REVIEW | doi:10.20944/preprints202204.0130.v1
Subject: Medicine & Pharmacology, Sport Sciences & Therapy Keywords: extracorporeal shock wave therapy; ESWT; focused extracorporeal shock wave therapy; fESWT; mechanisms of action; radial extracorporeal shock wave therapy; rESWT; systematic review
Online: 14 April 2022 (07:42:55 CEST)
Extracorporeal shock wave therapy (ESWT) is a safe and effective treatment option for various pathologies of the musculoskeletal system. Many studies addressed the molecular and cellular mechanisms of action of ESWT. However, no uniform concept could be established in this matter until now. We performed a systematic review of the effects of exposure of musculoskeletal tissue to extracorporeal shock waves (ESWs) reported in the literature. The key results were as follows: (i) compared to the effects of many other forms of therapy, the clinical benefit of ESWT does not appear to be based on a single mechanism; (ii) different tissues respond to the same mechanical stimulus in different ways; (iii) just because a mechanism of action of ESWT was described in a study does not automatically mean that this mechanism was relevant to the observed clinical effect; (iv) focused ESWs and radial ESWs seem to act in a similar way; and (v) even the most sophisticated research into the effects of exposure of musculoskeletal tissue to ESWs cannot substitute clinical research in order to determine the optimum intensity, treatment frequency and localization of ESWT.
CASE REPORT | doi:10.20944/preprints202110.0047.v1
Subject: Earth Sciences, Geophysics Keywords: shock waves; mechanism and dynamics of destruction; quartz; granites; calcite
Online: 4 October 2021 (11:03:20 CEST)
The spectra of the plasma emitted from the studied samples consist of several dozens of narrow bands superimposed on each other. Tables of spectral lines were used to interpret the spectra. It turned out that the largest number of bands corresponds to the radiation of positively charged ions and atoms of elements that make up the crystal lattices of minerals that make up the studied rocks. Thus, the spectra of the plasma emitted from quartz corresponded to the radiation of atoms and positively charged silicon ions, the charge of which varied from 1 to 4, as well as atoms and positively charged oxygen ions, the charge of which varied from 1 to 3. Positively charged ions and atoms of Si, O, K, Ca, Al and Na, which are part of the crystal lattices of quartz and feldspar, flew out of granites. Positively charged ions and Ca, C and O atoms flew out of the calcite.
ARTICLE | doi:10.20944/preprints202208.0455.v1
Subject: Life Sciences, Biotechnology Keywords: Shock waves; Acoustic cavitation; Gene expression; Aspergillus niger; Cell permeabilization; Fungal germination
Online: 26 August 2022 (09:34:23 CEST)
Shock waves, as used in medicine, can induce cell permeabilization, genetically transforming filamentous fungi; however, little is known on the interaction of shock waves with the cell wall. Because of this, the selection of parameters has been empirical. We studied the influence of shock waves on the germination of Aspergillus niger, to understand their effect on the modulation of four genes related to the growth of conidia. Parameters were varied in the range reported in protocols for genetic transformation. Vials containing conidia in suspension were exposed to either 50, 100 or 200 single-pulse or tandem shock waves, with different peak pressures (approximately 42, 66 and 83 MPa). In the tandem mode, three delays were tested. To equalize the total energy, the number of tandem “events” was halved compared to the number of single-pulse shock waves. Our results demonstrate that shock waves do not generate severe cellular effects on the viability and germination of A. niger conidia. Nevertheless, increase in the aggressiveness of the treatment induced a modification in the four genes tested. Scanning electron microscopy revealed significant changes to the cell wall of the conidia. Under optimized conditions, shock waves could be used for several biotechnological applications, surpassing conventional techniques.
ARTICLE | doi:10.20944/preprints202106.0546.v1
Subject: Physical Sciences, Acoustics Keywords: shock wave process; shock-wave structure; refraction; domain of existence
Online: 22 June 2021 (14:26:45 CEST)
Refraction of an oblique shock wave on a tangential discontinuity dividing two gas flows with different properties is considered. It is shown that its partial reflection occurs excepting of geometrical diffraction of an oblique shock. Another oblique shock, expansion wave or weak discontinuity that coincides with Mach line, can act as a reflected disturbance. This study focuses on relationships which define the type of reflected discontinuity and its parameters. Domains of existence of various shock-wave structures with reflected disturbances of two types and boundaries between them are defined. The domains of parameters with one or two solutions exist for the characteristic refraction. Conditions of the regular refraction and the Mach refraction are formulated, and boundaries between those two refraction types are defined for various types of gases. Refraction phenomena in various engineering problems (hydrocarbon gaseous fuel and its combustion products, diatomic gas, fuel mixture of oxygen and hydrogen etc.) are discussed.
ARTICLE | doi:10.20944/preprints202009.0467.v1
Subject: Engineering, Mechanical Engineering Keywords: helmet; blast overpressure; shock wave; peak overpressure; impulse; shock tube
Online: 20 September 2020 (14:21:02 CEST)
This study demonstrates the orientation and the ‘shape factor’ have pronounced effects on the development of the localized pressure fields inside of the helmet. We used anatomically accurate headform to evaluate four modern combat helmets under blast loading conditions in the shock tube. The Advanced Combat Helmet (ACH) is used to capture the effect of the orientation on pressure under the helmet. The three modern combat helmets: ECH, Ops-Core, and Airframe, were tested in frontal orientation to determine the effect of helmet geometry. Using the unhelmeted headform data as a reference, we characterized pressure distribution inside each helmet and identified pressure focal points. The nature of these localized “hot spots” is different than the elevated pressure in the parietal region of the headform under the helmet widely recognized as the under-wash effect also observed in our tests. It is the first experimental study which indicates that the helmet presence increased the pressure experienced by the eyes (as evidenced by the pressure sensors in the H8 and H9 locations), and the forehead (denoted as H1 location). Pressure fingerprinting using an array of sensors combined with the application of principle component analysis (PCA) helped elucidate the subtle differences between helmets.
ARTICLE | doi:10.20944/preprints201707.0072.v1
Subject: Engineering, Other Keywords: high speed flows; shock wave; turbulent boundary layer; shock-unsteadiness; separation bubble; turbulence modeling; single fin
Online: 26 July 2017 (07:48:07 CEST)
The three-dimensional single fin configuration finds application in an intake geometry where the cowl-shock wave interacts with the side-wall boundary-layer. Accurate numerical simulation of such three-dimensional shock/turbulent boundary-layer interaction flows, which are characterized by the appearance of strong crossflow separation, is a challenging task. Reynolds-averaged Navier-Stokes computations using the shock-unsteadiness modified Spalart-Allmaras model is carried out at Mach of 5 at large fin angle of 23◦. The computed results using the modified model are compared to the standard Spalart-Allmaras model and validated against the experimental data. The focus of work is to implement the modified model and to study the flow physics in detail in the complex region of swept-shock-wave turbulent boundary-layer interaction in terms of the shock structure, expansion fan, shear layer and the surface streamlines. The flow structure is correlated to the wall pressure and skin friction in detail. It is observed that the standard model predicts an initial pressure location downstream of the experiments. The modified model reduces the eddy viscosity at the shock and predicts close to the experiments. Overall, the surface pressure using modified model is predicted accurately at all the locations. The skin friction is under predicted by both the models in the reattachment region and is attributed to the poor performance of turbulence models due to flow laminarization.
TECHNICAL NOTE | doi:10.20944/preprints202205.0284.v1
Online: 23 May 2022 (05:12:39 CEST)
Fusion device and its structure may be designed by various means. Two of most popular are; weight basis (described in previous study by author) and energy basis. In present research, later method is explored and described. Energy basis is based on amount of energy released from device upon detonation followed by explosion. Its beneficial in a sense that device size can be kept as independent variable as compared to dependent in former case. Further, it shortens the design procedure. For example, heat transfer pattern in such approach directly helps in quantifying wall thickness which dictates material, fabrication, and manufacturing route. It may also eliminate anisotropy as wall thickness is direct function of amount of heat at which it will rupture and can be much thinner. Device geometry can also be flexibility controlled as it is no longer dependent on pay load bay capacity. This allows more freedom in designing subsystems (compartments, their locations, focusing, switches, and mixers). Such devices can be more compact and simpler. Few such design configurations are proposed.
ARTICLE | doi:10.20944/preprints201702.0094.v1
Subject: Materials Science, General Materials Science Keywords: laser wavelength; polysilicon; laser damage; thermal shock
Online: 27 February 2017 (06:56:01 CET)
Based on PVDF (piezoelectric sensing techniques), this paper attempts to study the propagation law of shock waves in brittle materials during the process of three-wavelength laser irradiation of polysilicon, and discusses the formation mechanism of thermal shock failure. The experimental results show that the vapor pressure effect and the plasma pressure effect in the process of pulsed laser irradiation lead to the splashing of high temperature and high density melt. With the decrease of the laser wavelength, the laser breakdown threshold decreases and the shock wave is weakened. Because of pressure effect of the laser shock, the brittle fracture zone is at the edge of the irradiated area. The surface tension gradient and surface shear wave caused by the surface wave are the result of coherent coupling between optical and thermodynamics. The average propagation velocity of laser shock wave in polysilicon is 8.47×103m/s, and the experiment has reached the conclusion that the laser shock wave pressure peak exponentially distributes attenuation in the polysilicon.
ARTICLE | doi:10.20944/preprints201607.0008.v1
Subject: Physical Sciences, Astronomy & Astrophysics Keywords: active galaxies; blazars; jets; polarization; shock acceleration
Online: 8 July 2016 (03:03:04 CEST)
Relativistic shocks are one of the most plausible sites of the emission of strongly variable, polarized multi-wavelength emission from relativistic jet sources such as blazars, via diffusive shock acceleration (DSA) of relativistic particles. This paper summarizes recent results on a self-consistent coupling of diffusive shock acceleration and radiation transfer in blazar jets. We demonstrate that the observed spectral energy distributions (SEDs) of blazars strongly constrain the nature of hydromagnetic turbulence responsible for pitch-angle scattering by requiring a strongly energy-dependent pitch-angle mean free path. The prominent soft X-ray excess (``Big Blue Bump'') in the SED of the BL Lac object AO 0235+164 can be modelled as the signature of bulk Compton scattering of external radiation fields by the thermal electron population, which places additional constraints on the level of hydromagnetic turbulence. It has further been demonstrated that internal shocks propagating in a jet pervaded by a helical magnetic field naturally produce polarization-angle swings by 180$^o$, in tandem with multi-wavelength flaring activity, without requiring any helical motion paths or other asymmetric jet structures. The specific application of this model to 3C279 presents the first consistent, simultaneous modeling of snap-shot SEDs, multi-wavelength light curves and time-dependent polarization signatures of a blazar during a polarization-angle (PA) rotation. This model has recently been generalized to a lepto-hadronic model, in which the high-energy emission is dominated by proton synchrotron radiation. It is shown that in this case, the high-energy (X-ray and $\gamma$-ray) polarization signatures are expected to be significantly more stable (not showing PA rotations) than the low-energy (electron-synchrotron) signatures.
