Secondary Changes Research Articles

Mitigation of the Deleterious Effect of Heavy Metals on the Conformational Stability of Ubiquitin through Osmoprotectants.

The Ubiquitin-Proteasome System (UPS) is important in protein homeostasis and is involved in many cell processes. UPS's wide range of regulatory activities is based on the unique and diverse signals transmitted through all-encompassing processes. Cells need a fully functional UPP to cope with oxidative stress, so cellular redox status modulates ubiquitin activity. However, these protein quality control systems are compromised under adverse conditions such as heavy metal stress, resulting in pathological conditions. Heavy metals disrupt the physiological action of sensitive proteins by forming complexes with side-chain functional groups or by dislocating critical metal ions in metalloproteins. In addition, perturbation in the structure of Ubiquitin may affect the ubiquitin-proteasome pathway. In this study, it has been investigated the effects of heavy metals likewise chromium (Cr), cadmium (Cd), and mercury chloride (HgCl2) on the conformational stability of Ubiquitin as well as overcome their hazardous effect, the interaction of osmo-protectants such as Sesamol, gallic acid, Glycine, and ascorbic acid have also been explored in the study. The near and far UV-circular dichroism measurements deduced the secondary and tertiary structural changes. The size of the Ubiquitin before and after exposure to heavy metals was measured by DLS (dynamic light scattering). Docking research was also used to investigate the interaction of Ubiquitin with various heavy metals. Near and far UV-circular dichroism (CD) measurements revealed that mercury, chromium, and cadmium disrupt Ubiquitin's secondary and tertiary structure. The effect of chromium, even at low concentrations, was significantly deleterious compared to cadmium and mercury chloride. Ubiquitin's far-UV circular dichroism spectra subjected to heavy metals were recorded in several osmo-protectants, such as ascorbic acid, Glycine, gallic acid, and Sesamol, which offset the adverse effects of heavy metals. DLS studies revealed a noteworthy change in the hydrodynamic radius of Ubiquitin in the presence of heavy metals. Docking analysis revealed a significant binding affinity of mercury and cadmium ions with Ubiquitin. This study can infer the heavy metals' disruption of Ubiquitin's secondary and tertiary structure. Osmo-protectants produced by animal cells are more effective against heavy metals than plant antioxidants.

Effects of stevia extract on production performance, serum biochemistry, antioxidant capacity, and gut health of laying hens

In the present study, we aimed to elucidate the effects of stevia extract on production performance, serum immune indexes, intestinal structure, and cecum microbial structure. We randomly divided eight hundred 46-wk-old Roman hens into 5 groups, with 8 replicates in each group and 20 chickens in each replicate. The control group was fed a basal diet, whereas the 4 experimental groups were fed 50, 100, 200, and 400 mg/kg stevia extracts. The study period was 24 wk. The addition of different concentrations of the stevia extract to the diet resulted in significant secondary changes in the egg production rate at 1 to 12 wk (P < 0.05). Furthermore, the addition of 50 and 100 mg/kg stevia extract to the diet significantly increased serum IgM and IgG levels in laying hens (P < 0.05) but linearly decreased serum IL-1β levels (P < 0.05). Serum T-SOD activity linearly increased (P=0.057); however, serum biochemical indexes showed no significant differences. Stevia extract tended to increase the ratio of the duodenal villi height to the depth of the crypt (P=0.067), with no obvious lesions in the duodenum, jejunum, and ileum. In addition, stevia extract increased the relative abundance of species at the phylum level, with the abundance of Bacteroides and Firmicutes exhibiting significant secondary changes (P < 0.05). The ACE and Chao1 indexes suggested that stevia extract addition significantly increased the alpha diversity of cecum microorganisms in laying hens. Furthermore, NMDS analysis based on operational taxonomic units revealed that stevia extract addition increased the beta diversity of cecum microorganisms in laying hens. Adding a certain amount of stevia extract to feed can improve the production performance, immune ability, and intestinal health of laying hens to some extent, and we recommend an effective level of 200mg/kg of stevia extract for laying hen diets.

