The endoplasmic reticulum (ER) is a multifunctional organelle required for lipid biosynthesis, calcium storage, and protein folding and processing. A number of physiological and pathological conditions, as well as a variety of pharmacological agents, are able to disturb proper ER function and thereby cause ER stress, which severely impairs protein folding and therefore poses the risk of proteotoxicity. Specific triggers for ER stress include, for example, particular intracellular alterations (e.g., calcium or redox imbalances), certain microenvironmental conditions (e.g., hypoglycemia, hypoxia, and acidosis), high-fat and high-sugar diet, a variety of natural compounds (e.g., thapsigargin, tunicamycin, and geldanamycin), and several prescription drugs (e.g., bortezomib/Velcade, celecoxib/Celebrex, and nelfinavir/Viracept). The cell reacts to ER stress by initiating a defensive process, called the unfolded protein response (UPR), which is comprised of cellular mechanisms aimed at adaptation and safeguarding cellular survival or, in cases of excessively severe stress, at initiation of apoptosis and elimination of the faulty cell. In recent years, this dichotomic stress response system has been linked to several human diseases, and efforts are underway to develop approaches to exploit ER stress mechanisms for therapy. For example, obesity and type 2 diabetes have been linked to ER stress-induced failure of insulin-producing pancreatic beta cells, and current research efforts are aimed at developing drugs that ameliorate cellular stress and thereby protect beta cell function. Other studies seek to pharmacologically aggravate chronic ER stress in cancer cells in order to enhance apoptosis and achieve tumor cell death. In the following, these principles will be presented and discussed.

https://downloads.hindawi.com/journals/scientifica/2012/857516.pdf

Endoplasmic Reticulum Stress: Its Role in Disease and Novel Prospects for Therapy

This note presents a modification of the integrated friction model structure proposed by Swevers et al. (2000), called the Leuven model. The Leuven model structure allows accurate modeling both in the presliding and the sliding regimes without the use of a switching function. The model incorporates a hysteresis function with nonlocal memory and arbitrary transition curves. This note presents two modifications of the Leuven model. A first modification overcomes a recently detected shortcoming of the original Leuven model: a discontinuity in the friction force which occurs during certain transitions in presliding. A second modification, using the general Maxwell slip model to implement the hysteresis force, eliminates the problem of stack overflow, which can occur with the implementation of the hysteresis force.

Technical Note: modification of the Leuven integrated friction model structure

Early fault diagnosis of bearing and stator faults of the single-phase induction motor using acoustic signals

A variety of organisms, such as bacteria, fungi, and plants, produce secondary metabolites, also known as natural products. Natural products have been a prolific source and an inspiration for numerous medical agents with widely divergent chemical structures and biological activities, including antimicrobial, immunosuppressive, anticancer, and anti-inflammatory activities, many of which have been developed as treatments and have potential therapeutic applications for human diseases. Aside from natural products, the recent development of recombinant DNA technology has sparked the development of a wide array of biopharmaceutical products, such as recombinant proteins, offering significant advances in treating a broad spectrum of medical illnesses and conditions. Herein, we will introduce the structures and diverse biological activities of natural products and recombinant proteins that have been exploited as valuable molecules in medicine, agriculture and insect control. In addition, we will explore past and ongoing efforts along with achievements in the development of robust and promising microorganisms as cell factories to produce biologically active molecules. Furthermore, we will review multi-disciplinary and comprehensive engineering approaches directed at improving yields of microbial production of natural products and proteins and generating novel molecules. Throughout this article, we will suggest ways in which microbial-derived biologically active molecular entities and their analogs could continue to inspire the development of new therapeutic agents in academia and industry.

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A Review of the Microbial Production of Bioactive Natural Products and Biologics.

Novel hotspot mutant p53 gain-of-function mouse model shows that tumours depend on its sustained expression, and genetic and pharmacological approaches reveal mutant p53 as an actionable cancer drug target The tumour suppressor TP53 is one of the most frequently mutated genes in human cancer Although some genetic alterations cause its complete loss, many are gain-of-function mutations in which mutant p53 protein gains new properties that promote tumorigenesis Ute Moll and colleagues now demonstrate in a mouse model that expression of such a p53 mutant is needed not only for tumour initiation but also for tumour maintenance They further show that they can target mutant p53 indirectly by inhibiting a chaperone called Hsp90 which is needed to keep mutant p53 protein stable In a mouse model of lymphoma, this approach led to degradation of mutant p53 and reduced tumour growth Missense mutations in p53 generate aberrant proteins with abrogated tumour suppressor functions that can also acquire oncogenic gain-of-function activities that promote malignant progression, invasion, metastasis and chemoresistance1,2,3,4,5 Mutant p53 (mutp53) proteins undergo massive constitutive stabilization specifically in tumours, which is the key requisite for the acquisition of gain-of-functions activities6,7,8 Although currently 11 million patients worldwide live with tumours expressing highly stabilized mutp53, it is unknown whether mutp53 is a therapeutic target in vivo Here we use a novel mutp53 mouse model expressing an inactivatable R248Q hotspot mutation (floxQ) to show that tumours depend on sustained mutp53 expression Upon tamoxifen-induced mutp53 ablation, allotransplanted and autochthonous tumours curb their growth, thus extending animal survival by 37%, and advanced tumours undergo apoptosis and tumour regression or stagnation The HSP90/HDAC6 chaperone machinery, which is significantly upregulated in cancer compared with normal tissues, is a major determinant of mutp53 stabilization9,10,11,12 We show that long-term HSP90 inhibition significantly extends the survival of mutp53 Q/− (R248Q allele2) and H/H (R172H allele3) mice by 59% and 48%, respectively, but not their corresponding p53−/− littermates This mutp53-dependent drug effect occurs in H/H mice treated with 17DMAG+SAHA and in H/H and Q/− mice treated with the potent Hsp90 inhibitor ganetespib Notably, drug activity correlates with induction of mutp53 degradation, tumour apoptosis and prevention of T-cell lymphomagenesis These proof-of-principle data identify mutp53 as an actionable cancer-specific drug target

Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment

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.

https://iris.unipa.it/bitstream/10447/201057/1/gorska%202011.pdf

Geldanamycin and its derivatives as Hsp90 inhibitors.

/pdf/analytical-model-coefficient-of-friction-cof-of-rail-disc-3g7t6s7ga7.pdf

Analytical model coefficient of friction (COF) of rail disc brake on the basis of multi-phase stationary tests

Abstract Due to their wide range of friction characteristics resulting from the application of different friction materials and good heat dissipation conditions, railway disc brakes have long replaced block brakes in many rail vehicles. A block brake still remains in use, however, in low speed cargo trains. The paper presents the assessment of the braking process through the analysis of vibrations generated by the components of the brake system during braking. It presents a possibility of a wider application of vibroacoustic diagnostics (VA), which aside from the assessment of technical conditions (wear of brake pads) also enables the determination of the changes of the average friction coefficient as a function of the braking onset speed. Vibration signals of XYZ were measured and analyzed. The analysis of the results has shown that there is a relation between the values of the point measures and the wear of the brake pads.

/pdf/the-application-of-vibration-accelerations-in-the-assessment-g2xfy19rlr.pdf

The Application of Vibration Accelerations in the Assessment of Average Friction Coefficient of a Railway Brake Disc

The article presents the results of friction and vibroacoustic tests of a railway disc brake carried out on a brake stand. The vibration signal generated by the friction linings provides information on their wear and offers evaluation of the braking process, i.e., changes in the average friction coefficient. The algorithm presents simple regression linear and non-linear models for the thickness of the friction linings and the average coefficient of friction based on the effective value of vibration acceleration. The vibration acceleration signals were analyzed in the amplitude and frequency domains. In both cases, satisfactory values of the dynamics of changes above 6 dB were obtained. In the case of spectral analysis using a mid-band filter, more accurate models of the friction lining thickness and the average coefficient of friction were obtained. However, the spectral analysis does not allow the estimation of the lining thickness and the friction coefficient at low braking speeds, i.e., 50 and 80 km/h. The analysis of amplitudes leads to the determination of models in the entire braking speed range from 50 to 200 km/h, despite the lower accuracy compared to the model, based on the spectral analysis. The vibroacoustic literature presents methods of diagnosis of the wear of various machine elements such as bearings or friction linings, based on amplitude or frequency analysis of vibrations. These signal analysis methods have their limitations with regard to their scope of use and the accuracy of diagnosis. There are no cases of simultaneous use of different methods of analysis. This article presents the simultaneous application of the amplitude and frequency methods in the analysis of vibroacoustic signals generated by brake linings. Moreover, algorithms for assessing the wear of friction linings and the average coefficient of friction were presented. The algorithm enables determination of the time at which the friction linings should be replaced with new ones. The final algorithm analyzes the vibration acceleration signals using both amplitude analysis for low braking speeds, as well as spectral analysis for medium and high braking speeds.

Evaluation of Wear of Disc Brake Friction Linings and the Variability of the Friction Coefficient on the Basis of Vibroacoustic Signals.

Vibrations generated by the braking systems, both in rail vehicles or car have been widely analyzed and presented in the literature for several decades. Most of the articles raise the problems abrasive wear [4, 14], but noise and vibration to disrupt the process of braking and comfort during this process [12]. There are many models that describe the vibrations generated by the braking systems which include Rudolph and Popp model [17], North [16] and Millner [21] (flutter binary model In contrast, a separate issue is the brake vibroacoustic diagnostics designed to diagnose selected brake components. The number of articles in this area is much smaller, which means that the issue of vibroacoustic diagnostics of the braking system is developed by few researchers. Works [10, 18] presents the possibility of using vibrations generated by the brakes to assess the condition of the brake friction pair, both in design and during utilization of the brakes. Data acquired during tests certified on the braking positions (In Poland there are only two positions for the research of railway braking systems on IPS TABOR in Poznan and Warsaw IK) and during driving tests are used for modelling the braking process, as shown in [1, 11] or predicting the damage [6]. While the diagnosis of the braking systems, the aim is to find the relationship between system condition and the diagnostic signal, according to the equation (1) [5]:

/pdf/application-of-vibroacoustic-diagnostics-to-evaluation-of-2my3ganylk.pdf

Wojciech Sawczuk

Papers

Geldanamycin and its derivatives as Hsp90 inhibitors.

Analytical model coefficient of friction (COF) of rail disc brake on the basis of multi-phase stationary tests

The Application of Vibration Accelerations in the Assessment of Average Friction Coefficient of a Railway Brake Disc

Evaluation of Wear of Disc Brake Friction Linings and the Variability of the Friction Coefficient on the Basis of Vibroacoustic Signals.

Application of vibroacoustic diagnostics to evaluation of wear of friction pads rail brake disc