ARTICLE | doi:10.20944/preprints202204.0018.v1
Subject: Physical Sciences, Applied Physics Keywords: Droplet; Laser shock; High temperatures; Dynamics; Focusing enhancement
Online: 4 April 2022 (12:02:37 CEST)
The temperature-assisted laser shock process has shown promising prospects in the fields of forming manufacturing and surface strengthening. However, large-scale application of this process is limited by the instability and failure of confinement medium at high temperatures (≥300 ℃). Aiming at this problem, we propose a novel laser shock strategy based on Leidenfrost effect, where the suspended droplets are utilized as the confinement medium. According to the sequence of images acquired by time delay system and high-speed camera, the droplet dynamics behavior is studied. The focusing enhancement effect of the droplet is comprehensively explored. And the correlations between droplet size, ambient temperature, vapor layer thickness and focusing effect are investigated. Combining the dynamics and focusing enhancement effect of droplets, a theoretical model of laser shock pressure under droplet confinement is established. Finally, the effectiveness and feasibility of the droplet-based laser shock strategy in high temperature processing environments are verified by typical applications in laser shock forming and laser shock peening fields. The results show that the droplet-based laser shock process presents better forming effect. And the mechanical property tests demonstrate that this process can obtain the simultaneous improvement of the strength (~51%) and ductility (~6.4%) of annealed Cu. The multiscale plasticity mechanisms of the strengthened material are comprehensively investigated. We believe that this low-energy, low-cost and high-quality process can provide a new solution for the industrial application of laser shock at high temperatures.
ARTICLE | doi:10.20944/preprints202112.0350.v1
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: HMGB1; trauma; hemorrhagic shock; inflammation; multiple organ failure
Online: 22 December 2021 (10:36:56 CET)
Several preclinical and clinical reports have demonstrated that levels of circulating high mobility group box 1 protein (HMGB1) are increased early after trauma and are associated with systemic inflammation and clinical outcomes. However, the mechanisms of the interaction between HMGB1 and inflammatory mediators that lead to the development of remote organ damage after trauma remain obscure. HMGB1 and inflammatory mediators were analyzed in plasma from 54 combat casualties, collected on admission to a military hospital in Iraq, and at 8 and 24 hours after admission. Forty-five (83%) of these patients had traumatic brain injury (TBI). Nine healthy volunteers were enrolled as controls. HMGB1 plasma levels were significantly increased in the first 8 hours after admission, and were found to be associated with systemic inflammatory responses, injury severity score, and presence of TBI. These data provided the rationale for designing experiments in rats subjected to blast injury and hemorrhage, to explore the effect of HMGB1 inhibition by CX-01. Animals were cannulated, then recovered for 5-7 days before blast injury in a shock tube and volume-controlled hemorrhage. Blast injury and hemorrhage induced an early increase in HMGB1 plasma levels that coincided with severity of tissue damage and mortality. CX-01 inhibited systemic HMGB1 release, decreased local and systemic inflammatory responses, significantly reduced tissue and organ damage, and tended to increase survival. These data suggest that CX-01 has potential as an adjuvant treatment for traumatic hemorrhage.
ARTICLE | doi:10.20944/preprints202007.0718.v1
Subject: Medicine & Pharmacology, Pediatrics Keywords: Sepsis, Septic shock, Lactic acid, Dynamic monitoring, Prognosis
Online: 30 July 2020 (11:23:48 CEST)
Objectives: To investigate the value of early lactate dynamic monitoring index in predicting prognosis of patients with sepsis and septic shock. Methods: We performed our test on 50 patients. Out of 50 patients, 28 are male, and 22 are female. Prospectively studied pediatric patients with septic shock were performed. Vital signs, Lactate clearance, were obtained at presentation 6 h, 12 h, 24 h over the first 48 h of hospitalization. The therapy received, outcome parameters of mortality and duration of hospitalization were recorded. Results: The statistical data and comparative analysis showed that an average of 16.88 days after admission, 5 patients have died, 17 patients are poorly prognosis leaves the hospital, and the remaining 28 are recovered and discharged. The primary outcome variable of mean 16 days hospitalization mortality rate was 10%. Poor prognosis 34% and fully recovery 56 % were observed. In this retrospective cohort study, a lactate level of more than 2.5mmol/L was the best threshold to predict 28-day mortality among severe sepsis and septic shock patients. In our research, we found mean LC 6 h 3.08mmol/L, and after 48 h mean it is 1.79mmol/L. Significant LC 6 h found, which is 8.08mmol/L in the death group patient where 48 h mmol/L shows significant high. Poor prognosis also presents a clinical increase of lactate level high in the LC 6 h analysis, which is 3.32mmol/L. Recovered patients showed a significant improvement after administering treatment depending on the patient organ involvement and good decrease of lactate reports achieved, which is 1.20mmol/L, where admission reports show it was 1.91mmol/L in LC 6 h. Mean Heart rate 94/51mmhg, pulse 119, temperature 39℃, respiratory rate 32.26, and urine output 456 ml recorded during our study. Death patient shows a remarkable detonation of those reports but has a significant clinical report with the recovered patients. Conclusion: The early lactate dynamic monitoring index has a high value in predicting sepsis and septic shock patients' prognosis, thus worth popularizing.
ARTICLE | doi:10.20944/preprints201909.0124.v1
Subject: Life Sciences, Other Keywords: Heat shock factor (HSF-1) knockdown; heat shock proteins 70 and 27; radiosensitization; Hsp90 inhibitor NVP-AUY922; homologous recombination (HR)
Online: 11 September 2019 (13:37:00 CEST)
The inhibition of heat shock protein 90 (Hsp90) a molecular chaperone for multiple oncogenic client proteins is considered as a promising approach to overcome radioresistance. Since most Hsp90 inhibitors activate HSF-1 that induces the transcription of cytoprotective and tumor-promoting stress proteins such as Hsp70 and Hsp27, a combined approach consisting of HSF-1 knockdown (k.d.) and Hsp90 inhibition was investigated. A specific HSF-1 k.d. was achieved in H1339 lung cancer cells using RNAi-Ready pSIRENRetroQ vectors with puromycin resistance. The Hsp90 inhibitor NVP-AUY922 was evaluated at low concentrations - ranging from 1-10nM - in control and HSF-1 k.d. cells. Protein expression (i.e., Hsp27/Hsp70, HSF-1, pHSF-1) and transcriptional activity was assessed by Western blot analysis and luciferase assays and radiosensitivity was measured by proliferation, apoptosis (Annexin V, active caspase 3), clonogenic cell survival, alkaline comet, γH2AX, 53BP1 and Rad51 foci assays. The k.d. of HSF-1 resulted in a significant reduction of basal and NVP-AUY922-induced Hsp70/Hsp27 expression levels. A combined approach consisting of HSF-1 k.d. and low concentrations of the Hsp90 inhibitor NVP-AUY922 potentiates radiosensitization which involves an impaired homologous recombination mediated by Rad51. Our findings are key for clinical applications of Hsp90 inhibitors with respect to adverse hepatotoxic effects.
ARTICLE | doi:10.20944/preprints202208.0038.v1
Subject: Physical Sciences, Fluids & Plasmas Keywords: ICF; shock compression; void collapse; hydrodynamic simulations; hydrodynamic instabilities
Online: 2 August 2022 (04:57:30 CEST)
Mesoscale imperfections, such as pores and voids, can strongly modify the properties and the mechanical response of materials under extreme conditions. Tracking the material response and microstructure evolution during void collapse is crucial for understanding its performance. In particular, imperfections in ablator materials, such as voids, can limit the efficiency of the fusion reaction and ultimately hinder ignition. To characterize how voids influence the response of materials during dynamic loading and seed hydrodynamic instabilities, we have developed a tailored fabrication procedure for designer targets with voids at specific locations. Our procedure uses SU-8 as a proxy for ablators materials and hollow silica microspheres as proxy for voids and pores. By using photolithography to design the targets’ geometry, we demonstrate precise and highly reproducible placement of a single void within the sample, which is key for a detailed understanding of its behavior under shock compression. This fabrication technique will benefit high-repetition rate experiments at x-ray and laser facilities. Insight from shock compression experiments will provide benchmarks for the next generation of microphysics modelling.
Subject: Engineering, Automotive Engineering Keywords: Particle method; Smoothed particle hydrodynamics; Modeling; Simulations; Shock wave
Online: 12 January 2021 (15:55:50 CET)
The non-symmetrical collapse of an empty cylindrical cavity is modelled using Smoothed Particle Hydrodynamics. The presence of a nearby surface produces an anisotropic pressure field generating a high velocity jet that hits the surface. The collapse follows a different dynamic based to the initial distance between the centre of the cavity and the surface. When the distance is greater than the cavity radius (detached cavity) the surface is hit by travelling shock waves. When the distance is less than the cavity radius (attached cavity) the surface is directly hit by the jet and later by other shock waves generated in the last stages of the of the collapse. The results show that the surface is hit by a stronger shock when distance between the centre of the cavity and the surface is zero while showing more complex double peaks behaviour for other distances.
Subject: Life Sciences, Immunology Keywords: Anti-inflammation; Endotoxin shock; Atraric acid; Lichen; Heterodermia hypoleuca
Online: 27 August 2020 (12:10:17 CEST)
As symbionts of fungi and algae, lichens produce a variety of secondary products which pharmacological activities. This study aimed to investigate the anti-inflammatory activities of Heterodermia hypoleuca and its main compound, atraric acid. The results confirmed that atraric acid could regulating induced pro-inflammatory cytokine, nitric oxide, induced nitric oxide synthase and cyclooxygenase-2 expression by lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Means while, atraric acid down-regulated expression of phosphorylated IκB, ERK and nuclear factor kappa B (NFκB) signaling pathway to exhibit anti-inflammatory effects in LPS-stimulated RAW264.7 cells. Based on these results, the anti-inflammatory effect of atraric acid during LPS-induced endotoxin shock in a mouse model was confirmed. In the atraric acid treated-group, cytokine production was decreased in the peritoneum and serum, and each organ damaged by LPS-stimulation was recovered. These results show that atraric acid has an anti-inflammatory effect and its molecular mechanism may be involved in the inactivation of the ERK/NFκB signaling pathway, demonstrating its value as a potential therapeutic for inflammatory diseases.
ARTICLE | doi:10.20944/preprints201911.0150.v1
Subject: Earth Sciences, Environmental Sciences Keywords: wetting shock fronts; shear flow; viscosity; capillarity; kinematic waves
Online: 13 November 2019 (15:45:38 CET)
The paper argues that universal approaches to infiltration and drainage in permeable media that pivot around capillarity and that led to dual porosity, non-equilibrium, or preferential flow need to be replaced by a dual process approach. One process has to account for relatively fast infiltration and drainage based on Newton's shear flow, while the other one is responsible for storage and relatively slow redistribution of soil water by focusing on capillarity. Already Schumacher (1864) postulated two separate processes. However, Buckingham's (1907) and Richards' (1931) apparent universal capillary-based approach to flow and storage of water in soils dominated. The paper introduces the basics of Newton's shear flow in permeable media. It presents experimental support for the four presumptions of (i) sharp wetting shock fronts; (ii) that move with constant velocities; (iii) atmospheric pressure prevails behind the wetting shock front; (iv) laminar flow. It further discusses the scale tolerance of the approach, its relationship to Darcy's (1856) law, and its extension to solute transport.