Structure, aggregation dynamics and crystallization of superfolder green fluorescent protein: Effect of long alkyl chain imidazolium ionic liquids

Green fluorescent protein (GFP) and its variants are widely used in medical and biological research, especially acting as indicators of protein structural integrity, protein-protein interactions and as biosensors. This study employs superfolder GFP (sfGFP) to investigate the impact of varying alkyl chain length of 1-Cn-3-methylimidazolium chloride ionic liquid (IL) series ([Cnmim]Cl, n = 2, 4, 6, 8, 10, 12) on the protein fluorescence, structure, hydration, aggregation dynamics and crystallization behaviour. The results revealed a concentration-dependent decrease in the sfGFP chromophore fluorescence, particularly in long alkyl chain ILs ([C10mim]Cl and [C12mim]Cl). Tryptophan (Trp) fluorescence showed the quenching rate increased with longer alkyl chains indicating a nonpolar interaction between Trp57 and the alkyl chain. Secondary structural changes were observed at the high IL concentration of 1.5 M in [C10mim]Cl and [C12mim]Cl. Small-angle X-ray scattering (SAXS) indicated relatively stable protein sizes, but with IL aggregates present in [C10mim]Cl and [C12mim]Cl solutions. Dynamic light scattering (DLS) data showed increased protein size and aggregation with longer alkyl chain ILs. Notably, ILs and salts, excluding [C2mim]Cl, promoted sfGFP crystallization. This study emphasizes the influence of the cation alkyl chain length and concentration on protein stability and aggregation, providing insights into utilizing IL solvents for protein stabilization and crystallization purposes.

Functional activity of the maxillofacial region muscles in children with arthrogryposis multiple congenita

BACKGROUND: Disorders of the maxillofacial region in children with аrthrogryposis multiplex congenita can be congenital or occur as secondary changes. The lower jaw and associated muscles play important roles in the functioning and development of the maxillofacial region. In children with аrthrogryposis multiplex congenita, the functional activity of the muscles of the maxillofacial region has not been studied.&#x0D; AIM: To estimate the functional activity of the muscles of the maxillofacial region in children with аrthrogryposis multiplex congenita.&#x0D; MATERIALS AND METHODS: Surface electromyography was used to examine the masticatory and facial muscles of 47 children aged 317 years with arthrogryposis (main group) and 20 healthy children with orthognathic bite (control group). The main and control groups were examined by a dentist and had not previously received orthodontic treatment. The bioelectric activities of the temporalis and masseter muscles on the right and left sides were simultaneously registered at rest and during functional tests (opening of the mouth, moving the lower jaw forward, jaw compression, and chewing). The average activity amplitudes were taken into account, and asymmetry coefficients were calculated. The obtained data are statistically processed.&#x0D; RESULTS: Electromyography results, according to different functional tests, revealed disorders in 65%88% of children with аrthrogryposis multiplex congenita. In all samples, the tonic activity of the masticatory muscles increased at rest, the amplitude of the activity of masseter and temporalis muscles decreased, signs of an imbalance of the masticatory muscles such as the hyperactivation of the temporalis muscle compared with the masseter muscle with jaw compression and chewing were noted, and muscle asymmetry indices increased. The frequency and degree of functional muscle disorders prevailed in children with deciduous and temporary occlusion.&#x0D; CONCLUSIONS: Arthrogryposis multiplex congenita in children is characterized by a high frequency of impaired functional activity of the muscles of the maxillofacial region, which can negatively affect bite formation, chewing function, and articulation.

Resection of Traumatic Triradiate Bar Led To Restored Triradiate Growth

Case: A 2-year-old boy suffered an injury to the acetabular physis resulting in the formation of an osseus bar across all 3 limbs of the triradiate, growth arrest, and secondary hip dysplasia. This condition was treated with bony bar resection using an anterior intrapelvic approach. Over a follow-up period of more than 3 years, there was notable restoration of triradiate cartilage growth. Conclusion: Our case demonstrates that resection of a triradiate bar can be an effective treatment of premature traumatic triradiate closure. Early recognition and intervention are preferable before secondary changes in the acetabulum have fully developed.

Infrared spectroscopy analysis determining secondary structure change in albumin by cerium oxide nanoparticles.

Cerium oxide (CeO2) nanoparticles are expected to have applications in the biomedical field because of their antioxidative properties. Inorganic nanoparticles interact with proteins at the nanoparticle surface and change their conformation when administered; however, the principle underlying this interaction is still unclear. This study aimed to investigate the secondary structural changes occurring in bovine serum albumin (BSA) mixed with CeO2 nanoparticles having different surface modifications using Fourier transform infrared spectroscopy. CeO2 nanoparticles (diameter: 240nm) were synthesized from an aqueous cerium (III) nitrate solution using a homogeneous precipitation method. The surfaces of the nanoparticles were modified by the catechol compounds dopamine and 3,4-dihydroxyhydrocinnamic acid (DHCA). In the presence of these CeO2 nanoparticles (0.11-0.43mg/mL), β-sheet formation of BSA (30mg/mL) was promoted especially on the amine-modified (positively charged) nanoparticles. The local concentration of BSA on the surface of the positively charged nanoparticles may have resulted in structural changes due to electrostatic and other interactions with BSA. Further investigations of the interaction mechanism between nanoparticles and proteins are expected to lead to the safe biomedical applications of inorganic nanoparticles.

