Контролируемые прочностные показатели для различных видов мебели

Методические указания по курсам «Расчет конструкций изделий из древесины и испытания мебели», «Технология изделий из древесины» для выполнения практических и лабораторных работ обучающимися по направлениям 35.03.02, 35.04.02 «Технология лесозаготовительных и деревоперерабатывающих производств», профиль «Технология деревообработки

Forming low-cost, high quality carbon tows for automotive application.

Carbon fiber reinforced composites are widely used in many industries due to their high performance. Its application in the aerospace industry has increased significantly, however, in mass produced automobile sector it is still limited. The current production of carbon fiber tow is slow and capital intensive. Thus, carbon manufactures produce higher tow counts to increase production rate to reduce its cost. In order to offset the higher cost of carbon fiber composite, an innovative and unique approach has been developed. The higher tow count carbon spools are split into smaller tow counts. Due to the delicate nature of carbon fiber, it is important to control the filamentation during that process. Different splitting process line strategies have been developed in this research work for understanding the process limitations and challenges involved. The process was made feasible for production by developing a fully automated process line with a laser feedback system. The system splits a 12K spool into two 6K tows. The quality of the 6K split tows has been determined statistically by recording real time data from the laser during the splitting process. It was demonstrated that the proposed process effectively controls filamentation and produces consistent tow quality.Company research funding by Bentley Motors Limite

The quaternary architecture of RARβ–RXRα heterodimer facilitates domain–domain signal transmission

Assessing the physical connections and allosteric communications in multi-domain nuclear receptor (NR) polypeptides has remained challenging, with few crystal structures available to show their overall structural organizations. Here we report the quaternary architecture of multi-domain retinoic acid receptor β–retinoic X receptor α (RARβ–RXRα) heterodimer bound to DNA, ligands and coactivator peptides, examined through crystallographic, hydrogen–deuterium exchange mass spectrometry, mutagenesis and functional studies. The RARβ ligand-binding domain (LBD) and DNA-binding domain (DBD) are physically connected to foster allosteric signal transmission between them. Direct comparisons among all the multi-domain NRs studied crystallographically to date show significant variations within their quaternary architectures, rather than a common architecture adhering to strict rules. RXR remains flexible and adaptive by maintaining loosely organized domains, while its heterodimerization partners use a surface patch on their LBDs to form domain-domain interactions with DBDs

Discovery of FNDR-20123, a histone deacetylase inhibitor for the treatment of Plasmodium falciparum malaria

BACKGROUND: Emergence of anti-malarial drug resistance and perpetual increase in malaria incidence necessitates the development of novel anti-malarials. Histone deacetylases (HDAC) has been shown to be a promising target for malaria, despite this, there are no HDAC inhibitors in clinical trials for malaria treatment. This can be attributed to the poor pharmacokinetics, bioavailability and selectivity of the HDAC inhibitors. METHODS: A collection of HDAC inhibitors were screened for anti-malarial activity, and the best candidate was profiled in parasite-killing kinetics, growth inhibition of sensitive and multi-drug resistant (MDR) strains and against gametocytes. Absorption, distribution, metabolism and excretion pharmacokinetics (ADME-PK) parameters of FNDR-20123 were determined, and in vivo efficacy was studied in a mouse model for Plasmodium falciparum infection. RESULTS: A compound library of HDAC inhibitors (180 in number) was screened for anti-malarial activity, of which FNDR-20123 was the most potent candidate. The compound had been shown to inhibit Plasmodium HDAC with IC50 of 31 nM and human HDAC with IC50 of 3 nM. The IC50 obtained for P. falciparum in asexual blood-stage assay was 42 nM. When compared to atovaquone and pyrimethamine, the killing profiles of FNDR-20123 were better than atovaquone and comparable to pyrimethamine. The IC50 values for the growth inhibition of sensitive and MDR strains were similar, indicating that there is no cross-resistance and a low risk of resistance development. The selected compound was also active against gametocytes, indicating a potential for transmission control: IC50 values being 190 nM for male and > 5 microM for female gametocytes. FNDR-20123 is a stable candidate in human/mouse/rat liver microsomes (> 75% remaining post 2-h incubation), exhibits low plasma protein binding (57% in humans) with no human Ether-a-go-go-Related Gene (hERG) liability (> 100 microM), and does not inhibit any of the cytochrome P450 (CYP) isoforms tested (IC50 > 25 microM). It also shows negligible cytotoxicity to HepG-2 and THP-1 cell lines. The oral pharmacokinetics in rats at 100 mg/kg body weight shows good exposures (Cmax = 1.1 microM) and half-life (T1/2 = 5.5 h). Furthermore, a 14-day toxicokinetic study at 100 mg/kg daily dose did not show any abnormality in body weight or gross organ pathology. FNDR-20123 is also able to reduce parasitaemia significantly in a mouse model for P. falciparum infection when dosed orally and subcutaneously. CONCLUSION: FNDR-20123 may be a suitable candidate for the treatment of malaria, which can be further developed