REVIEW | doi:10.20944/preprints201810.0285.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: sepsis; septic shock; hydrocortisone; vitamin C; ascorbic acid; thiamine
Online: 15 October 2018 (06:25:26 CEST)
Sepsis is a devastating disease that carries an enormous toll in terms of human suffering and lives lost. Over 100 novel pharmacologic agents which targeted specific molecules or pathways have failed to improve the outcome of sepsis. Preliminary data suggests that the combination of Hydrocortisone, Ascorbic Acid and Thiamine (HAT therapy) may reduce organ failure and mortality in patients with sepsis and septic shock. HAT therapy is based on the concept that a combination of readily available, safe and cheap agents which target multiple components of the host’s response to an infectious agent will synergistically restore the dysregulated immune response and thereby prevent organ failure and death. This paper reviews the rationale for HAT therapy with a focus on vitamin C.
ARTICLE | doi:10.20944/preprints201809.0536.v1
Subject: Engineering, Electrical & Electronic Engineering Keywords: electromagnetic shock absorber; tubular machine; energy harvesting; Halbach array
Online: 27 September 2018 (08:29:13 CEST)
In this paper, modification of dual-Halbach permanent magnet (PM) array is investigated to improve performance of tubular linear machine, in terms of flux density and output power. Instead of a classical Halbach array with only radial and axial PMs, proposed model involves insertion of mig-magnets, which have magnetized angle shifted from the reference magnetized angles of axial and radial PMs. This structure leads to elimination of flux leakage and concentration of flux linkage in middle of the coil; therefore, the performance of machine is increased.
HYPOTHESIS | doi:10.20944/preprints202101.0138.v1
Subject: Medicine & Pharmacology, Allergology Keywords: extracorporeal shock wave therapy; ESWT, laser therapy; musculoskeletal system, rehabilitation
Online: 8 January 2021 (10:39:40 CET)
Extracorporeal shock wave therapy (ESWT) is a well investigated and widely used treatment modality for a number of musculoskeletal disorders. A limitation of ESWT is its potential painfulness at higher, clinically relevant energy flux density (EFD), which may limit its applicability and, thus, effectiveness. Various studies in the literature demonstrated that neither application of a higher number of extracorporeal shock waves with lower EFD nor use of local anesthesia may solve this problem. Based on the results of several other studies in the literature it is hypothesized here that in patients suffering from musculoskeletal disorders that can be treated with ESWT, pretreatment with a pulsed, high power laser with a wavelength of 904 or 905 nanometers (hereafter: "laser pretreatment") does not only allow to apply higher EFDs in subsequent ESWT but actually results in faster and/or better treatment outcome than ESWT without laser pretreatment. Accordingly, it is hypothesized here that combining ESWT with laser pretreatment leads to synergistic effects and, thus, is superior to either treatment modality alone. Confirming this hypothesis in preclinical and clinical research may raise significance and increase the use of ESWT in physical and rehabilitation medicine, with immediate benefit for patients.
ARTICLE | doi:10.20944/preprints202005.0150.v2
Subject: Biology, Other Keywords: chaperone function; heat-shock proteins; lipid binding; phosphatidylserine; protein refolding
Online: 29 July 2020 (12:18:02 CEST)
HspA1A, a molecular chaperone, translocates to the plasma membrane (PM) of stressed and cancer cells. This translocation results in HspA1A’s cell-surface presentation, which renders tumors radiation insensitive. To specifically inhibit the lipid-driven HspA1A’s PM translocation and devise new therapeutics it is imperative to characterize the unknown HspA1A’s lipid-binding regions and determine the relationship between the chaperone and lipid-binding functions. To elucidate this relationship, we determined the effect of phosphatidylserine (PS)-binding on the secondary structure and chaperone functions of HspA1A. Circular dichroism revealed that binding to PS resulted in minimal modification on HspA1A’s secondary structure. Measuring the release of inorganic phosphate revealed that PS-binding had no effect on HspA1A’s ATPase activity. In contrast, PS-binding showed subtle but consistent increases in HspA1A’s refolding activities. Furthermore, using a Lysine-71-Arginine mutation (K71A; a null-ATPase mutant) of HspA1A we show that although K71A binds to PS with affinities similar to the WT, the kinetics of the binding are significantly different, probably because of the mutant’s inability to achieve specific conformations. These observations suggest a two-step binding model that includes conformational changes and strongly support the notion that the chaperone and lipid-binding activities of HspA1A are dependent but the regions mediating these functions do not overlap. These findings provide the basis for future interventions to inhibit HspA1A’s PM-translocation in tumor cells, making them sensitive to radiation therapy.
REVIEW | doi:10.20944/preprints202005.0160.v1
Subject: Medicine & Pharmacology, Pediatrics Keywords: Sars-Cov2; Covid-19; Children; Kawasaki disease; toxic shock syndrome
Online: 9 May 2020 (09:01:24 CEST)
In the end of April nearly 100 cases of children aged between 6 month and 9 years with Kawasaki like disease were reported (mostly in Europe) probably linked to COVID-19. With the increasing awareness of this condition the number of cases reported is increasing worldwide. We aim to sum up the known data about this new entity based on published data (in a case report, a series of 8 cases and in newspapers and society statement) and using our knowledge of classical Kawasaki disease. It seems to be a post infectious disease with an onset between 2-4 weeks after the infection, probably in genetically predisposed children aged between 6 month to 17 years. A very rough estimation of incidence based on current data from Bergamo, Italy, and New York State and a lot assumption is between 0.016% (95% CI:0.013-0.02%) - 0.31% (95% CI: 0.2-0.47%) of infected children. Clinical signs overlaps with Kawasaki disease in some children, but another feature is prominent gastrointestinal manifestations. For the 9 detailed patients most had incomplete presentation for Kawasaki disease (with a mean 1.7 (+/-1.2) criteria per patient for the 5 non fever criterion) and only one had a classical form. In some cases, presentation is closer to toxic shock syndrome or isolated myocarditis. Persistent fever seems to be constant and biological exploration are consistent with inflammation (elevated CRP, ferritin and D-Dimers). Management is described as supportive and children seem to improve rapidly, but can require cardiac or respiratory support. In date of 11 may 2020 there is 4 deaths confirmed linked to these new entities (1 in UK and 3 in New York). Paediatricians and general practitioners need to be aware of these possible evolution following COVID-19 infection. However it seems to be rare and children are probably still spared from most morbidities and mortality linked to COVID-19 infection .There are need of published detailed cohorts to better delineate these entities.
REVIEW | doi:10.20944/preprints201907.0081.v1
Subject: Biology, Other Keywords: Heat shock protein 27; HSP27 inhibitor; Anti-cancer drugs, Resistance
Online: 4 July 2019 (13:19:51 CEST)
Heat shock protein 27 (HSP27), induced by heat shock, environmental, and pathophysiological stressors, is a multi-dimensional protein that acts as a protein chaperone and an antioxidant. HSP27 plays a major role in the inhibition of apoptosis and actin cytoskeletal remodeling. HSP27 is upregulated in many cancers and is associated with poor prognosis, as well as treatment resistance whereby cells are protected from therapeutic agents that normally induce apoptosis. This review highlights the most recent findings and role of HSP27 in cancer, as well as strategies for using HSP27 inhibitors for therapeutic purposes.
ARTICLE | doi:10.20944/preprints201905.0103.v2
Subject: Life Sciences, Molecular Biology Keywords: L-arginine, embryonic development, intracytoplasmic vacuoles, immunoglobulin, heat shock proteins
Online: 10 May 2019 (14:03:49 CEST)
The objective of this study was to evaluate the effect of in ovo injection of L-arginine (L-Arg) into Ross broiler eggs at different embryonic developmental stages on their survival, hatchability, and body weight (BW). Additionally, we have analyzed the levels of serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT), protein expression of heat shock proteins (HSPs), also we have the determined micronuclei (MN) and nuclear abnormality (NA). Results showed that survival and hatching rates as well as body weight were increased on the 14th day incubation compared to 8th and 18th day incubation at lower concentration of L-Arg. Moreover, the levels of SGOT and SGPT were also significantly (P < 0.05) increased at 14th day incubation at the same concentration (100μg/μl/egg) of injection. In addition, IgM levels were increased on the 14th day incubation compared to other days. The protein expressions of HSP-47, HSP-60, and HSP-70 in the liver were significantly down-regulated whereas the expression of myogenin and MyoD were significantly up-regulated on the 14th day after incubation in treated with all different doses such as 100μg, 1000μg and 2500μg/μl/egg namely 3T1, 3T2 and 3T3 respectively. However, the treatment with low dose of L-Arg down-regulated expression levels of those proteins on the 14th day incubation. Histopathology of liver by hematoxylin and eosin (H&E) straining showed that the majority of liver damage, specifically intracytoplasmic vacuoles, were observed in 3T1, 3T2, and 3T3. The minimum dose of 100 μg/ml/egg on the 14th day of incubation significantly prevented intracytoplasmic vacuole damages. These results demonstrate that in ovo administration of L-Arg at (100μg/μl/egg) may be an effective method to increase chick BW, hatch rate, increasing muscle growth related proteins and promote the immune response through increasing IgM on the 14th day of incubation period.
ARTICLE | doi:10.20944/preprints201812.0048.v1
Subject: Materials Science, General Materials Science Keywords: effective transition field, volume stability, thermal shock durability, self-restoration
Online: 4 December 2018 (08:52:15 CET)
In this study, a parameter of volume stability was proposed for the first time to design polymorph zirconia ceramics used for special components. A series of heterogeneous polymorph zirconia ceramics with various amounts of monoclinic (M) phase were fabricated by two-step sintering. Samples with about 27%, 31%, and 51% M phase content were selected to study the properties. The thermal shock durability was found to be associated with thermal expansion behavior and noncritical micro cracks, which both based on M phase initial content. In good agreement with experimental results, the correlation of normalized K versus M phase initial content was established. It could provide a repeatable reference to prepare special zirconia components without loss of density.
ARTICLE | doi:10.20944/preprints201806.0125.v1
Subject: Materials Science, General Materials Science Keywords: Impact-sliding wear; Titanium alloy; Laser shock peening; Wear rate
Online: 7 June 2018 (15:13:24 CEST)
Outer particles collision with certain dynamic object is not a pure impact wear behavior; it is typically accompanied by sliding wear phenomena. This study aimed investigating the impact-sliding wear performance of three different TC17 titanium alloys. One was untreated, and the other two were subjected to laser shock peening (LSP) by 5 and 7 J pulse energy, respectively. Wear test was performed on a novel impact-sliding wear testing rig, which can realize multiple impact-sliding motions by changing motion parameters in x and z directions. Present results showed that wear resistance of both treated samples improved compared with the untreated alloy. Given the increase in wear cycles, increment in wear rate of the untreated sample was constantly higher than those of treated samples. All results can be attributed to the increase in surface hardness of the material and residual compressive stress, which was also introduced after LSP.