The Effectiveness of Robotic Mechanotherapy in the Rehabilitation of Patients with Shoulder Joint Pathology: Randomized Clinical Trial

INTRODUCTION. Prolonged inactivity associated with exacerbation of a chronic disease or immobilization of the upper limb after injuries and operations leads to the development of functional disorders in the shoulder joint and the development of secondary changes, such as muscle atrophy, contractures, osteoporosis. Therefore, the early application of functional methods of treatment is pathogenetically justified, among which mechanotherapy on robotic devices occupies an important place.&#x0D; AIM. To study the effectiveness of using the FLEX-F04 device in diseases and injuries of the shoulder joint.&#x0D; MATERIALS AND METHODS. According to the inclusion criteria, 60 patients were under our supervision. By random sampling, all patients were divided into two groups of 30 people each. All patients underwent a clinical examination, assessed algofunctional index on the VAS scale, the degree of dysfunction in the arm, shoulder and hand according to the DASH questionnaire, electrothermometry.&#x0D; RESULTS. As a result of treatment and rehabilitation measures, there was a significant increase in the angles of flexion, horizontal adduction, abduction, external and internal rotation in the shoulder joint, a decrease in pain syndrome and an increase in daily activity according to the DASH questionnaire in patients of both groups. In the main group, these indicators were significantly better than in the comparison group. The increase in thermal radiation as a result of the robotic mechanotherapy procedure averaged 0.6 0.1C.&#x0D; DISCUSSION. Robotic mechanotherapy allows movement in the shoulder joint in accordance with its biomechanics, reduces the load on the musculoskeletal system and thereby prevents the appearance or strengthening of the pain component during the procedure. This contributes to an active increase in the amplitude of movements and improvement of the functional capabilities of the shoulder joint, which has a positive effect on daily activity. An increase in thermal radiation in the shoulder joint area during the procedure can serve as an indirect sign of improved microcirculation and neuro-vascular regulation.&#x0D; CONCLUSION. The use of the FLEX-F04 robotic mechanotherapy device of the upper extremities according to the proposed method increases the volume of movements in the shoulder joint, reduces pain syndrome, increases blood circulation of the shoulder joint area and improves neuro-vascular regulation, increases daily household activity. Early inclusion of the device in the rehabilitation process makes it possible to shorten the duration of rehabilitation treatment and achieve a functional range of movements in the shoulder joint.

Cholesterol catalyzes unfolding in membrane-inserted motifs of the pore forming protein cytolysin A

Plasma membrane-induced protein folding and conformational transitions play a central role in cellular homeostasis. Several transmembrane proteins are folded in the complex lipid milieu to acquire a specific structure and function. Bacterial pore forming toxins (PFTs) are proteins expressed by a large class of pathogenic bacteria that exploit the plasma membrane environment to efficiently undergo secondary structure changes, oligomerize, and form transmembrane pores. Unregulated pore formation causes ion imbalance, leading to cell death and infection. Determining the free energy landscape of these membrane-driven-driven transitions remains a challenging problem. Although cholesterol recognition is required for lytic activity of several proteins in the PFT family of toxins, the regulatory role of cholesterol for the α-PFT, cytolysin A expressed by Escherichia coli remains unexplained. In a recent free energy computation, we showed that the β tongue, a critical membrane-inserted motif of the ClyA toxin, has an on-pathway partially unfolded intermediate that refolds into the helix-turn-helix motif of the pore state. To understand the molecular role played by cholesterol, we carry out string-method-based computations in membranes devoid of cholesterol, which reveals an increase of ∼30 times in the free energy barrier for the loss of β sheet secondary structure when compared with membranes containing cholesterol. Specifically, the tyrosine-cholesterol interaction was found to be critical to creating the unfolded intermediate. Cholesterol also increases the packing and hydrophobicity of the bilayer, resulting in enhanced interactions of the bound protein before complete membrane insertion. Our study illustrates that cholesterol is critical to catalyzing and stabilizing the membrane-inserted unfolded state of the β tongue motif of ClyA, opening up fresh insights into cholesterol-assisted unfolding of membrane proteins.