"Fake it till You Make it"! Contaminating Rubber Hands ("Multisensory Stimulation Therapy") to Treat Obsessive-Compulsive Disorder.

Obsessive-compulsive disorder (OCD) is a deeply enigmatic psychiatric condition associated with immense suffering worldwide. Efficacious therapies for OCD, like exposure and response prevention (ERP), are sometimes poorly tolerated by patients. As many as 25% of patients refuse to initiate ERP mainly because they are too anxious to follow exposure procedures. Accordingly, we proposed a simple and tolerable (immersive yet indirect) low-cost technique for treating OCD that we call "multisensory stimulation therapy." This method involves contaminating a rubber hand during the so-called "rubber hand illusion" (RHI) in which tactile sensations may be perceived as arising from a fake hand. Notably, Jalal et al. (2015) showed that such fake hand contamination during the RHI provokes powerful disgust reactions in healthy volunteers. In the current study, we explored the therapeutic potential of this novel approach. OCD patients (n = 29) watched as their hidden real hand was being stroked together with a visible fake hand; either synchronously (inducing the RHI; i.e., the experimental condition; n = 16) or asynchronously (i.e., the control condition; n = 13). After 5 min of tactile stimulation, the rubber hand was contaminated with fake feces, simulating conventional exposure therapy. Intriguingly, results suggested sensory assimilation of contamination sensations into the body image via the RHI: patients undergoing synchronous stimulation did not report greater contamination sensations when the fake hand was initially contaminated relative to asynchronous stroking. But contrary to expectations, they did so after the rubber hand had been contaminated for 5 min, as assessed via disgust facial expressions (a secondary outcome) and in vivo exposure (upon discontinuing the illusion). Further, to our surprise, synchronous and asynchronous stroking induced an equally vivid and fast-emerging illusion, which helps explain why both conditions initially (5 min after initiating tactile stimulation) provoked contamination reactions of equal magnitude. This study is the first to suggest heightened malleability of body image in OCD. Importantly, it may pave the way for a tolerable technique for the treatment of OCD-highly suitable for poorly resourced and emergency settings, including low-income and developing countries with minimal access to high-tech solutions like virtual reality

KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients

The activity of the transcription factor nuclear factor-erythroid 2 p45-derived factor 2 (NRF2) is orchestrated and amplified through enhanced transcription of antioxidant and antiinflammatory target genes. The present study has characterized a triazole-containing inducer of NRF2 and elucidated the mechanism by which this molecule activates NRF2 signaling. In a highly selective manner, the compound covalently modifies a critical stress-sensor cysteine (C151) of the E3 ligase substrate adaptor protein Kelch-like ECH-associated protein 1 (KEAP1), the primary negative regulator of NRF2. We further used this inducer to probe the functional consequences of selective activation of NRF2 signaling in Huntington's disease (HD) mouse and human model systems. Surprisingly, we discovered a muted NRF2 activation response in human HD neural stem cells, which was restored by genetic correction of the disease-causing mutation. In contrast, selective activation of NRF2 signaling potently repressed the release of the proinflammatory cytokine IL-6 in primary mouse HD and WT microglia and astrocytes. Moreover, in primary monocytes from HD patients and healthy subjects, NRF2 induction repressed expression of the proinflammatory cytokines IL-1, IL-6, IL-8, and TNFα. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology