Geldanamycin and its derivatives as Hsp90 inhibitors

The Hsp90 molecule, one of the most abundant heat shock proteins in mammalian cells, maintains homeostasis and prevents stress-induced cellular damage. Hsp90 is expressed under normal conditions at a level of about 1-2 Percent of total proteins, while its expression increases 2-10 fold in cancer cells. The two main constitutively expressed isoforms of Hsp90 are known as Hsp90-alpha and Hsp90-beta, and their upregulation is associated with tumor progression, invasion and formation of metastases, as well as development of drug resistance. The Hsp90 is a key target for many newly established, potent anticancer agents containing Hsp90 N-terminal ATP binding inhibitors, such as geldanamycin, and its analogues 17AAG and 17DMAG. The therapeutic usage of geldanamycin has been limited due to its poor water solubility and severe hepatotoxicity. Therefore, its analogues, including 17AAG, 17DMAG, Tanespimycin and Retaspimycin hydrochloride, with improved pharmacokinetic profiles, have been developed

The NOS3 G894T (rs1799983) and-786T/C (rs2070744) polymorphisms are associated with elite swimmer status

Endothelial nitric oxide synthase (NOS3) generates nitric oxide in blood vessels and is involved in the regulation of vascular function, metabolism and muscle fibre type transformations. Evidence suggests that the NOS3 G894T (rs1799983) and -786T/C (rs2070744) polymorphisms are associated with athletic performance. The purpose of this study was to determine the association between the NOS3 G894T and -786T/C polymorphisms with elite swimmer status in Polish athletes. One hundred and ninety-seven Polish swimmers (104 males and 93 females), who competed in national and international events, and 379 healthy control subjects (222 males and 157 females) were recruited for this study. The swimmers were divided into two groups: short distance swimmers (SDS; n=147; 50-200 m) and long distance swimmers (LDS; n=49; more than 500 m). As expected, the frequencies of the -786T/C T allele (77.0 vs. 63.1%, p = 0.0085) and G-T haplotype (63.7 vs. 52.0, p=0.025) were significantly higher in the LDS group in comparison with controls. Compared with the -786T/C CC genotype, the chance of being a long distance swimmer was 8.49 times higher (CI=1.14-62.78, p=0.023) for the carriers of -786T/C T allele than in control subjects. On the other hand, the Asp allele frequency was significantly higher in the female SDS group compared with controls (34.3 vs. 18.5%, p=0.00043). In conclusion, our results demonstrate that the T allele and the G-T haplotype of the -786T/C and G894T polymorphisms may be beneficial for long distance swimmers

Diverse tick-borne microorganisms identified in free-living ungulates in Slovakia