ARTICLE | doi:10.20944/preprints201804.0362.v1
Subject: Engineering, Mechanical Engineering Keywords: Laser Shock Peening (LSP); bainitic ferrites; plastic deformation; hardness; fatigue
Online: 27 April 2018 (15:59:27 CEST)
The study proposes laser shock peening without a coating of high strength ultrafine bainitic steel to mitigating the fatigue failures for automotive and structural engineering applications. Laser pulse density of 2500 pulses/cm2 (75% overlapping) was optimised based on the induced residual stresses for employing the wide range of characterisations. The roughness and topographic results showed that surface roughening was controlled by tuning the laser pulse density. The High-Resolution X-ray Diffraction analysis confirmed the lattice misorientation resulting peak shift and the trend towards martensite phase transformations. The electron microscopic micro/nanostructure analyses revealed the grain refinement features such as nano-twins, micro shear bands and shear cells. The work hardening depth and nanomechanical properties were significantly enhanced. A fully reversed (R= -1) high-cycle fatigue tests extended the lifespan by an average of fifteen times than the untreated. Also, it has potential to repair the structural components effectively.
REVIEW | doi:10.20944/preprints201803.0239.v1
Subject: Engineering, Mechanical Engineering Keywords: regenerative, shock absorber, drive mode, vehicle dynamics, output power, nonlinearity
Online: 28 March 2018 (14:18:30 CEST)
In this paper, the current technologies of the regenerative shock absorber systems have been categorized and evaluated. Three drive modes of the regenerative shock absorber systems, namely the direct drive mode, the indirect drive mode and hybrid drive mode are reviewed for their readiness to be implemented. The damping performances of the three different modes are listed and compared. Electrical circuit and control algorithms have also been evaluated to maximize the power output and to deliver the premium ride comfort and handling performance. Different types of parameterized road excitations have been applied to vehicle suspension systems to investigate the performance of the regenerative shock absorbers including that of the nonlinear regenerative shock absorber. The research gaps for comparison of the different drive modes and the nonlinearity analysis of the regenerative shock absorbers are identified and, the corresponding research questions have been proposed for future work.
REVIEW | doi:10.20944/preprints202208.0141.v1
Subject: Medicine & Pharmacology, Anesthesiology Keywords: hemorrhagic shock; multimodal monitoring; individualized therapy; fluid therapy; critical care; trauma
Online: 8 August 2022 (09:56:33 CEST)
Worldwide, one of the main causes of death among young adults is multiple trauma. In these pa-tients hemorrhagic shock represents the leading cause for worsening of the clinical status and for increased morbidity and mortality. This is due to a multifactorial complex involving cellular, bi-ological, and biophysical mechanisms. The most important mechanisms affecting clinical out-come are oxidative stress, the augmentation of pro-inflammatory status, immune deficiency, dis-ruptions in the coagulation cascade, imbalances in electrolyte and acid-base homeostasis. Poly-trauma patients in hemorrhagic shock need adequate fluid management to ensure hemodynamic stability that must consider not only the maintenance of adequate blood pressure, but also the ad-equate oxygenation of tissues for optimal cellular function. In the current clinical practice, fluid resuscitation in polytrauma patients uses a variety of widely studied pharmacological products, such as crystalloids, colloids, blood transfusions, and the infusion of other blood products. Alt-hough these products exist, an agreement was not reached on a standard administration protocol that could be generally applied for all patients. Moreover, numerous studies have reported a se-ries of adverse events related to fluid resuscitation and to the inadequate use of these products. This review aims at describing the impact the administration of all the solutions used in fluid re-suscitation might have on the cellular and pathophysiological mechanisms in the case of poly-trauma patients suffering from hemorrhagic shock.
ARTICLE | doi:10.20944/preprints202204.0171.v1
Subject: Materials Science, Surfaces, Coatings & Films Keywords: Selective laser shock peening; Hydrophobic properties; Mechanical properties; 3D gradient structure
Online: 18 April 2022 (11:58:44 CEST)
The mechanical properties and stability of hydrophobic surface structures prepared by traditional methods are still the main technical bottlenecks restricting the broad application of hydrophobic systems on workpiece surfaces. In this contribution, we propose a technique called selective laser shock peening (SLSP) to enable large-scale high efficient, low-cost manufacturing of hydrophobic metal surfaces with enhanced mechanical properties for durable applications. Using the method of experimental investigation combined with numerical calculation, the hydrophobic properties, mechanical properties, and tribological properties of the samples prepared under SLSP, all-laser shock peening (ALSP), and non-laser shock peening (NLSP) are studied. The SLSP process could prepare a 3D gradient structure material with surface structures, a two-phase (strong phase, soft phase) distribution on the surface, and a multi-level gradient distribution in the thickness direction. Compared with the 2D gradient structure prepared by the traditional process, 3D gradient structures by SLSP have more significant advantages in improving the wetting behavior and the mechanical properties of the material, which proves SLSP to be a novel method to fabricate functional metal surface structures, with highly high engineering application value.
ARTICLE | doi:10.20944/preprints202105.0668.v1
Subject: Medicine & Pharmacology, Allergology Keywords: prolonged infusion; ß-lactams; septic shock; mortality; antibiotic therapy; critical care
Online: 27 May 2021 (13:13:52 CEST)
Septic shock substantially alters the pharmacokinetic properties of ß-lactams with a subsequently high risk of insufficiently low serum concentrations and treatment failure. Considering their pharmacokinetic (PK)/pharmacodynamic (PD) index, prolonged infusions (PI) of ß-lactams extend the time that the unbound fraction of the drug remains above the minimal inhibitory concentration MIC (ft >MIC) and may improve patient survival. The present study is a monocentric, retrospective before-and-after analysis of septic shock patients treated with ß-lactams. Patients of the years 2015-2017 received intermittent bolus application whereas patients of 2017-2020 received PI of ß-lactams. The primary outcome was mortality at day 30 and 90 after diagnosis of septic shock. Mortality rates in the PI group were significantly lower on day 30 (PI: 41%, n=119/290 vs. IB: 54.8%, n=68/114; p=0.0097) and day 90 (PI: 47.9%, n=139/290 vs. IB: 62.9%, n=78/124; p=0.005). After propensity-score matching, 30- and 90-day mortality remained lower for the PI group (-10%). PI further reduced duration of invasive ventilation. PI of β-lactam antibiotics led to a stronger decrease in SOFA scores within a 14d-observation period. PI of ß-lactams significantly reduces mortality in patients with septic shock and may have beneficial effects on invasive ventilation and recovery from sepsis-related organ failure.
ARTICLE | doi:10.20944/preprints202003.0454.v1
Subject: Engineering, Mechanical Engineering Keywords: bollard; honeycomb; Polylactic acid (PLA); LS-DYNA; shock-absorption; in-plane
Online: 31 March 2020 (10:14:16 CEST)
Lack of shock absorption capability of conventional steel bollards causes significant vehicle damage and consequently high repair costs. This research studies a solution to reduce vehicle damage by inserting PLA honeycomb structures. A honeycomb-inserted bollard was designed based on numerical simulations using LS-DYNA, which yielded the bollard designed for actual vehicle-bollard collision experiments. Simulation efforts were focused on calculating the acceleration characteristics when a vehicle collides with steel and honeycomb-inserted bollards. Compared to the simulated steel bollards, 20 MPa yield-strength honeycomb-inserted bollard showed 0.017s delay in the maximum acceleration occurrence time, reduction of the maximum acceleration to 37.4% of that of steel bollards, and 13.1% reduction in the B-pillar maximum acceleration. Actual vehicle-bollard collision experiments, with a gyro-sensor installed at the test vehicle front bumper frame, also proved improved shock absorption characteristics of the honeycomb-inserted bollards. An experiment with honeycomb-inserted bollard showed 0.783s delay in the maximum acceleration occurrence time, a significant delay when compared to steel bollards. The maximum acceleration measured by the gyro-sensor was 0.35m/s2 when the simulation predicted it to be 0.388 m/s2, proving the similarity in the simulations and experiments. Thus, this study of shock absorption characteristics promised reduced damage to vehicles and lower repair cost.
ARTICLE | doi:10.20944/preprints201811.0145.v1
Subject: Biology, Forestry Keywords: Highway Beautification; Transplant Shock; Transportation; Tree Health; Tree Establishment; Urban Forestry
Online: 6 November 2018 (14:22:48 CET)
Urban tree planting initiatives can experience high levels of mortality during establishment years. Mortality tied to the stresses of transplanting can be partially negated or exacerbated depending on the species selected, nursery materials used, site conditions present, and management practices employed. Past research has quantified post-planting survival, health, and growth. However, varying climates, species, land use types, and management practices warrant additional region-specific research. The purpose of this study is to assess the success of plantings along Florida highways and identify species, site, and management factors related to tree and palm health and establishment. Results show high annual establishment survival (98.5%) across 21 planting projects ranging from 9 to 58 months after installation, (n = 2711). For transplanted palms, the presence of on-site irrigation significantly improved establishment from 96.2% to 99.4%. No establishment differences were detected with regard to irrigation treatment for small-stature trees, shade trees, and conifers. Additionally, there were significant differences in tree health response among tree groups given species, management, and site factors.
ARTICLE | doi:10.20944/preprints201704.0166.v1
Subject: Engineering, Biomedical & Chemical Engineering Keywords: optoelectronic sensor; near-infrared spectroscopy; thrombus diagnosis; shock monitoring; fatigue evaluation
Online: 26 April 2017 (06:05:07 CEST)
We attempted to apply the optoelectronic sensor entitled 'OPT101' in intensive care unit clinics, based on its optoelectronic response characteristics in near-infrared wavelength range and near-infrared spectroscopy principle. The successful novel applications in our lab include early-diagnosis and therapeutic effect tracking of thrombus, noninvasive monitoring of patients' shock severity, and fatigue evaluation. This study also expects further improvements of the detector in noninvasive clinical applications.
Subject: Engineering, Mechanical Engineering Keywords: Laser shock peening; FE simulation; Residual stress; Minimum principal stress; Static damping
Online: 18 August 2021 (10:51:34 CEST)
Laser shock peening is a process which can reduce stress corrosion cracking and improve fatigue life by forming compressive residual stress on the surface of the material. In a computational FE simulation of laser shock peening, during applying the pressure load generated by the laser pulse to the surface of simulation geometry, the peening is simulated by explicit analysis and then convert to implicit analysis to dissipate the dynamic energy remaining in the geometry. In this study, static damping is applied to dissipate residual dynamic energy without converting it into an implicit analysis. The compressive residual stress distribution is compared between the simulation results for the stainless steel 304 material and the same material subjected to actual laser shock peening. The laser shock peening parameters were 4.2J laser pulse energy, 50% overlap of 3mm diameter of the laser beam and water as a confinement layer. As a result, the compressive residual stress from the surface to the depth direction is similar to both the simulation and the experimental result measured by the hole drilling method.
REVIEW | doi:10.20944/preprints202008.0257.v1
Subject: Medicine & Pharmacology, Cardiology Keywords: COVID-19; SARS-CoV2; Acute Cardiac Injury; Arrhythmia; Heart Failure; Cardiogenic Shock
Online: 11 August 2020 (07:47:51 CEST)
A newly identified novel coronavirus named as severe acute respiratory syndrome-related coronavirus2 (SARS‐CoV 2) has given rise to the global pandemic. SARS-CoV2 which causes coronavirus disease 2019 (COVID-19), is a positive-stranded RNA virus with nucleocapsid. It binds to host angiotensin-converting enzyme2 (ACE2) receptor through surface glycoprotein (S protein). These ACE 2 receptors are attached to the cell membranes of many organs. Thus, COVID-19 does not only result in acute respiratory distress syndrome but also affects multiple organ systems, requiring a multidisciplinary approach to manage this disease. COVID-19 can damage the myocardial cells and result in fulminant myocarditis, acute cardiac injury, cardiomyopathy, heart failure, cardiogenic shock, or arrhythmia. COVID-19 seeds harmful immune response through cytokine storm leading to indirect organ damage. In this literature review, the available data is comprehended regarding cardiovascular complications in COVID-19, and the correlation of biomarkers with the disease activity is discussed. This literature review also highlights the important treatment options and outcomes of the individual study.
