Особенности процесса трещинообразования в массиве при управлении его газодинамикой

Исследован процесс сдерживания перехода угля из потенциально устойчивого состояния в стадию бурного разрушения. Ей, как правило, предшествует некоторый промежуток времени относительного затишья. Особенно важно улавливать этот момент среди массы различных откликов массива на ведение горных работ. Одним из вариантов управления развитием и релаксацией системы трещин может служить физико-химическая обработка.The inhibition process of coal transition from the potentially stable state in the stage of stormy destruction is investigation. As a rule, to it is preceded some interval of relative time calm. It is especially important to catch this moment among mass of different responses of array on the conduct of mountain works. Physical and chemical treatment can serve as one of control variants the development and relaxation of the cracks system

Synthesis and Evaluation of Polymyxins Bearing Reductively Labile Disulfide-Linked Lipids

Polymyxins are a class of lipopeptide anti-infective agents with potent and specific activity against Gram-negative bacteria. While toxicity concerns associated with polymyxin B and E (colistin) have historically limited their clinical application, today they are increasingly used as last-resort antibiotics given the rise of multidrug-resistant Gram-negative pathogens. The adverse side effects of polymyxins are well known, particularly as related to their nephrotoxicity. Here, we describe the synthesis and evaluation of a novel series of polymyxin analogues, aimed at reducing their nephrotoxic effects. Using a semisynthetic approach, we explored modifications of the exocyclic part of the polymyxin scaffold, namely, the terminal amino acid and lipophilic tail. By incorporating a reductively labile disulfide linkage in the lipid tail, we obtained novel polymyxins that exhibit potent antibacterial activity on par with polymyxin B but with reduced toxicity toward human renal proximal tubular epithelial cells

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Environmental enrichment has antidepressant-like action without improving learning and memory deficits in olfactory bulbectomized rats

Depression, especially in the elderly, is associated with poor cognitive functioning. Exercise has received much attention in the treatment for depression and also dementia. Here we studied the effect of an enriched environment combined with voluntary exercise (EE/VE) on the olfactory bulbectomized (OBX) rat. The OBX rat is hyperactive in an open field, which is normalized by chronic antidepressant treatment, and suffers from learning and memory impairments. Neurotrophic factors are thought to be involved in the antidepressant action of EE/VE. Hyperactivity and cognitive functioning (both hippocampal dependent and independent tasks) were investigated before and after EE/VE. We quantified hippocampal mRNA levels of the neurotrophic factors BDNF, VGF and VEGF. VEGF receptor (FLK-1) inhibition was achieved by i.c.v administration of the antagonist SU5416 during the period of EE/VE. OBX almost completely blocked fear memory acquired either 48 h or 28 days before surgery. EE/EV normalized OBX-induced hyperactivity in open field, while having no effect on the decrease in hippocampal dependent learning and memory. VEGF mRNA levels in hippocampus were significantly increased both in OBX and control rats following EE/VE. OBX reduced BDNF mRNA levels, but EE did not reverse this. Inhibition of the FLK-1 receptor did not suppress EE/VE induced normalization of the hyperactivity of the OBX rat. The lack of effect of EE/VE on cognitive parameters, while normalizing hyperactivity, suggests different neuronal mechanisms underlying OBX-induced behavioral changes. Since EE/VE still normalizes the OBX-induced hyperactivity while the FLK-1 receptor was blocked, we assume that VEGF is not obligatory for the antidepressant effect of EE/VE. This article is part of a Special Issue entitled 'Anxiety and Depression'

Recellularized native kidney scaffolds as a novel tool in nephrotoxicity screening

Drug-induced kidney injury (DIKI) in medicinal compound development accounts for over 20% of clinical trials failure and involves damage to different nephron segments, mostly the proximal tubule. Yet, currently applied cell models fail to reliably predict nephrotoxicity nor are easy to establish. Here, we developed a novel three-dimensional (3D) nephrotoxicity platform based on decellularized rat kidneys scaffolds (DS) recellularized with conditionally immortalized human renal proximal tubule epithelial cells overexpressing the organic anion transporter 1 (ciPTEC-OAT1). A 5-days sodium dodecyl sulfate (SDS)-based decellularization protocol was used to generate DS , of which 100 um slices were cut and used for cell seeding. After 8 days of culturing, recellularized scaffolds (RS) demonstrated 3D tubules formation along with tubular epithelial characteristics, including drug transporter funcion. Exposure of RS to cisplatin (CDDP), tenofovir (TFV) or cyclosporin A (CsA) as prototypical nephrotoxic drugs, revealed concentration-dependent reduction in cell viability, as assessed by PrestoBlue and Live/Dead staining assays. CDDP, TFV and CsA TC50-values were 108 ± 1 and 12 ± 1, 212 ± 1 and 97 ± 1, 129 ± 2 and 294 ± 2 μM in 2D and 3D cultures, respectively. This was most likely due to specific uptake of CDDP by the organic cation transporter 2 (OCT2), TFV through organic anion transporter 1 (OAT1) and CsA competing for P-glycoprotein-mediated efflux. As compared to 2D cultures, RS showed an increased sensitivity to cisplatin and tenofovir toxicity after 24h exposure (9 and 2.2 fold, respectively). In conclusion, we developed a physiologically-relevant 3D nephrotoxicity screening platform that could potentially be suitable as a novel alternative in drug development

Recellularized native kidney scaffolds as a novel tool in nephrotoxicity screening

Drug-induced kidney injury (DIKI) in medicinal compound development accounts for over 20% of clinical trials failure and involves damage to different nephron segments, mostly the proximal tubule. Yet, currently applied cell models fail to reliably predict nephrotoxicity nor are easy to establish. Here, we developed a novel three-dimensional (3D) nephrotoxicity platform based on decellularized rat kidneys scaffolds (DS) recellularized with conditionally immortalized human renal proximal tubule epithelial cells overexpressing the organic anion transporter 1 (ciPTEC-OAT1). A 5-days sodium dodecyl sulfate (SDS)-based decellularization protocol was used to generate DS , of which 100 um slices were cut and used for cell seeding. After 8 days of culturing, recellularized scaffolds (RS) demonstrated 3D tubules formation along with tubular epithelial characteristics, including drug transporter funcion. Exposure of RS to cisplatin (CDDP), tenofovir (TFV) or cyclosporin A (CsA) as prototypical nephrotoxic drugs, revealed concentration-dependent reduction in cell viability, as assessed by PrestoBlue and Live/Dead staining assays. CDDP, TFV and CsA TC50-values were 108 ± 1 and 12 ± 1, 212 ± 1 and 97 ± 1, 129 ± 2 and 294 ± 2 μM in 2D and 3D cultures, respectively. This was most likely due to specific uptake of CDDP by the organic cation transporter 2 (OCT2), TFV through organic anion transporter 1 (OAT1) and CsA competing for P-glycoprotein-mediated efflux. As compared to 2D cultures, RS showed an increased sensitivity to cisplatin and tenofovir toxicity after 24h exposure (9 and 2.2 fold, respectively). In conclusion, we developed a physiologically-relevant 3D nephrotoxicity screening platform that could potentially be suitable as a novel alternative in drug development

Inducible, Site-Specific Protein Labeling by Tyrosine Oxidation-Strain-Promoted (4 + 2) Cycloaddition

Genetically encoded tyrosine (Y-tag) can be utilized as a latent anchor for inducible and site-selective conjugation. Upon oxidation of tyrosine with mushroom tyrosinase, strain-promoted cycloaddition (SPOCQ) of the resulting 1,2-quinone with various bicyclo[6.1.0]nonyne (BCN) derivatives led to efficient conjugation. The method was applied for fluorophore labeling of laminarinase A and for the site-specific preparation of an antibody-drug conjugate.</p

The many different faces of major depression: it is time for personalized medicine

First line antidepressants are the so-called SSRIs (selective serotonin reuptake inhibitors), e.g. fluvoxamine, fluoxetine, sertraline, paroxetine and escitalopram. Unfortunately, these drugs mostly do not provide full symptom relief and have a slow onset of action. Therefore other antidepressants are also being prescribed that inhibit the reuptake of norepinephrine (e.g. reboxetine, desipramine) or the reuptake of both serotonin (5-HT) and norepinephrine (e.g. venlafaxine, duloxetine, milnacipran). Nevertheless, many patients encounter residual symptoms such as impaired pleasure, impaired motivation, and lack of energy. It is hypothesized that an impaired brain reward system may underlie these residual symptoms. In agreement, there is some evidence that reuptake inhibitors of both norepinephrine and dopamine (e.g. methylphenidate, bupropion, nomifensine) affect these residual symptoms. In the pipeline are new drugs that block all three monoamine transporters for the reuptake of 5-HT, norepinephrine and dopamine, the so-called triple reuptake inhibitors (TRI). The working mechanisms of the above-mentioned antidepressants are discussed, and it is speculated whether depressed patients with different symptoms, sometimes even opposite ones due to atypical or melancholic features, can be matched with the different drug treatments available. In other words, is personalized medicine for major depression an option in the near future

Synthesis and Evaluation of Polymyxins Bearing Reductively Labile Disulfide-Linked Lipids

Polymyxins are a class of lipopeptide anti-infective agents with potent and specific activity against Gram-negative bacteria. While toxicity concerns associated with polymyxin B and E (colistin) have historically limited their clinical application, today they are increasingly used as last-resort antibiotics given the rise of multidrug-resistant Gram-negative pathogens. The adverse side effects of polymyxins are well known, particularly as related to their nephrotoxicity. Here, we describe the synthesis and evaluation of a novel series of polymyxin analogues, aimed at reducing their nephrotoxic effects. Using a semisynthetic approach, we explored modifications of the exocyclic part of the polymyxin scaffold, namely, the terminal amino acid and lipophilic tail. By incorporating a reductively labile disulfide linkage in the lipid tail, we obtained novel polymyxins that exhibit potent antibacterial activity on par with polymyxin B but with reduced toxicity toward human renal proximal tubular epithelial cells