AUC = 0.797) and dVPVA of 12 7.5\ub0 (AUC = 0.831) to identify type III\u2013IV LSTV; cVPVA of 20.4\ub0 (AUC = 0.693) and dVPVA of 12 1.8\ub0 (AUC = 0.665) to differentiate type II from III\u2013IV LSTV; cVPVA of 17.9\ub0 (AUC = 0.741) and dVPVA of 12 4.5\ub0 (AUC = 0.774) to differentiate L5 sacralization from S1 lumbarization. Conclusion: The cVPVA and dVPVA measured on EOS showed good diagnostic performance to identify LSTV, to correctly classify it, and to differentiate L5 sacralization from S1 lumbarization

The splicing regulators Tra and Tra2 are unusually potent activators of pre-mRNA splicing

Sexual differentiation in Drosophila is regulated through alternative splicing of doublesex. Female-specific splicing is activated through the activity of splicing enhancer complexes assembled on multiple repeat elements. Each of these repeats serves as a binding platform for the cooperative assembly of a heterotrimeric complex consisting of the SR proteins Tra, Tra2 and 9G8. Using quantitative kinetic analyses, we demonstrate that each component of the enhancer complex is capable of recruiting the spliceosome. Surprisingly, Tra, Tra2 and 9G8 are much stronger splicing activators than other SR protein family members and their activation potential is significantly higher than expected from their serine/arginine content. 9G8 activates splicing not only through its RS domains but also through its RNA-binding domain. The RS domains of Tra and Tra2 are required but not sufficient for efficient complex assembly. Thus, the regulated assembly of the dsx enhancer complexes leads to the generation of an extended activation domain to guarantee the ‘all or none’ splicing switch that is required during Drosophila sexual differentiation

Timbre from Sound Synthesis and High-level Control Perspectives

International audienceExploring the many surprising facets of timbre through sound manipulations has been a common practice among composers and instrument makers of all times. The digital era radically changed the approach to sounds thanks to the unlimited possibilities offered by computers that made it possible to investigate sounds without physical constraints. In this chapter we describe investigations on timbre based on the analysis by synthesis approach that consists in using digital synthesis algorithms to reproduce sounds and further modify the parameters of the algorithms to investigate their perceptual relevance. In the first part of the chapter timbre is investigated in a musical context. An examination of the sound quality of different wood species for xylophone making is first presented. Then the influence of instrumental control on timbre is described in the case of clarinet and cello performances. In the second part of the chapter, we mainly focus on the identification of sound morphologies, so called invariant sound structures responsible for the evocations induced by environmental sounds by relating basic signal descriptors and timbre descriptors to evocations in the case of car door noises, motor noises, solid objects, and their interactions

Hsc70 Focus Formation at the Periphery of HSV-1 Transcription Sites Requires ICP27

The cellular chaperone protein Hsc70, along with components of the 26S proteasome and ubiquitin-conjugated proteins have been shown to be sequestered in discrete foci in the nuclei of herpes simplex virus 1 (HSV-1) infected cells. We recently reported that cellular RNA polymerase II (RNAP II) undergoes proteasomal degradation during robust HSV-1 transcription, and that the immediate early protein ICP27 interacts with the C-terminal domain and is involved in the recruitment of RNAP II to viral transcription/replication compartments.Here we show that ICP27 also interacts with Hsc70, and is required for the formation of Hsc70 nuclear foci. During infection with ICP27 mutants that are unable to recruit RNAP II to viral replication sites, viral transcript levels were greatly reduced, viral replication compartments were poorly formed and Hsc70 focus formation was curtailed. Further, a dominant negative Hsc70 mutant that cannot hydrolyze ATP, interfered with RNAP II degradation during HSV-1 infection, and an increase in ubiquitinated forms of RNAP II was observed. There was also a decrease in virus yields, indicating that proteasomal degradation of stalled RNAP II complexes during robust HSV-1 transcription and replication benefits viral gene expression.We propose that one function of the Hsc70 nuclear foci may be to serve to facilitate the process of clearing stalled RNAP II complexes from viral genomes during times of highly active transcription

The splicing regulators Tra and Tra2 are unusually potent activators of pre-mRNA splicing

Sexual differentiation in Drosophila is regulated through alternative splicing of doublesex. Female-specific splicing is activated through the activity of splicing enhancer complexes assembled on multiple repeat elements. Each of these repeats serves as a binding platform for the cooperative assembly of a heterotrimeric complex consisting of the SR proteins Tra, Tra2 and 9G8. Using quantitative kinetic analyses, we demonstrate that each component of the enhancer complex is capable of recruiting the spliceosome. Surprisingly, Tra, Tra2 and 9G8 are much stronger splicing activators than other SR protein family members and their activation potential is significantly higher than expected from their serine/arginine content. 9G8 activates splicing not only through its RS domains but also through its RNA-binding domain. The RS domains of Tra and Tra2 are required but not sufficient for efficient complex assembly. Thus, the regulated assembly of the dsx enhancer complexes leads to the generation of an extended activation domain to guarantee the ‘all or none’ splicing switch that is required during Drosophila sexual differentiation

Iranian medicinal plants: From ethnomedicine to actual studies

Iran has a rich and diverse cultural heritage, consisting of a complex traditional medicine deeply rooted in the history of the territory that goes back to the Assyrian and Babylonian civilizations. The ethnomedical practices that can be identifiable nowadays derive from the experience of local people who have developed remedies against a wide range of diseases handing down the knowledge from generation to generation over the millennia. Traditional medicine practices represent an important source of inspiration in the process of the development of new drugs and therapeutic strategies. In this context, it is useful to determine the state of the art of ethnomedical studies, concerning the Iranian territory, and of scientific studies on plants used in traditional Iranian medicine. Data regarding 245 plants used in Iranian ethnomedical practices and scientific studies conducted on 89 plants collected in the Iranian territory have been reported. All of the scientific studies here reported draw inspiration from traditional medicine. The World Health Organization (WHO) has repeatedly called for an intensification of the scientific validation processes of traditional medicines intended as an important contribution to public health in various parts of the world. The process of study and validation of Iranian ethnomedical practices appears to be at an early stage

Towards the timbre modeling of interior car sound

Presented at the 15th International Conference on Auditory Display (ICAD2009), Copenhagen, Denmark, May 18-22, 2009Quality investigations and design of interior car sounds constitute an important challenge for the car industry. Such sounds are complex and time-varying, inducing considerable timbre variations depending on the driving conditions. An interior car sound is indeed a mixture between several sound sources, with two main contributions, i.e. the engine noise, the aerodynamic and tire-road noise. That’s why masking phenomena between these two components should be considered when studying perceptive attributes of interior car sounds. Additive synthesis is used to simulate the harmonic engine noise. Nevertheless, this synthesis is controlled by a large number of parameters and no relation between these parameters and their perceptive relevance has been clearly identified. By combining sensory analysis and signal analysis associated with an auditory model, we can find a relation between a reduced number of signal parameters and perceptive attributes. This study develops a method to simplify the timbre description of interior card sounds and presents the first results of auditory model application on such sounds