BRIEF REPORT | doi:10.20944/preprints202004.0150.v1
Subject: Medicine & Pharmacology, Dermatology Keywords: actinic keratosis; cutaneous squamous cell carcinoma; cytoplams; skin cancer; heat shock protein
Online: 9 April 2020 (12:21:19 CEST)
Background: Cutaneous squamous skin cell carcinoma (SCC) is the second most frequent type of non- melanoma skin cancer and the second cause of death by skin cancer in caucasian population. However, at present it is difficult to predict patients with worst SCC prognosis. Objective: To identify proteins whose expression level could predict SCC infiltration in SCC arising from actinic keratosis (AC). Methods: A total of 20 biopsies of 20 different patients were studied, 10 were from SCC-AK samples and 10 from normal skin. Early infiltrated SCC-AK were selected on histological examination and to determine the expression of proteins fresh skin samples were processed by 2DE-electrophoresis Results: The expression levels of three proteins namely alpha-hemoglobin, heat shock protein (Hsp)-27 and 70 were significantly increased in SCC-AK samples with respect to normal control skin. However, only the expression level of Hsp70 protein positively correlated with the level of SCC-AK dermis infiltration. Immnunohistological examination suggested that the increased expression of Hsp70 proteins seems to mainly occur in the keratinocytes cytoplasm. The increased cytoplasmic Hsp70 expression in SCC-AK was confirmed by Western-blot experiments. Conclusion: Cytoplasmic expression of Hsp70 could be potential biomarker of early infiltration of SCC arising from an AK. Keywords: actinic keratosis, cutaneous squamous cell carcinoma; cytoplasm, skin cancer; heat shock protein.
ARTICLE | doi:10.20944/preprints202003.0426.v1
Subject: Physical Sciences, Fluids & Plasmas Keywords: solitons; electrostatic solitary waves; pickup ions; perpendicular shock waves; multi-fluid plasma
Online: 29 March 2020 (06:53:25 CEST)
The need to understand the process by which particles, including solar wind and coronal ions as well as pickup ions, are accelerated to high energies (ultimately to become anomalous cosmic rays) motivate a multi-fluid shock wave model which includes kinetic effects (e.g. ion acceleration) in an electromagnetically self-consistent framework. Particle reflection at the cross-shock potential leads to ion acceleration in the motional electric field and thus anisotropic heating and pressure in the shock layer, with important consequences for the multi-fluid dynamics. This motivates development of a multi-fluid model of solar wind electrons and ions treated as fluid, coupled self-consistently with a small population of kinetically treated ions (e.g. pickup ions.) Consideration of both the time dependent and steady state regimes, indicate that such a multi-fluid approach is necessary for resolving the, Debye scale, particle reflecting cross-shock potential and subsequent dynamics. To study charge separation effects in narrow, supersonic wave layers we consider a reduction of the system to the steady state for cold ions and hot electrons and find two types of solitary waves inherent to the reduced two-fluid system in this limiting case.
ARTICLE | doi:10.20944/preprints201611.0083.v2
Subject: Engineering, Civil Engineering Keywords: air shock wave; rock-fall; two-phase model; computational fluid dynamics (CFD)
Online: 23 January 2017 (09:15:34 CET)
In this paper, a two-phase model of air shock wave induced by rock-fall was described. The model was made up of the uniform motion phase (velocity was close to 0 m·s-1) and the acceleration movement phase. The uniform motion phase was determined by experience, meanwhile the acceleration movement phase was derived by the theoretical analysis. A series of experiments were performed to verify the two-phase model and obtained the law of the uniform motion phase. The acceleration movement phase was taking a larger portion when height of rock-fall was higher with the observations. Experimental results of different falling heights showed good agreements with theoretical analysis values. Computational fluid dynamics (CFD) numerical simulation had been carried out to study the variation velocity with different falling height. As a result of this, the two-phase model could accurately and convenient estimating the velocity of air shock wave induced by rock-fall. The two-phase model could provide a reference and basis for estimating the air shock waves' velocity and designing the protective measures.
ARTICLE | doi:10.20944/preprints202205.0089.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: placenta-derived stem cells; placenta; stem cells; proteostasis; heat-shock; chaperones; HSPA1B; HSPA1A
Online: 7 May 2022 (03:37:17 CEST)
Placenta-derived stem cells (PDSCs) offer the advantages of possessing mesenchymal and embryonic traits, broad differentiation potential, large-scale availability, and no ethical constraints in their utilization in therapeutic applications. Elevated protein synthesis and consequently enhanced protein maintenance networks become necessary both due to the requirement to maintain stemness and respond to different stresses. This study aimed to identify the primary determinants of proteotoxic stress response in PDSCs. We generated heat-induced dose-responsive proteotoxic stress models of three stem cell types DBMSCs, DPMSCs, and pMSCs, and measured stress induction through biochemical and cell proliferation assays. RT-PCR array analysis of 84 genes involved in protein folding and protein quality control led to the identification of Hsp70 isoforms HSPA1A and HSPA1B as the prominent ones among 17 significantly expressed genes and with further analysis at the protein level through western blotting. A 24-hours’ time series analysis of stress-response allowed a detailed kinetic analysis of HSPA1A and HSPA1B gene and protein expression. More prominent differences between the two Hsp70 isoforms were detected at the translational level eluding to a potential higher requirement for HSPA1B during proteotoxic stress in PDSCs. To conclude, consideration should be given to the manipulation of definitely characterized chaperones at their expression or functional levels when utilizing PDSCs in therapeutic and regenerative applications.
CASE REPORT | doi:10.20944/preprints202103.0192.v1
Subject: Medicine & Pharmacology, Allergology Keywords: COVID-19; shortness of breath; chest pain; radial extracorporeal shock wave therapy; rESWT
Online: 5 March 2021 (17:02:02 CET)
Many patients with Coronavirus disease 2019 (COVID-19) suffer from shortness of breath and severe chest pain. Here we report successful therapy of a patient with diagnosis of COVID-19, severe chest pain and significant shortness of breath, using radial extracorporeal shock wave therapy (rESWT). The latter started seven days after beginning of symptoms and drug therapy without success, and involved daily application of 15.000 to 20.000 radial extracorporeal shock waves over the intercostal muscles as well as the paravertebral muscles of the thoracic and lumbar spine, diaphragm and flanks. Immediately after the first rESWT session the patient experienced significant pain relief and improvement of breathing. Four days later the pain had completely subsided and breathing was largely normalized. This type of noninvasive, non-pharmacologic treatment could help many COVID-19 patients or patients who still suffer from breathing problems weeks after having been infected with SARS-CoV-2, giving them back quality of life.
REVIEW | doi:10.20944/preprints202010.0292.v1
Subject: Materials Science, Biomaterials Keywords: laser powder bed fusion; Inconel 718; high temperature; material characterisation; laser shock peening
Online: 14 October 2020 (09:11:10 CEST)
This paper reviews state of the art Additive Manufactured (AM) IN718 alloy intended for high temperature applications. AM processes have been around for decades and have gained traction in the past five years due to the huge economic benefit it brings to manufacturers. It is crucial for the scientific community to look into AM IN718 applicability in order to see a step-change in the production. Microstructural studies reveal that the grain structure plays a significant role in determining the fatigue lifespan of the material. Controlling IN718 respective phases such as the ϒ’', δ and Laves phase is seen to be crucial. Literature reviews have shown that the mechanical properties of AM IN718 were very close to its wrought counterpart when treated appropriately. Higher homogenization temperature and longer ageing were recommended to dissolve the damaging phases. Various surface enhancement techniques were examined to find out their compatibility to AM IN718 alloy that is intended for high temperature application. Laser shock peening (LSP) technology stands out due to the ability to impart low cold work which helps in containing the beneficial compressive residual stress it brings in high temperature fatigue environment.
ARTICLE | doi:10.20944/preprints202009.0369.v1
Subject: Engineering, Mechanical Engineering Keywords: warm laser shock peening (WLSP); GH4169 nickel-base super-alloy; microstructure; residual stress
Online: 17 September 2020 (04:12:58 CEST)
Laser shock peening as an innovative surface treatment technology can effectively improve the fatigue life, sur-face hardness, corrosion resistance, and residual compressive stress. Compared with the laser shock peening, the warm laser shock peening (WLSP) is a new surface treatment technology to improve materials’ surface performances, which takes advantage of thermal mechanical effects on stress strengthening and micro-structure strengthening, results in more stable distribution of the residual compressive stress under heating and cyclic loading process. In this paper, the microstructure of GH4169 nickel super-alloy processed by WLSP technology with differ-ent laser parameters were investigated. The proliferation and tangling of dislocations in GH4169 were observed and the dislocation density increased after WLSP treatment. The influences of different treatment by LSP and WLSP on the microhardness distribution of the surface and along cross-sectional depth were investi-gated. The microstructure evolution of the GH4169 alloy being shocked with WLSP were studied by TEM. The effect of temperature on the stability of high temperature microstructure and properties of GH4169 alloy WLP was investigated.
Subject: Life Sciences, Biochemistry Keywords: heat shock proteins; Diabetes mellitus; beta-cells; endoplasmic reticulum stress; proteostasis; HSPB1; cytoprotection; apoptosis.
Online: 8 July 2021 (14:03:59 CEST)
During type 1 diabetes mellitus (T1DM) development, beta-cells undergo intense endoplasmic reticulum (ER) stress that could result in apoptosis through the failure of adaptation to the unfolded protein response (UPR). Islet transplantation is considered an attractive alternative among beta-cell replacement therapies for T1DM. To avoid the loss of beta-cells that will jeopardize the transplant´s outcome, several strategies are being studied. We have previously shown that prolactin induces protection against pro-inflammatory cytokines and redox imbalance-induced beta-cell death by increasing heat shock protein B1 (HSPB1) levels. Since the role of HSPB1 in beta cells has not been deeply studied, we investigated the mechanisms involved in unbalanced protein homeostasis caused by intense ER stress and overload of the proteasomal protein degradation pathway. We tested whether HSPB1-mediated cytoprotective effects involved UPR modulation and improvement of protein degradation via the ubiquitin-proteasome system. We demonstrated that increased levels of HSPB1: attenuated levels of pro-apoptotic proteins like CHOP and BIM, increased protein ubiquitination and the speed of proteasomal protein degradation. Our data showed that HSPB1 induced resistance to proteotoxic stress and thus enhanced cell survival via an increase in beta-cell proteolytic capacity. These results could contribute to generate strategies aiming at optimization of beta-cell replacement therapies.
