Conservative method for vertical electrooculogram attenuation based on local suppression of ongoing EEG artifact templates.

Eye movement during blinking can be a significant artifact in Event-Related Potentials (ERP) analysis. Blinks produce a positive potential in the vertical electrooculogram (VEOG), spreading towards the posterior direction. Two methods are frequently used to suppress VEOGs: linear regression to subtract the VEOG signal from the electroencephalogram (EEG) and Independent Component Analysis (ICA). However, some information is lost in both. The present algorithm (1) statistically identifies the position of VEOGs in the frontopolar channels; (2) performs EEG averaging for each channel, which results in 'blink templates'; (3) subtracts each template from the respective EEG at each VEOG position, only when the linear correlation index between the template and the segment is greater than a chosen threshold L. The signals from twenty subjects were acquired using a behavioral test and were treated using FilterBlink for subsequent ERP analysis. A model was designed to test the method for each subject using twenty copies of the EEG signal from the subject's mid-central channel (with nearly no VEOG) representing the EEG channels and their respective blink templates. At the same 200 equidistant time points (marks), a signal (2.5 sinusoidal cycles at 1050 ms emulating an ERP) was mixed with each model channel and the respective blink template of that channel, between 500 to 1200 ms after each mark. According to the model, VEOGs interfered with both ERPs and the ongoing EEG, mainly on the anterior medial leads, and no significant effect was observed on the mid-central channel (Cz). FilterBlink recovered approximately 90% (Fp1) to 98% (Fz) of the original ERP and EEG signals for L = 0.1. The method reduced the VEOG effect on the EEG after ERP and blink-artifact averaging in analyzing real signals. The method is straightforward and effective for VEOG attenuation without significant distortion in the EEG signal and embedded ERPs.

High-sensitivity and high-speed measurements of ultrashort pulses as short as 74 fs at 1.9 µm using a GRENOUILLE device.

Ultrashort laser pulse sources in the wavelength range of 1.8 to 2 µm have many potential applications including medicine, materials processing, and sensing. In the use of such lasers, a crucial task is to measure their pulse's temporal intensity and phase. Such measurement devices are most useful when they are simple to build and operate and also have high speed and high sensitivity. The GRENOUILLE measurement device with few components, no moving parts, sensitivity of hundreds of picojoules, and measurement speed of hundreds of milliseconds, is commonly used to solve this problem at other wavelengths. In this paper, the measurement of ultrashort pulses by a GRENOUILLE device, developed using a silicon matrix sensor, for pulses in the wavelength range of 1.8 to 2 µm has been demonstrated. It is shown that ultrashort pulses with durations of 74 to 900 fs and a maximum spectral FWHM of 85 nm can be measured with this device. The recently developed ultra-reliable RANA approach was used for pulse retrieval from the measured traces. The device's performance was validated by comparing its measurements with those obtained by the robust FROG technique.

Laser induced damage threshold of GaSe with antireflection microstructures at a wavelength of 5 µm.

Large GaSe crystals were grown and various antireflection microstructures (ARMs) were fabricated on their cleaved surfaces using optimized femtosecond laser ablation, which provided the antireflection effect in a wide wavelength range of 4-16 µm. The influence of ARMs created on the GaSe surface on the change of the laser-induced damage threshold (LIDT) of the crystal at a wavelength of 5 µm was evaluated. The 5-µm Fe:ZnMgSe laser with the pulse duration of 135 ns was used for the LIDT test in conditions close to single pulse exposure. The measured values of LIDT of 56 ± 6 MW/cm2 and 51 ± 9 MW/cm2 for two GaSe substrates, respectively, were comparable with the known data of single pulse LIDT of GaSe. The average LIDT intensities of 54 ± 6 MW/cm2 and 52 ± 7 MW/cm2 for the ARMs at two GaSe plates, respectively, were close to LIDT intensities for the corresponding GaSe substrates. The ARMs with lower structural quality had lower LIDT (50-52 MW/cm2) in comparison with the high-quality ARMs (58-60 MW/cm2). High LIDT for high-quality ARMs can be caused by increased selenium content in the ARMs. In any case, all the tested ARMs on the GaSe plates with different surface quality are workable for development of widely tunable mid-infrared nonlinear optical converters.

Novel mechanism of drug resistance triggered by tumor-associated macrophages through Heat Shock Factor-1 activation.

Macrophages constitute a major part of tumor microenvironment, and most of existing data demonstrate their ruling role in the development of anti-drug resistance of cancer cell. One of the most powerful protection system is based on heat shock proteins whose synthesis is triggered by activated Heat Shock Factor-1 (HSF1); the inhibition of the HSF1 with CL-43 sensitized A549 lung cancer cells to the anti-cancer effect of etoposide. Notably, analyzing A549 tumor xenografts in mice we observed nest-like pattern of co-localization of A549 cells demonstrating enhanced expression of HSF1 with macrophages, and decided to check whether the above arrangement has a functional value for both cell types. It was found that the incubation of A549 or DLD1 colon cancer cells with either human monocytes or THP1 monocyte-like cells activated HSF1 and increased resistance to etoposide. Importantly, the same effect was shown when primary cultures of colon tumors were incubated with THP1 cells or with human monocytes. To prove that HSF1 is implicated in enhanced resistance caused by monocytic cells, we generated an A549 cell subline devoid of HSF1 which did not respond to incubation with THP1 cells. The pharmacological inhibition of HSF1 with CL-43 also abolished the effect of THP1 cells on primary tumor cells, highlighting a new target of tumor-associated macrophages in a cell proteostasis mechanism.

Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex.

BACKGROUND: Cancer recurrence is regulated by a variety of factors, among which is the material of dying tumor cells; it is suggested that remaining after anti-cancer therapy tumor cells receive a signal from proteins called damage-associated molecular patterns (DAMPs), one of which is heat shock protein 70 (Hsp70). METHODS: Two models of tumor repopulation were employed, based on minimal population of cancer cells and application of conditioned medium (CM). To deplete the CMs of Hsp70 affinity chromatography on ATP-agarose and immunoprecipitation were used. Cell proliferation and the dynamics of cell growth were measured using MTT assay and xCELLigence technology; cell growth markers were estimated using qPCR and with the aid of ELISA for prostaglandin E detection. Immunoprecipitation followed by mass-spectrometry was employed to identify Hsp70-binding proteins and protein-protein interaction assays were developed to reveal the above protein complexes. RESULTS: It was found that CM of dying tumor cells contains tumor regrowth-initiating factors and the removal of one of them, Hsp70, caused a reduction in the relapse-activating capacity. The pull out of Hsp70 alone using ATP-agarose had no effect on repopulation, while the immunodepletion of Hsp70 dramatically reduced its repopulation activity. Using proteomic and immunochemical approaches, we showed that Hsp70 in conditioned medium binds and binds another abundant alarmin, the High Mobility Group B1 (HMGB1) protein; the complex is formed in tumor cells treated with anti-cancer drugs, persists in the cytosol and is further released from dying tumor cells. Recurrence-activating power of Hsp70-HMGB1 complex was proved by the enhanced expression of proliferation markers, Ki67, Aurka and MCM-10 as well as by increase of prostaglandin E production and autophagy activation. Accordingly, dissociating the complex with Hsp70 chaperone inhibitors significantly inhibited the pro-growth effects of the above complex, in both in vitro and in vivo tumor relapse models. CONCLUSIONS: These data led us to suggest that the abundance of the Hsp70-HMGB1 complex in the extracellular matrix may serve as a novel marker of relapse state in cancer patients, while specific targeting of the complex may be promising in the treatment of cancers with a high risk of recurrence.

Protein Interactome of Amyloid-ß as a Therapeutic Target.

The amyloid concept of Alzheimer's disease (AD) assumes the ß-amyloid peptide (Aß) as the main pathogenic factor, which injures neural and other brain cells, causing their malfunction and death. Although Aß has been documented to exert its cytotoxic effect in a solitary manner, there is much evidence to claim that its toxicity can be modulated by other proteins. The list of such Aß co-factors or interactors includes tau, APOE, transthyretin, and others. These molecules interact with the peptide and affect the ability of Aß to form oligomers or aggregates, modulating its toxicity. Thus, the list of potential substances able to reduce the harmful effects of the peptide should include ones that can prevent the pathogenic interactions by specifically binding Aß and/or its partners. In the present review, we discuss the data on Aß-based complexes in AD pathogenesis and on the compounds directly targeting Aß or the destructors of its complexes with other polypeptides.

Diffuse reflectance spectroscopy of the cartilage tissue in the fourth optical window.