Background: Free-living ungulates are hosts of ixodid ticks and reservoirs of tick-borne microorganisms in central Europe and many regions around the world. Tissue samples and engorged ticks were obtained from roe deer, red deer, fallow deer, mouflon, and wild boar hunted in deciduous forests of south-western Slovakia. DNA isolated from these samples was screened for the presence of tick-borne microorganisms by PCR-based methods. Results: Ticks were found to infest all examined ungulate species. The principal infesting tick was Ixodes ricinus, identified on 90.4% of wildlife, and included all developmental stages. Larvae and nymphs of Haemaphysalis concinna were feeding on 9.6% of wildlife. Two specimens of Dermacentor reticulatus were also identified. Ungulates were positive for A. phagocytophilum and Theileria spp. Anaplasma phagocytophilum was found to infect 96.1% of cervids, 88.9% of mouflon, and 28.2% of wild boar, whereas Theileria spp. was detected only in cervids (94.6%). Importantly, a high rate of cervids (89%) showed mixed infections with both these microorganisms. In addition to A. phagocytophilum and Theileria spp., Rickettsia helvetica, R. monacensis, unidentified Rickettsia sp., Coxiella burnetii, "Candidatus Neoehrlichia mikurensis", Borrelia burgdorferi (s.l.) and Babesia venatorum were identified in engorged I. ricinus. Furthermore, A. phagocytophilum, Babesia spp. and Theileria spp. were detected in engorged H. concinna. Analysis of 16S rRNA and groEL gene sequences revealed the presence of five and two A. phagocytophilum variants, respectively, among which sequences identified in wild boar showed identity to the sequence of the causative agent of human granulocytic anaplasmosis (HGA). Phylogenetic analysis of Theileria 18S rRNA gene sequences amplified from cervids and engorged I. ricinus ticks segregated jointly with sequences of T. capreoli isolates into a moderately supported monophyletic clade. Conclusions: The findings indicate that free-living ungulates are reservoirs for A. phagocytophilum and Theileria spp. and engorged ixodid ticks attached to ungulates are good sentinels for the presence of agents of public and veterinary concern. Further analyses of the A. phagocytophilum genetic variants and Theileria species and their associations with vector ticks and free-living ungulates are required.Fil: Kazimírová, Mária. Slovak Academy of Sciences. Institute of Zoology; EslovaquiaFil: Hamšíková, Zuzana. Slovak Academy of Sciences. Institute of Zoology; EslovaquiaFil: Spitalská, Eva. Slovak Academy of Sciences. Institute of Virology. Biomedical Research Center,; EslovaquiaFil: Minichová, Lenka. Slovak Academy of Sciences. Institute of Virology. Biomedical Research Center,; EslovaquiaFil: Mahríková, Lenka. Slovak Academy of Sciences. Institute of Zoology; EslovaquiaFil: Caban, Radoslav. Široká ; EslovaquiaFil: Sprong, Hein. National Institute for Public Health and Environment.Laboratory for Zoonoses and Environmental Microbiology; Países BajosFil: Fonville, Manoj. National Institute for Public Health and Environment.Laboratory for Zoonoses and Environmental Microbiology; Países BajosFil: Schnittger, Leonhard. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Patobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Kocianová, Elena. Slovak Academy of Sciences. Institute of Virology. Biomedical Research Center,; Eslovaqui

The agt gene m235t polymorphism and response of power-related variables to aerobic training

© Journal of Sports Science and Medicine.The C allele of the M235T (rs699) polymorphism of the AGT gene correlates with higher levels of angiotensin II and has been associated with power and strength sport performance. The aim of the study was to investigate whether or not selected power-related variables and their response to a 12-week program of aerobic dance training are modulated by the AGT M235T genotype in healthy participants. Two hundred and one Polish Caucasian women aged 21 ± 1 years met the inclusion criteria and were included in the study. All women completed a 12-week program of low and high impact aerobics. Wingate peak power and total work capacity, 5 m, 10 m, and 30 m running times and jump height and jump power were determined before and after the training programme. All power-related variables improved significantly in response to aerobic dance training. We found a significant association between the M235T polymorphism and jump-based variables (squat jump (SJ) height, p = 0.005; SJ power, p = 0.015; countermovement jump height, p = 0.025; average of 10 countermovement jumps with arm swing (ACMJ) height, p = 0.001; ACMJ power, p = 0.035). Specifically, greater improvements were observed in the C allele carriers in comparison with TT homozygotes. In conclusion, aerobic dance, one of the most commonly practiced adult fitness activities in the world, provides sufficient training stimuli for augmenting the explosive strength necessary to increase vertical jump performance. The AGT gene M235T polymorphism seems to be not only a candidate gene variant for power/strength related pheno-types, but also a genetic marker for predicting response to training

Why has not it worked? An empirical application of the extended Burns and Scapens' framework within the implementation of a controlling department

ABSTRACT The aim of this study is to understand the implementation of a controlling department within Bogt and Scapens' framework (2014) as an empirical observation mechanism towards investigating rationalities that prevented its implementation. This study was conducted in a quite successful 63-year old company in the South of Brazil. We hope these results promote practical insight to those interested in supporting changes within this field of organizational environment. There had been two main reasons leading to such work: a lack of equivalent study in the scholarly literature as well as empirical application of Burns and Scapens' framework (2000) reorganized by Bogt and Scapens (2014). Bogt and Scapens (2014), inspired by different logics (Bogt & Scapens, 2012) and in order to revaluate their original framework (2000), suggest the introduction of a fairly important term: rationality. This new element shows the deliberate action from the organizational player - his/her way of thinking. However, even with the introduction of rationales within the model by Bogt and Scapens (2014), rules and routines remain as important elements so that actions take shape. Used methodology consists of an interpretational case study with document analysis, direct observation, and application of semi-structured interviews. Through the interviews and discussions with individuals involved in the study, it can be observed that some rationality resulted in conflicts. Different rationales and the culture of the individual and the organization are relevant aspects observed in the speeches analyzed; all may be factors, which led to the gap within the process of implementation of controlling department in the organization. In addition, time factors suggested in the extended Bogt and Scapens' (2014) framework is of utmost importance for changes must occur gradually

Athlome Project Consortium: a concerted effort to discover genomic and other "omic" markers of athletic performance.