BRIEF REPORT | doi:10.20944/preprints202102.0110.v1
Subject: Life Sciences, Biochemistry Keywords: ZIKV; Guillain-Barré Syndrome; Molecular Mimicry; Calcium Channel Voltage Dependent; Heat Shock Protein; Vaccine
Online: 3 February 2021 (10:18:18 CET)
Neurological complications of infection by the mosquito-borne Zika virus (ZIKV) include Guillain-Barré syndrome (GBS), an acute inflammatory demyelinating polyneuritis. GBS was first associated with recent ZIKV epidemics caused by the emergence of ZIKV Asian lineage in South Pacific. Here, we hypothesize that ZIKV-associated GBS relates to a molecular mimicry between viral envelope E (E) protein and neural proteins involved in GBS. Analysis of ZIKV epidemic strains showed that glycan loop (GL) region of the E protein includes an IVNDT motif which is conserved in voltage-dependent L-type calcium channel subunit alpha-1C (Cav1.2) and Heat Shock 70 kDa protein 12A (HSP70 12A). Both VSCC-alpha 1C and HSP70 12A belong to protein families which have been associated with neurological autoimmune diseases in central nervous system. The purpose of our in silico analysis is to point out that IVNDT motif of ZIKV E-GL region should be taken in consideration for the development of safe and effective anti-Zika vaccines by precluding the possibility of adverse neurologic events including autoimmune diseases such as GBS.
ARTICLE | doi:10.20944/preprints202004.0297.v1
Subject: Life Sciences, Biophysics Keywords: gold nanoparticle; heat shock protein 70; molecular imaging; biomarker; spectral-CT; k-edge imaging
Online: 17 April 2020 (08:42:18 CEST)
Imaging techniques such as computed tomographies (CT) play a major role in clinical imaging and diagnosis of malignant lesions. In recent years, spectral CT has emerged in the field of computed tomographies, utilizing detailed information from extracted spectral parameters of the specimen. Metal nanoparticle platforms enable effective payload delivery for this technique. Due to the possibility of surface modification, metal nanoparticles are predestined to facilitate molecular tumor targeting. In this work, we demonstrate the feasibility of anti-plasma membrane Heat shock protein 70 functionalized gold nanoparticles (AuNPs) for tumor specific multimodal imaging. Membrane-associated Hsp70 is exclusively presented on the plasma membrane of malignant cells of multiple tumor entities, but not on corresponding normal tissue cells, predestining this target epitope for tumor-selective in vivo targeting. In vitro microscopical analysis revealed the presence of cmHsp70.1-AuNP in the cytosol of tumor cell lines, being internalized via the endosomal-lysosomal pathway. In tumor bearing mice the biodistribution as well as the intratumorally enrichment of AuNP were examined 24h after i.v. application, in vivo. In parallel to spectral CT analysis, histological analysis confirmed the presence of tumor cells. In contrast to control NP, a significant enrichment of cmHsp70.1-AuNPs has been detected selectively in tumors of different preclinical mouse models. Furthermore, the biodistribution of AuNP, following i.v. injection, was analyzed by a machine-learning approach on digitalized slides. In summary, utilizing mHsp70 on tumor cells for guidance of cmHsp70.1 antibody functionalized nanoparticles enables sufficient enrichment and uniform distribution of AuNPs in mHsp70-expressing tumor cells, adequate for various microscopical imaging techniques and spectral-CT-based tumor delineation, in vivo.
ARTICLE | doi:10.20944/preprints201905.0054.v2
Subject: Medicine & Pharmacology, Sport Sciences & Therapy Keywords: acute hamstring muscle complex injury; radial extracorporeal shock wave therapy; rESWT, RSWT; soccer medicine
Online: 14 July 2019 (09:01:08 CEST)
Background: Acute injuries of the hamstring muscle complex (HMC) Type 3b (interfascicle / bundle-tear) are frequently observed in various sports disciplines both in elite and recreational sport. The treatment of choice of acute HMC injuries Type 3b is a progressive physiotherapeutic exercise program. Besides this, there is currently only insufficient scientific evidence to support other treatment methods, including local infiltrations and injections of platelet-rich-plasma. Very recently it was demonstrated that extracorporeal shock wave therapy (ESWT) may accelerate regeneration after acute skeletal muscle injury. The aim of the present study is to test the hypothesis that the combination of radial ESWT (rESWT) and a specific rehabilitation program (RP) is effective and safe in treatment of acute HMC injury Type 3b in athletes, and is statistically significantly more effective than the combination of sham-rESWT and RP. Methods/Design: We will perform a double blind, randomized, sham-controlled clinical trial at the clinic KinEf Kinesiología Deportiva, Ciudad Autónoma de Buenos Aires, Argentina. Fourty patients with acute HMC injury Type 3b will be randomly allocated to receive either rESWT (nine rESWT sessions; three sessions per week; 2500 radial extracorporeal shock waves (rESWs) per session; energy density depending on what the patient tolerates) or sham-rESWT. In addition, all patients will receive a specific rehabilitation program that will last for eight weeks. The primary outcome measure will be the individual time (days) necessary to return to play. Secondary outcomes will include the presence or absence of reinjury during a time period of six months after inclusion into the study. Discussion: Because of the lack of adequate treatment options for acute HMC injury Type 3b in athletes and particularly the high reinjury rate, we hypothesize that the results of this trial will be of importance and have impact on clinical practice. Trial registration: ClinicalTrials.gov ID NCT03473899. Registered March 22, 2018.
ARTICLE | doi:10.20944/preprints201810.0211.v1
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: lipoprotein; extracellular vesicles; exosome; ectosome; stress response; resistant cancer; metastatic cancer; heat shock stress
Online: 10 October 2018 (09:44:17 CEST)
Resistant cancer often shows a particular secretory trait such as heat shock proteins (HSPs) and extracellular vesicles (EVs), including exosomes and oncosomes surrounded by lipid bilayers. Lipoproteins are biochemical assemblies that transport hydrophobic lipid (a.k.a. fat) molecules in body fluid and are composed of a single-layer phospholipid and cholesterol outer shell, lipids molecules within the particles, and apolipoproteins embedded in the membrane. However, lipoprotein storage and secretion by cancer cells have not well-investigated yet. We found lipoproteins were stored and abundantly secreted by neuroendocrine, castration-resistant prostate cancer (NEPC / CRPC) cells but barely secreted by colon cancer cells and oral squamous cell carcinoma (OSCC) cells. In addition, large EVs (approx. 300 nm diameter) and potential oncosomes were released by CRPC and OSCC cells. Proteomics revealed that CRPC cells secreted EVs enriched with tetraspanins and extracellular matrices which were reduced upon heat shock stress and alternatively lipoproteins and HSPs were secreted upon stress. Heat shock stress triggered secretion of lipoprotein-EV complexes that contained apolipoprotein A, B, C and E. These data suggested that vesicular assembly composed of EVs and lipoproteins enriched with cholesterols and phospholipids may be stored in resistant cancer cells but released upon cell stress that is increased in cancer therapies.
REVIEW | doi:10.20944/preprints202110.0168.v1
Subject: Life Sciences, Cell & Developmental Biology Keywords: heat shock proteins; co-chaperones; protein quality control; protein folding; protein degradation; cardioprotection; neuroprotection; cancer
Online: 11 October 2021 (14:38:49 CEST)
Heat shock proteins (HSPs) are a family of molecular chaperones that regulate essential protein refolding and triage decisions to maintaining protein homeostasis. Numerous co-chaperone proteins directly interact and modify the function of HSPs, and these interactions impact the outcome of protein triage, impacting everything from structural proteins to cell signaling mediators. The chaperone/co-chaperone machinery protects against various stressors to ensuring cellular function in the face of stress. However, coding mutations, expression changes, and post-translational modifications of the chaperone/co-chaperone machinery can alter the cellular stress response. Importantly, these dysfunctions appear to contribute to numerous human diseases. Therapeutic targeting of chaperones is an attractive but challenging approach due to the vast functions of HSPs, likely contributing to the off-target effects of these therapies. Current efforts focus on targeting co-chaperones to develop precise treatments for numerous diseases caused by defects in protein quality control. This review focuses on the recent developments regarding selected HSP70/HSP90 co-chaperones, focusing on cardioprotection, neuroprotection, and cancer. We also discuss therapeutic approaches that highlight both the utility and challenges of targeting co-chaperones.
ARTICLE | doi:10.20944/preprints202107.0531.v1
Subject: Biology, Anatomy & Morphology Keywords: A.thaliana; HaloTag; RNA-binding proteins; RNA pulldown assay; RNA-protein complexes; cold shock domain protein
Online: 23 July 2021 (09:32:28 CEST)
Study of RNA-protein interactions and identification of RNA targets are among the key aspects of understanding the RNA biology. Currently, various methods are available to investigate these interactions, in particular, RNA pulldown assay. In the present paper, a method based on the HaloTag technology is presented that is called Halo-RPD (HaloTag RNA PullDown). The proposed protocol uses plants with stable fusion protein expression and the MagneBeads magnetic beads to capture RNA-protein complexes directly from the cytoplasmic lysate of transgenic A. thaliana plants. The key stages described in the paper are as follows: 1) preparation of the magnetic beads 2) tissue homogenization and collection of control samples 3) precipitation and wash of RNA-protein complexes; 4) evaluation of protein binding efficacy; 5) RNA isolation; 6) analysis of the obtained RNA. Recommendations for better NGS assay designs are provided.
ARTICLE | doi:10.20944/preprints202104.0464.v1
Subject: Medicine & Pharmacology, Allergology Keywords: tumor-associated macrophage; exosomes; extracellular vesicles; heat shock proteins; oral cancer; fluorescent labeling of exosomes
Online: 19 April 2021 (11:50:52 CEST)
Tumor-associated macrophages are a key component in the tumor microenvironment, secreting extracellular vesicles (EVs) such as exosomes and other various factors for intercellular communication. However, macrophage-derived EVs heterogeneity and their cytotoxicity to cancer cells has not been well understood. Here, we aimed to separately isolate various types of macro-phage-EVs by size exclusion chromatography (SEC) method and investigate EV transmission and cytotoxicity to oral cancer cells. For fluorescence-labeling of cellular and EV membranes, palmitoylation signal-fused GFP and tdTomato were expressed in THP-1 monocytic cells and HSC-3 oral cancer cells, respectively. We found that fluorescence-labeled EVs secreted by macrophages were highly transmissive to oral cancer cells than those from parental monocytic cells. In a co-culture system and conditioned medium (CM), a macrophage-secreted unidentified factor was cytotoxic to oral cancer cells. We fractionated macrophage-derived EVs by the SEC method and performed western blotting to characterize various EV types. Three fractions were characterized: small exosomes (EXO-S: < 50 nm) fraction containing HSP90α, HSP90β, CD63 (EV marker) and β-actin; large exosomes (EXO-L: 50-200 nm) fraction containing CD9 (EV marker) and HSP90β; large EVs (100-500 nm) fraction. Notably, the macrophage-derived small exosomes fraction was cytotoxic to oral cancer cells, while large exosomes and large EVs were not. There-fore, it was implicated that macrophage-derived small exosomes are cytotoxic with high trans-mission potential to cancer cells.
ARTICLE | doi:10.20944/preprints202102.0138.v1
Subject: Mathematics & Computer Science, Probability And Statistics Keywords: Mean time to failure; Poisson shock; Steady-state availability; Steady-state frequency; Supplementary variable technique.