Studies of the optical properties of biological tissues in the infrared range have demonstrated significant potential for diagnostic tasks. One of the insufficiently explored ranges for diagnostic problems at the moment is the fourth transparency window, or short wavelength infrared region II (SWIR II). A Cr2+:ZnSe laser with tuning capability in the range from 2.1 to 2.4 µm was developed to explore the possibilities in this region. The capability of diffuse reflectance spectroscopy to analyze water and collagen content in biosamples was investigated using the optical gelatin phantoms and the cartilage tissue samples during their drying process. It was demonstrated that decomposition components of the optical density spectra correlated with the partial content of the collagen and water in the samples. The present study indicates the possibility of using this spectral range for the development of diagnostic methods, in particular, for observation of the changes in the content of cartilage tissue components in degenerative diseases such as osteoarthritis.

Antireflection microstructures fabricated on the surface of a LiGaSe2 nonlinear crystal.

LiGaSe2 is a propitious material for nonlinear parametric conversion in the mid-infrared (mid-IR) range. Its refractive index of n = 2.25 in the 2-12 µm wavelength range results in significant losses due to Fresnel reflection. However, the conventional method of increasing the transmittance with antireflection coatings (ARCs) significantly reduces the damage threshold of the material. Fabrication of the antireflection microstructures (ARMs) is an alternative approach for increasing the surface transmittance. In this work, ARMs were fabricated on the surface of a LiGaSe2 crystal using a single-pulse femtosecond laser ablation method. An average transmittance of 97.2% in the 2-8 µm spectral range and the maximum transmittance of 98.6% at 4.1 µm were achieved.

Grading cartilage damage with diffuse reflectance spectroscopy: Optical markers and mechanical properties.

Osteoarthritis (OA) is one of the most common joint diseases worldwide. Unfortunately, clinical methods lack the ability to detect OA in the early stages. Timely detection of the knee joint degradation at the level of tissue changes can prevent its progressive damage. Here, diffuse reflectance spectroscopy (DRS) in the NIR range was used to obtain optical markers of the cartilage damage grades and to assess its mechanical properties. It was observed that the water content obtained by DRS strongly correlates with the cartilage thickness (R = .82) and viscoelastic relaxation time (R = .7). Moreover, the spectral parameters, including water content (OH-band), protein content (CH-band), and scattering parameters allowed for discrimination between the cartilage damage grades (10-4 < P ≤ 10-3 ). The developed approach may become a valuable addition to arthroscopy, helping to identify lesions at the microscopic level in the early stages of OA and complement the surgical analysis.

Indolylazine Derivative Induces Chaperone Expression in Aged Neural Cells and Prevents the Progression of Alzheimer's Disease.

The risk of progression of most sporadic neurodegenerative diseases, including Alzheimer's disease, increases with age. Traditionally, this is associated with a decrease in the efficiency of cell protection systems, in particular, molecular chaperones. Thus, the development of small molecules able to induce the synthesis of chaperones is a promising therapeutic approach to prevent neural diseases associated with ageing. Here, we describe a new compound IA-50, belonging to the class of indolylazines and featured by a low size of topological polar surface area, the property related to substances with potentially high membrane-penetrating activity. We also estimated the absorption, distribution, metabolism and excretion characteristics of IA-50 and found the substance to fit the effective drug criteria. The new compound was found to induce the synthesis and accumulation of Hsp70 in normal and aged neurons and in the hippocampi of young and old mice. The transgenic model of Alzheimer's disease, based on 5xFAD mice, confirmed that the injection of IA-50 prevented the formation of ß-amyloid aggregates, loss of hippocampal neurons and the development of memory impairment. These data indicate that this novel substance may induce the expression of chaperones in neural cells and brain tissues, suggesting its possible application in the therapy of ageing-associated disorders.

Mismatch Negativity is associated with affective social behavior in microcephaly.

Some children with severe microcephaly related to Zika virus infection show affective social-like behavior, such as smiling and rejection to a stranger's lap. Our objective was to check the association between this behavior and the occurrence of Mismatch Response (MMR) in event-related potentials. Twenty eight microcephalic children, aged 1-3 years, were divided in Affect(+) and Affect(-) groups, according to either the presence or absence of affective social-like behavior, respectively, and underwent the OddBall paradigm with vowels as auditory stimuli. MMR was statistically estimated comparing MMR sample means between both groups. The Affect(+) group significantly differed from the Affect(-) group and, as opposed to the latter, showed MMR as Mismatch Negativity (MMN) in the left occipital, left and right posterior temporal, and (especially) the right and median parietal leads. The relationship observed between MMN and affective social-like behavior suggests that these children may have cognitive mechanisms capable of providing some social interaction, despite their profound neurological dysfunction. MMN diagnostic techniques seem to be promising for the triage of microcephalic subjects regarding cognitive functions and for choosing a strategy for some social adaptation.