Despite numerous attempts to discover genetic variants associated with elite athletic performance, injury predisposition, and elite/world-class athletic status, there has been limited progress to date. Past reliance on candidate gene studies predominantly focusing on genotyping a limited number of single nucleotide polymorphisms or the insertion/deletion variants in small, often heterogeneous cohorts (i.e., made up of athletes of quite different sport specialties) have not generated the kind of results that could offer solid opportunities to bridge the gap between basic research in exercise sciences and deliverables in biomedicine. A retrospective view of genetic association studies with complex disease traits indicates that transition to hypothesis-free genome-wide approaches will be more fruitful. In studies of complex disease, it is well recognized that the magnitude of genetic association is often smaller than initially anticipated, and, as such, large sample sizes are required to identify the gene effects robustly. A symposium was held in Athens and on the Greek island of Santorini from 14-17 May 2015 to review the main findings in exercise genetics and genomics and to explore promising trends and possibilities. The symposium also offered a forum for the development of a position stand (the Santorini Declaration). Among the participants, many were involved in ongoing collaborative studies (e.g., ELITE, GAMES, Gene SMART, GENESIS, and POWERGENE). A consensus emerged among participants that it would be advantageous to bring together all current studies and those recently launched into one new large collaborative initiative, which was subsequently named the Athlome Project Consortium

Estimation of the distribution of the average friction coefficient of disk brake station

Jednym z badań prowadzonych na bezwładnościowym stanowisku hamulcowym jest pomiar współczynnika tarcia dla hamulca tarczowego lub klockowego przy różnych symulacjach hamowań pociągu. Podczas symulowanych badań hamulcowych zgodnie z programem badań przewidzianym dla kolejowego hamulca tarczowego [3], rejestruje się przebiegi chwilowego współczynnika tarcia w funkcji czasu hamowania. Następnie obliczany jest średni współczynnik tarcia wyznaczony z całki chwilowego współczynnika tarcia po drodze hamowania. Jest to badanie jakie prowadzi się dla pary ciernej hamulca w szczególności dla dopuszczenia do eksploatacji danego materiału z jakiego wykonany jest klocek lub okładzina cierna. Celem artykułu jest ocena wyników badań rozkładu średniego współczynnika tarcia hamulca tarczowego uzyskanego w czasie serii hamowań w tych samych warunkach początkowych przy różnym stanie technicznym tarczy hamulcowej.One of the studies conducted on stationary test position of the brake measurement of the coefficient of friction for disc brakes or block brake at various imitations of braking of the train. During the model tests of brake pads in accordance with the test program provided for the station disk brake [3] registers the mileage of temporary friction coefficient in function of time of braking. Then calculated the average coefficient of friction calculated from the integral of the temporary coefficient of friction on the way of braking. This study, conducted for friction pairs of brakes, in particular, approval of this material, and what made the block or friction pad. The purpose of this paper is to assess the results of studies of the distribution of average coefficient of friction of disk brakes, are obtained during a series of braking in the same initial conditions under different technical condition of the brake disc

Zastosowanie diagnostyki wibroakustycznej w ocenie zużycia okładzin ciernych kolejowego hamulca tarczowego