Online: 4 February 2021 (13:07:59 CET)
This article examines the impact of some system parameters on an industrial system composed of two dissimilar parallel units with one repairman. The active unit may fail due to essential factors like aging or deteriorating, or exterior phenomena such as Poisson shocks that occur at various time periods. Whenever the value of a shock is larger than the specified threshold of the active unit, the active unit will fail. The article assumes that the repairman has the right to take any of two decisions at the beginning of the system operation: either a takes a vacation if the two units work in a normal way, or stay in the system to monitor the system until the first system failure. In case of having a failure in any of the two units during the absence of the repairman, the failing unit will have to wait until the repairman is called back to work. We suppose that the value of every shock is assumed to be i.i.d. with some known distribution. The length of the repairman’s vacation, repair time, and recall time are arbitrary distributions. Various reliability measures have been calculated by the supplementary variable technique and the Markov’s vector process theory. At last, numerical computation and graphical analysis have been given for a particular case to validate the derived indices.
ARTICLE | doi:10.20944/preprints202002.0041.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: geranylgeranyl acetone (GGA); heat shock proteins (Hsps); HT-22 (hippocampal neuronal) cells; mitochondrial membrane potentials
Online: 4 February 2020 (10:24:57 CET)
Geranylgeranyl acetone (GGA) protects against various types of cell damages by upregulating heat shock proteins. We investigated whether GGA protect neuronal cells from cell death induced by oxidative stress. Glutamate exposure was lethal to HT-22 cells which comprise a neuronal line derived from mouse hippocampus. This configuration is often used as a model for hippocampus neurodegeneration in vitro. In the present study, GGA protected HT-22 cells from glutamate-induced oxidative stress. GGA pretreatment did not induce Hsps. Moreover, reactive oxygen species increased to the same extent in both GGA-pretreated and untreated cells exposed to glutamate. In contrast, glutamate exposure and GGA pretreatment increased mitochondrial membrane potential. However, increases in intracellular Ca2+ concentration were inhibited by GGA pretreatment. In addition, the increase of phosphorylated ERKs by the glutamate exposure was inhibited by GGA pretreatment. These findings suggest that GGA protects HT-22 cells from glutamate-provoked cell death without Hsp induction and that the mitochondrial calcium buffering capacity plays an important role in this protective effect.
ARTICLE | doi:10.20944/preprints201701.0091.v1
Subject: Engineering, Mechanical Engineering Keywords: fault diagnosis; shock pulse index; maximum correlated kurtosis deconvolution; teager energy operator; rolling element bearings
Online: 20 January 2017 (04:12:25 CET)
Properties of time domain parameters of the vibration signal have been extensively studied for the fault diagnosis of rolling element bearings (REB). Parameters like kurtosis and Envelope Harmonic-to-Noise Ratio are most widely applied in this field and some important progress has been made. However, since only one-sided information is contained in these parameters respectively, problems still exist in practice when the signals collected are of complicated structure and/or contaminated by strong background noises. A new parameter, named Shock pulse index (SPI), is proposed in this paper. It integrates the mutual advantage of both parameters above and can help effectively identify fault related impulse components under the interference of strong background noises, unrelated harmonic components and random impulses. The SPI optimizes the parameters of Maximum Correlated Kurtosis Deconvolution (MCKD), which is used to filter the signals under consideration. Finally, the interested transient information contained in the filtered signal can be highlighted through demodulation with Teager Energy Operator (TEO). Fault related impulse components can therefore be extracted accurately. Simulations and experiment analyses verify the effectiveness and correctness of the SPI.
REVIEW | doi:10.20944/preprints201611.0060.v1
Subject: Materials Science, Biomaterials Keywords: cell-penetrating peptides (CPPs); reverse-transcriptase-subunit of telomerase (hTERT); GV1001; heat shock protein 90
Online: 11 November 2016 (09:59:30 CET)
Cell-penetrating peptides (CPPs), a group of small peptides capable of promoting the transport of molecular cargo across the plasma membrane, have become important tools in promoting the cellular uptake of exogenously delivered macromolecules. GV1001, a peptide derived from a reverse-transcriptase subunit of telomerase (hTERT) and developed as a vaccine against various cancers, reportedly has unexpected CPP properties. Unlike typical CPPs, such as the HIV-1 TAT peptide, GV1001 enabled the cytosolic delivery of macromolecules such as proteins, DNA and siRNA via extracellular heat shock protein 90 (eHSP90) and 70 (eHSP70) complexes. The eHSP-GV1001 interaction may have biological effects in addition to its cytosolic delivery function. GV1001 was originally designed as a MHC class II-binding cancer epitope, but its CPP properties may contribute to its strong anti-cancer immune response relative to other telomerase peptide-based vaccines. Cell signaling via eHSP-GV1001 binding may lead to unexpected biological effects, such as direct anticancer or antiviral effects. In this review, we focus on the CPP effects of GV1001 bound to eHSP90 and ehsp70.
ARTICLE | doi:10.20944/preprints201701.0105.v1
Subject: Life Sciences, Biotechnology Keywords: magnetic hyperthermia; gene therapies; heat shock protein promoter; in vivo optical imaging; magnetic polymer-coated nanoparticles
Online: 24 January 2017 (04:14:19 CET)
The present work aims to demonstrate that colloidal dispersions of magnetic iron oxide nanoparticles stabilized with dextran macromolecules placed in an alternating magnetic field can not only produce heat, but also that these particles could be used in vivo for local and non-invasive deposition of a thermal dose sufficient to trigger thermo-induced gene expression. Iron oxide nanoparticles were first characterized in vitro on a bio-inspired setup, and then they were assayed in vivo using a transgenic mouse strain expressing the luciferase reporter gene under transcriptional control of a thermosensitive promoter. Iron oxide nanoparticles dispersions were applied topically on the mouse skin or injected sub-cutaneously with Matrigel™ to generate so called pseudo tumors. Temperature was monitored continuously with a feedback loop to control the power of the magnetic field generator and to avoid overheating. Thermo-induced luciferase expression was followed by bioluminescence imaging 6 hours after heating. We showed that dextran-coated magnetic iron oxide nanoparticles dispersions were able to induce in vivo mild hyperthermia compatible with thermo-induced gene expression in surrounding tissues and without impairing cell viability. These data open new therapeutic perspectives for using mild magnetic hyperthermia as non-invasive modulation of tumor microenvironment by local thermo-induced gene expression or drug release.
REVIEW | doi:10.20944/preprints202010.0011.v1
Subject: Keywords: Anterior spinal artery syndrome; Spinal cord Infarction; Aortic insufficiency; Aortic surgery; Spinal shock; Quadriplegia; Bowel-bladder incontinence
Online: 1 October 2020 (09:15:58 CEST)
As an uncommon cause of spinal cord infarction, anterior spinal cord syndrome can manifest with motor paralysis, loss of pain, and temperature sensation distal to the site of the lesion. The main pathogenesis of this syndrome is the disruption of blood flow in the anterior spinal artery. Mortality and morbidity differ with the etiology of the syndrome. So knowing the etiology of blood flow disruption is essential for patient management. This review article highlights the important clinical manifestation of Anterior spinal artery syndrome. Also describes etiology, pathogenesis, diagnosis, prognosis, possible management, and complications.
REVIEW | doi:10.20944/preprints202001.0030.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: histone deacetylase 6 inhibitor; personalized treatment; heat shock protein 90α; leukemia stem cells; imatinib resistance; targeted therapy
Online: 4 January 2020 (06:18:22 CET)
Imatinib became the standard treatment for chronic myeloid leukemia (CML) about 20 years ago, which was a major breakthrough in stabilizing the pathology and improving the quality of life of patients. However, the emergence of resistance to imatinib and other tyrosine kinase inhibitors leads researchers to characterize new therapeutic targets. Several studies have highlighted the role of histone deacetylase 6 (HDAC6) in various pathologies, including cancer. This protein effectively intervenes in cellular activities by its primarily cytoplasmic localization. In this review, we will discuss the molecular characteristics of the HDAC6 protein, as well as its overexpression in CML leukemic stem cells, which make it a promising therapeutic target for the treatment of CML.
REVIEW | doi:10.20944/preprints202107.0367.v1
Subject: Biology, Anatomy & Morphology Keywords: Fever; Beneficial fever; Infections; WHO; Fever Management; Guidelines; Antipyretic; Mortality; Heat Shock; Inflammation; COVID-19; Respiratory diseases; Paracetamol
Online: 16 July 2021 (09:40:35 CEST)
Fever remains an integral part of the acute clinical diseases management, esp. viral, for which effective therapeutics remain desired. However, the presence of often confusing fever reduction recommendations for COVID-19 in the public domain during the pandemic, as late as 28 April 2021, seems to suggest the reduction of any ‘uncomfortable’ fever ranging from 37.8 - 39oC, as opposed to WHO fever reduction guidelines (≥39oC), urgently need attention. The confusion could percolate down into different agencies who look up to these agencies for guidance in framing their own, denying the benefits of fever to populations, and effectively undo whatever successive WHO’s guidelines have achieved in the last two decades. The existence of conflicting guidelines in public domains which are open to interpretations has consequences to public health and the healthcare infrastructure, on implementation. For controlling acute infectious diseases, esp. viral, the fever remains the most important enabler. Historically, our chief obstacles to harnessing the benefits of fever in acute clinical diseases with limited therapeutics had been: a) widespread myths about ‘fevers’ arising from a general misunderstanding of basic facts; b) presence of confusing guidelines by different agencies which are open to alternate interpretation. The article attempts to briefly indicate the benefits of fever in disease resolution, dispel myths, underline vagueness in illustrative national guidelines and the need to align them with evidence-based WHO guidelines, as it has the potential to perpetuate myths/confusion in masses leading to adverse impact on disease management – more morbidity and mortality from diseases including COVID-19.
ARTICLE | doi:10.20944/preprints202012.0579.v1
Subject: Physical Sciences, Acoustics Keywords: Korteweg-de Vries-Burgers equation; cylindrical and spherical waves; saw-tooth solutions; periodic boundary conditions; head shock wave
Online: 23 December 2020 (09:44:50 CET)
For the KdV-Burgers equations on cylindrical and spherical waves the development of a regular profile starting from an equilibrium under a periodic perturbation at the boundary is studied. The equations describe a medium which is both dissipative and dispersive. Symmetries, invariant solutions and conservation laws are investigated. For an appropriate combination of dispersion and dissipation the asymptotic profile looks like a periodical chain of shock fronts with a decreasing amplitude (sawtooth waves). The development of such a profile is preceded by a head shock of a constant height and equal velocity which depends on spatial dimension as well as on integral characteristics of boundary condition; an explicit asymptotic for this head shock and a median of the oscillating part is found.