Combination of a Chaperone Synthesis Inducer and an Inhibitor of GAPDH Aggregation for Rehabilitation after Traumatic Brain Injury: A Pilot Study.

The recovery period after traumatic brain injury (TBI) is often complicated by secondary damage that may last for days or even months after trauma. Two proteins, Hsp70 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), were recently described as modulating post-traumatic processes, and in this study, we test them as targets for combination therapy using an inhibitor of GAPDH aggregation (derivative of hydrocortisone RX624) and an inducer of Hsp70 synthesis (the pyrrolylazine derivative PQ-29). The protective effect of the combination on C6 rat glioblastoma cells treated with the cerebrospinal fluid of traumatized animals resulted in an increase in the cell index and in a reduced level of apoptosis. Using a rat weight drop model of TBI, we found that the combined use of both drugs prevented memory impairment and motor deficits, as well as a reduction of neurons and accumulation of GAPDH aggregates in brain tissue. In conclusion, we developed and tested a new approach to the treatment of TBI based on influencing distinct molecular mechanisms in brain cells.

All-fiber ultrafast amplifier at 1.9 µm based on thulium-doped normal dispersion fiber and LMA fiber compressor.

The duration reduction and the peak power increase of ultrashort pulses generated by all-fiber sources at a wavelength of [Formula: see text] are urgent tasks. Finding an effective and easy way to improve these characteristics of ultrafast lasers can allow a broad implementation of wideband coherent supercontinuum sources in the mid-IR range required for various applications. As an alternative approach to sub-100 fs pulse generation, we present an ultrafast all-fiber amplifier based on a normal-dispersion germanosilicate thulium-doped active fiber and a large-mode-area silica-fiber compressor. The output pulses have the following characteristics: the central wavelength of [Formula: see text], the repetition rate of 23.8 MHz, the energy per pulse period of 25 nJ, the average power of 600 mW, and a random output polarization. The pulse intensity and phase profiles were measured via the second-harmonic-generation frequency-resolved optical gating technique for a linearly polarized pulse. The linearly polarized pulse has a duration of 71 fs and a peak power of 128.7 kW. The maximum estimated peak power for all polarizations is 220 kW. The dynamics of ultrashort-pulse propagation in the amplifier were analyzed using numerical simulations.

Dataset of NMR-spectra pyrrolyl- and indolylazines and evidence of their ability to induce heat shock genes expression in human neurons.

These data are related to our previous paper "Synthesis and approbation of new neuroprotective chemicals of pyrrolyl- and indolylazine classes in a cell model of Alzheimer's disease" (Dutysheva et al., 2021), in which we demonstrate neuroprotective abilities of pyrrolyl- and indolylazines in a cell model of Alzheimer's disease. Using a novel procedure of photocatalysis we have synthesized a group of new compounds. The current article presents nuclear magnetic resonance spectra including heteronuclear single quantum coherence spectra of chemicals synthesized by us. The effect of new compounds have on heat shock proteins genes expression in reprogrammed human neurons are presented. We also presented data that verify neuronal phenotype of reprogrammed cells.

Extracellular GAPDH Promotes Alzheimer Disease Progression by Enhancing Amyloid-ß Aggregation and Cytotoxicity.

Neuronal cell death at late stages of Alzheimer's disease (AD) causes the release of cytosolic proteins. One of the most abundant such proteins, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), forms stable aggregates with extracellular amyloid-ß (Aß). We detect these aggregates in cerebrospinal fluid (CSF) from AD patients at levels directly proportional to the progressive stages of AD. We found that GAPDH forms a covalent bond with Q15 of Aß that is mediated by transglutaminase (tTG). The Q15A substitution weakens the interaction between Aß and GAPDH and reduces Aß-GAPDH cytotoxicity. Lentivirus-driven GAPDH overexpression in two AD animal models increased the level of apoptosis of hippocampal cells, neural degeneration, and cognitive dysfunction. In contrast, in vivo knockdown of GAPDH reversed these pathogenic abnormalities suggesting a pivotal role of GAPDH in Aß-stimulated neurodegeneration. CSF from animals with enhanced GAPDH expression demonstrates increased cytotoxicity in vitro. Furthermore, RX-624, a specific GAPDH small molecular ligand reduced accumulation of Aß aggregates and reversed memory deficit in AD transgenic mice. These findings argue that extracellular GAPDH compromises Aß clearance and accelerates neurodegeneration, and, thus, is a promising pharmacological target for AD.