Vibrationacoustic diagnostics is increasingly used in new technical facilities to assess their condition. The main advantages of this diagnosis is the easiness of measurement, high speed transmission of information, the opportunity to assess the state of the whole or the individual components and high information content of the signal. All these features make it also possible to use WA diagnostic to assess the state of the braking system components. The article gives the possibility of determining the use of disc brake friction elements. This can be done on the basis of the analysis of vibration accelerations signals generated by the brake friction pads. The article presents diagnosis regression models [15] based on the analysis of vibration acceleration signals in the field of amplitude and frequency.Diagnostyka wibroakustyczna ze względu na swoje zalety znajduje coraz to nowe zastosowania w obiektach technicznych do oceny ich stanu. Główne zalety tej diagnostyki to łatwość pomiaru, duża szybkość przekazywania informacji, możliwość oceny stanu całego obiektu lub poszczególnych elementów oraz duża zawartość informacji w sygnale. Wszystkie te zalety sprawiają, że również możliwe jest zastosowanie diagnostyki WA do oceny stanu elementów układu hamulcowego. W artykule przedstawiono możliwości określenia zużycia elementów ciernych kolejowego hamulca tarczowego na podstawie analiz sygnałów przyspieszeń drgań generowanych przez okładziny cierne hamulca. W artykule przedstawiono regresyjne modele diagnostyczne [15] bazujące na analizie sygnałów przyspieszeń drgań w dziedzinie amplitud oraz w dziedzinie częstotliwości

The evaluation of a rail disc brake braking process by using a thermal camera

In the rail vehicles due to the ever-increasing speed a disc brake is used as a friction brake which gradually displaces the brake-blocks. In the public transport vehicles, electrical traction units or subway; the disc break collaborates with an electrodynamic brake that limits the use of the friction brake with a simultaneous possibility of power return due to the generator character of the traction engines work. Prior to the release of brake for testing, the tests are carried out on the break positions, wherein one of the measurements is the measurement of the disc temperature by the use of thermocouples. The aim of this article is to present the use of a thermal imaging camera while testing the disc brake friction pair elements in the breaking process evaluation

The Mi-2 helicopter with built-in floating equipment for flights over water

W artykule omówiono wyposażenie pływakowe do śmigłowca Mi-2. Pływaki zastosowane na śmigłowcu mają na celu zwiększenie bezpieczeństwa lotów nad wodą poprzez możliwość wodowania podczas awarii silników. Cztery pływaki otwierają się jednocześnie po zetknięciu kadłuba z wodą. Zadaniem pływaków jest utrzymanie śmigłowca na wodzie na czas umożliwiający bezpieczne opuszczenie śmigłowca przez załogę i pasażerów. Pływaki w czasie lotu i postoju śmigłowca są zwinięte i osłonięte elastycznymi pokrowcami. W artykule opisano proces konstruowania i dowodzenia spełnienia przepisów zdatności do lotu śmigłowca Mi-2 z zabudowanym wyposażeniem i dopuszczeniu do realizacji procedury awaryjnego wodowania. W skład wyposażenia pływakowego wchodzą cztery pływaki napełniane gazem, zespół butli i tratwy ratunkowe. Ocena zdatności do lotu w przypadku wyposażenia pływakowego obejmowała ocenę wytrzymałości statycznej, ocenę stateczności statycznej i dynamicznej, ocenę poziomu drgań, możliwości ewakuacyjnych załogi i pasażerów oraz ogólną ocenę funkcjonalności zastosowanych rozwiązań. Proces dowodzenia objął takie działania jak: analizy obliczeniowe, próby modelowe, próby statyczne i funkcjonalne oraz próby w locie.In the article, the floating equipment for the Mi-2 helicopter is discussed. The floats applied on the helicopter have as their aim the increase in safety of flights over water throught the possibility of loading on water during an engine failure. Four floats are opened at the same time after contact of the fuselage with water. The purpose of the floats is to keep the helicopter floating for a time sufficient to enable the crew and passengers to evacuate the helicopter. The floats are folded and covered by elastic protective covers during flight and while on ground. The process of construction and confirmation of fulfillment of the airworthiness regulations for the Mi-2 helicopter with fitted equipment, as well as the realization of the procedure of emergency landing on water, is described in the article. The float equipment is made up of four floates filled with gas, a set of bottles and life rafts. The asswssment of suitability to flight in the case of float equipment included of static strength, static and dynamic stability, the levels of vibration, the ability to evacuate the passengers and flight crew, as well as general assessment of the functionability of the applied solutions. The process of confirmation also included process such as numerical calculations, tests on models, static and functionability tests as well as in-flight tests