ARTICLE | doi:10.20944/preprints202009.0713.v1
Subject: Mathematics & Computer Science, Probability And Statistics Keywords: Bivariate family, Kumaraswamy-G family; Marshall and Olkin shock model; maximum likelihood method; parameter induction; T-X family; Weibull distribution
Online: 29 September 2020 (14:33:09 CEST)
For bounded unit interval, we propose a new Kumaraswamy generalized (G) family of distributions from a new generator which could be an alternate to the Kumaraswamy-G family proposed earlier by Cordeiro and de-Castro in 2011. This new generator can also be used to develop alternate G-classes such as beta-G, McDonald-G, Topp-Leone-G, Marshall-Olkin-G and Transmuted-G for bounded unit interval. Some mathematical properties of this new family are obtained and maximum likelihood method is used for estimating the family parameters. We investigate the properties of one special model called a new Kumaraswamy-Weibull (NKwW) distribution. Parameter estimation is dealt and maximum likelihood estimators are assessed through simulation study. Two real life data sets are analyzed to illustrate the importance and flexibility of this distribution. In fact, this model outperforms some generalized Weibull models such as the Kumaraswamy-Weibull, McDonald-Weibull, beta-Weibull, exponentiated-generalized Weibull, gamma-Weibull, odd log-logistic-Weibull, Marshall-Olkin-Weibull, transmuted-Weibull, exponentiated-Weibull and Weibull distributions when applied to these data sets. The bivariate extension of the family is proposed and the estimation of parameters is given. The usefulness of the bivariate NKwW model is illustrated empirically by means of a real-life data set.
ARTICLE | doi:10.20944/preprints202002.0148.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: cell stress response; stressome; extracellular vesicle; heat shock protein 90 (HSP90); cell division control 37 (CDC37); prostate cancer; exosome; ectosome
Online: 11 February 2020 (14:50:14 CET)
Tumor cells exhibit a resistance-associated secretory phenotype involving extracellular vesicles (EVs) and heat shock proteins (HSPs). This response occurs in response to cell stress and cancer therapeutics. HSPs are stress-responsive molecular chaperones promoting proper protein folding, while also being released from cells with EVs as well as in free form as alarmins. We have here investigated the secretory phenotype of castration-resistant prostate cancer (CRPC) cells using proteome analysis. We have also examined the roles of the key co-chaperone CDC37 in stressome release, epithelial-to-mesenchymal transition (EMT), and tumor progression. A number of HSP family members and their common receptor CD91/LRP1 were enriched at high levels in CRPC cell-derived EVs among over 700 other protein species. The small EVs (30 to 200 nm in size, potentially exosomes) were released even in a non-heated condition from the prostate cancer cells, whereas EMT-coupled release of EVs (200 to 500 nm, likely ectosomes) with associated HSP90α was increased after heat shock stress (HSS). Lactate dehydrogenase, a marker of membrane leakage/damage of cells, was also released upon HSS from the prostate cancer cells. During this stress response, intracellular CDC37 was also transcriptionally inducible by heat shock factor 1, and knockdown of CDC37 decreased EMT-coupled release of EVs. Triple knockdown of CDC37, HSP90α, and HSP90β was required for efficient reduction of the chaperone trio and to reduce tumorigenicity of the CRPC cells in vivo. Taken together, the data indicated that CDC37 and HSP90 are essential for stressome release and for tumorigenesis in resistant cancer.
ARTICLE | doi:10.20944/preprints201806.0042.v1
Subject: Biology, Plant Sciences Keywords: epigenetics; H3K9 methylation; H3K4 methylation; DNA methylation; seasonal climate change; summer dormancy; heat shock proteins; ribosomal proteins; Zygophyllum dumosum Boiss
Online: 4 June 2018 (12:49:59 CEST)
Plants thriving in desert environments are suitable for studying mechanisms for plant survival under extreme seasonal climate variation. Zygophyllum dumosum Boiss, like many other Zygophyllaceae species, displays a unique epigenetic mechanism whereby the repressive markers di- and tri-methyl of H3K9 do not exist. We studied epigenetic mechanisms underlying seasonal growth cycles in Z. dumosum and their association with factors regulating basic cell functions. We showed strong association between rainfall and seasonal growth and the epigenetic marker of dimethyl H3K4, which disappears on entry into the dry season and the acquisition of dormant state. DNA methylation is not affected by lack of H3K9 di and tri methyl and changes in methylation pattern are apparent on entry into the dry season. Proteome analysis of acid soluble fractions revealed extensive reduction in ribosomal proteins and in proteins involved in chloroplasts and mitochondria activities during the dry seasons concomitantly with up-regulation of molecular chaperone HSPs. Our results highlight mechanisms underlying Z. dumosum adaptation to seasonal climate variation. Particularly, summer dormancy is associated with loss of the permissive epigenetic marker dimethyl H3K4, which might facilitate genome compaction, concomitantly with significant reduction in proteins involved in basic cell functions (i.e., protein synthesis, photosynthesis and respiration).
REVIEW | doi:10.20944/preprints202205.0037.v1
Subject: Medicine & Pharmacology, Dermatology Keywords: Melanoma; Chemo-thermo-immuno-therapy; Melanogenesis; Magnetite nanoparticle; Drug delivery system; Heat shock protein; In situ vaccine therapy; Immune checkpoint inhibitor
Online: 5 May 2022 (12:23:27 CEST)
A major advance of drug discovery and targeted therapy directed to cancer cells may be achieved by exploitation and immunomodulation of their unique biological property. This re-view summarizes our efforts to develop novel chemo-thermo-immuno-therapy (CTI therapy) by conjugating a melanogenesis substrate, N-propionyl cysteaminylphenol (NPrCAP: amine analog of tyrosine), with magnetite nanoparticles (MNP). In our approach, NPrCAP provides a unique drug delivery system (DDS) because of its selective incorporation into melanoma cells. It also functions as a melanoma-targeted therapeutic drug because of its production of highly reactive free radicals (melanoma-targeted chemotherapy). Moreover, utilization of MNP is a platform to develop thermo-immunotherapy because of heat shock protein (HSP) generation upon exposure to an alternating magnetic field (AMF). The feasibility of our approach was successfully shown in experimental in vivo and in vitro mouse melanoma models and in preliminary clinical trials to a limited number of advanced melanoma patients.
REVIEW | doi:10.20944/preprints201908.0186.v1
Subject: Life Sciences, Immunology Keywords: heat shock protein (HSP); extracellular vesicle (EV); exosome; oncosome; immune evasion; resistance-associated secretory phenotype (RASP); EMT; hypoxia; biomarker; liquid biopsy
Online: 17 August 2019 (16:15:01 CEST)
Extracellular vesicles (EV) released by tumor cells are a major aspect of the resistance-associated secretory phenotype (RASP), by which immune evasion can be established. Heat shock proteins (HSPs) are an evolutionarily conserved family of molecular chaperones, which stabilize proteins, minimize protein misfolding and aggregation within the cell, besides facilitating protein translocation, refolding and degradation. (i) Releases of extracellular HSPs (ex-HSP) and EV-associated HSPs (EV-HSP) are essential in RASP, by which molecular cotransfer of HSPs with oncogenic factors into recipient cells can promote cancer progression and resistance against stress such as hypoxia, radiation, chemicals, and immune system. (ii) RASP of tumor cells can eject anticancer drugs, molecularly targeted therapeutics, and immune checkpoint inhibitors with EVs. (iii) Cytotoxic lipids can be also released from tumor cells as RASP. Nevertheless, ex-HSP and EV-HSP can play immunostimulatory and immunosuppressive roles by binding to receptors such as LRP1/CD91/A2MR, scavenger receptors, and toll-like receptors expressed on recipient cells. Liquid biopsy of HSPs in body fluids may be useful in diagnosis, prognosis, and treatment in cancer. Regarding HSP90-targeted therapeutics, we summarize the pros, cons, and problem solutions in this review. Although production of HSPs are canonically induced by heat shock factor 1 (HSF1) and hypoxia-inducible factor 1 (HIF-1), recent studies discovered that production of HSPs is also regulated by matrix metalloproteinase 3 (MMP3) and heterochromatin protein 1 (HP1) and production of cochaperone CDC37 is reciprocally regulated by myeloid zinc finger 1 (MZF1) and SCAN-D1.
ARTICLE | doi:10.20944/preprints202206.0242.v1
Subject: Biology, Other Keywords: nerve repair; median nerve; rat; autologous nerve graft; muscle-in-vein conduit; extracorporeal shock wave therapy; grasping test; gait analysis; CatWalk, nerve regeneration
Online: 17 June 2022 (03:17:43 CEST)
Investigations reporting positive effects of Extracorporeal Shock Wave Therapy (ESWT) on nerve regeneration are limited to the rat sciatic nerve model. The effects of ESWT on muscle-in-vein conduits (MVCs) have also not been investigated yet. This study aimed to evaluate the effects of ESWT after repair of the rat median nerve with either autografts (ANGs) or MVCs. In male Lewis rats, a 7-mm segment of the right median nerve was reconstructed either with an ANG or MVC. For each reconstructive technique, one group of animals received one application of ESWT while the other rats served as controls. Animals were observed for 12 weeks and nerve regeneration was assessed via computerized gait analysis, the grasping test, electrophysiological evaluations and histological quantification of axons, blood vessels and lymphatic vasculature. Here we provide for the first time a comprehensive analysis of ESWT effects on nerve regeneration in a rat model of median nerve injury. Furthermore, this study is among the first reporting the quantification of lymphatic vessels following peripheral nerve injury and reconstruction in vivo. While we found no significant direct positive effects of ESWT on peripheral nerve regeneration, results following nerve repair with MVCs were significantly inferior to those after ANG repair.
REVIEW | doi:10.20944/preprints201912.0386.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: resistance-associated secretory phenotype (RASP); extracellular vesicle (EV); exosome; oncosome; drug resistance; epithelial-mesenchymal transition (EMT); heat shock protein (HSP); cell stress response; hypoxia; acidosis; tumor immunology
Online: 29 December 2019 (13:46:21 CET)
Extracellular vesicles (EVs), such as exosomes or oncosomes are released with molecules unfavorable for survival from cells. In addition, accumulating evidence has shown that tumor cells often eject anti-cancer drugs such as chemotherapeutics and targeted drugs within EVs, a novel mechanism of drug resistance. The EV-releasing, drug resistance phenotype is often coupled with cellular dedifferentiation and transformation, cells undergoing epithelial-mesenchymal transition (EMT) and taking on a cancer stem cell phenotype. Recent studies have shown that the release of EVs is also involved in immunosuppression. The concept of the resistance-associated secretory phenotype (RASP) is reviewed herein.
REVIEW | doi:10.20944/preprints201903.0108.v1
Subject: Life Sciences, Cell & Developmental Biology Keywords: Nucleolar sequestration, nucleolus, physiological amyloids, ribosomal intergenic spacer, rIGSRNA, liquid-liquid phase separation, liquid-to-solid phase transition, complex coacervation, biomolecular condensates, beta-amyloid, MDM2, VHL, Cdc14, low complexity RNA, acidosis, heat shock
Online: 8 March 2019 (15:12:29 CET)
This year marks the 20th anniversary of the discovery that proteins with various cellular functions can be temporarily immobilized in the nucleolus, a process known as nucleolar sequestration. This review reflects on the progress made to understand the physiological roles of nucleolar sequestration and the mechanisms involved in protein immobilization. We discuss how nucleolar sequestration consists of a highly choreographed amyloidogenic liquid-to-solid phase transition that converts the nucleolus into Amyloid bodies (A-bodies). The study of solid condensates A-bodies will offer unique perspectives on cellular assembly of membrane-less compartments and provide alternative insights on pathological amyloidogenesis involved in neurological disorders.