Synthesis and approbation of new neuroprotective chemicals of pyrrolyl- and indolylazine classes in a cell model of Alzheimer's disease.

One of the major causes of neurodegeneration in the pathogenesis of Alzheimer's disease is the accumulation of cytotoxic amyloid species within the intercellular compartments of the brain. The efficacy of the anti-proteotoxic mechanism based on the molecular chaperones Hsp70 and Hsp90 in numerous types of neurons is often low, while its pharmacological enhancement has been shown to ameliorate the physiological and cognitive functions of the brain. Suggesting that the chemicals able to induce heat shock protein synthesis and therefore rescue neural cells from cytotoxicity associated with amyloid, we have synthesized a group of pyrrolyl- and indolylazines that cause the accumulation of heat shock proteins, using a novel method of photocatalysis that is employed in green chemistry. The selected compounds were tested in a cell model of Alzheimer's disease and demonstrated a pronounced neuroprotective effect. These substances increased the survival of neurons, blocked the activation of ß-galactosidase, and prevented apoptosis in neurons cultured in the presence of ß-amyloid.

Speed characterization of p-i-n photodiode based on GaSb/GaInAsSb/GaAlAsSb heterostructure with frontal bridge contact at 1.9 µm.

We report a study of the response function parameters (amplitude and rise/fall time) of a high-speed GaSb/GaInAsSb/GaAlAsSb photodiode operating at 1.9 µm as a function of optical input power and reverse bias voltage. The experimental measurement results yield the optimal pulse energy and optimal reverse bias voltage for the photodiode. The 44 ps minimal rise time of the response function and 3.6 GHz bandwidth are achieved under a 3 V reverse bias voltage and pulse energy in the 0.27-2.5 pJ range.

Disruption of the Complex between GAPDH and Hsp70 Sensitizes C6 Glioblastoma Cells to Hypoxic Stress.

Hypoxia, which commonly accompanies tumor growth, depending on its strength may cause the enhancement of tumorigenicity of cancer cells or their death. One of the proteins targeted by hypoxia is glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and we demonstrated here that hypoxia mimicked by treating C6 rat glioblastoma cells with cobalt chloride caused an up-regulation of the enzyme expression, while further elevation of hypoxic stress caused the enzyme aggregation concomitantly with cell death. Reduction or elevation of GAPDH performed with the aid of specific shRNAs resulted in the augmentation of the tumorigenicity of C6 cells or their sensitization to hypoxic stress. Another hypoxia-regulated protein, Hsp70 chaperone, was shown to prevent the aggregation of oxidized GAPDH and to reduce hypoxia-mediated cell death. In order to release the enzyme molecules from the chaperone, we employed its inhibitor, derivative of colchicine. The compound was found to substantially increase aggregation of GAPDH and to sensitize C6 cells to hypoxia both in vitro and in animals bearing tumors with distinct levels of the enzyme expression. In conclusion, blocking the chaperonic activity of Hsp70 and its interaction with GAPDH may become a promising strategy to overcome tumor resistance to multiple environmental stresses and enhance existing therapeutic tools.

Fabrication of antireflection microstructures on the surface of GaSe crystal by single-pulse femtosecond laser ablation.

GaSe crystals are promising as nonlinear optical converters in the mid- and far-IR ranges. However, it is challenging to increase the GaSe surface transmittance of 77% with conventional antireflection coatings because of poor surface quality, leading to coating adhesion problems. Antireflection microstructures (ARMs) offer an alternative way of increasing surface transmittance. In this work, ARMs were fabricated on the surface of a GaSe plate by single-pulse femtosecond laser ablation. An average GaSe surface transmittance of 94% in the 7-11 µm range and a maximum transmittance of 97.8% at 8.5 µm were obtained. The proposed method can be used to increase the efficiency of GaSe-based nonlinear converters.