Molecular Evidence of Structural Changes in Silk Using Unlimited Degradation Mass Spectrometry.

Proteomics has important uses in archeological science because it can distinguish species, reveal the evolution of paleontology, and provide biological evidence of historical events. However, this technique still has full potential in the study of silk aging mechanisms. In this work, we propose a strategy combining unlimited degradation with mass-spectrometry-based proteomics techniques, which interpret protein fragmentation propensity and secondary structure changes by detecting content changes of specific peptide groups in complex proteomes. This approach was employed to study the conformational changes in silk microscopic crystals after heat treatment. Combining conventional mechanics and crystallographic characterization, a thermal aging degradation mechanism model was proposed. At the same time, it explained the interesting problem that the crystallinity remained unchanged, but the mechanical properties decreased significantly. Focusing on the unlimited degradation process, this method will be widely applicable to the study of silk and wool aging processes and regenerated silk fibroin.

Menstrual cycle alterations in reproductive age women after anti COVID-19 vaccination. A survey in 419 Italian women and quality of life and sexual function evaluation.

Pharmacovigilance agencies did not collect data regarding menstrual changes after COVID-19 vaccination even if many women experienced it. Our aim was to evaluate whether COVID-19 vaccination is associated with secondary changes in menstrual cycle and to assess both quality of life (QoL) and sexual function (SF). This study is a retrospective analysis referred to our Department from January 2021 to December 2021. The study cohort responded to same questionnaires before the second dose of vaccination (referring to previous 3 months) and 3 months after that (referring to three menstrual cycles after full-dose vaccination). The surveys administered were FSFI, FSDS, SF-36, MEDI-Q and the VAS-scale for dysmenorrhea. Four-hundred-nineteen vaccinated women were included in the study. The survey did not show a significant change in menstrual cycle length before and after COVID-19 vaccine (5.88±3.67 vs. 4.97±2.89, P=0.21); the interval between periods was significantly higher after a full-cycle vaccination (28.32±7.34 vs. 32.38±7.45, P<0.02); 32 patients (7.6%) developed amenorrhea after the second dose; VAS Scale did not change significantly (median range 3 (3-5) vs. 4 (3-6), P=0.20). MEDI-Q did not show significant variations before and after the vaccination (43.21±11.65 vs. 40.28±9.88, P=0.35). QoL and SF did not change significantly (FSFI median 27 [24-29] vs. 28 [25-30], P=0.12, FSDS median 9 [5-11] vs. 8 [4-12], P=0.22), SF-36 median 81 [70-85] vs. 82 [72-86], P=0.43). COVID-19 vaccination is associated with a significant change in intervals between menstrual cycles without other alterations in menstrual characteristics, in QoL or SF.

A Study on Avalanche-Triggering Factors and Activity Characteristics in Aerxiangou, West Tianshan Mountains, China

Through analyzing the triggering factors and activity characteristics of avalanches in Aerxiangou in the Western Tianshan Mountains, the formation and disaster-causing process of avalanches were studied to provide theoretical support and a scientific basis for avalanche disaster prevention. In this paper, based on remote sensing interpretation and field investigation, a spatial distribution map of avalanches was established, and the induced and triggering factors in disaster-prone environments were analyzed using the certainty factor model. The degree of influence (E) of the disaster-causing factors on avalanche triggering was quantified, and the main control conditions conducive to avalanche occurrence in different periods were obtained. The RAMMS-avalanche model was used to analyze the activity characteristics at points where multiple avalanches occurred. Research results: (1) The E values of the average temperature, average snowfall, and surface roughness in February were significantly higher than those of other hazard-causing factors, reaching 1.83 and 1.71, respectively, indicating strong control. The E values of the surface cutting degree, average temperature, and average snow depth in March were all higher than 1.8, indicating that these control factors were more prominent than the other factors. In contrast, there were four hazard-causing factors with E values higher than 1.5 in April: the mean temperature, slope, surface roughness, and mean wind speed, with clear control. (2) Under the influence of the different hazard-causing factors, the types of avalanches from February–April mainly included new full-layer avalanches, surface avalanches, and full-layer wet avalanches. (3) In the RAMMS-avalanche simulation test, considering the deposition effect, compared to the previous avalanche movement path, the secondary avalanche flow accumulation area impact range changes were slight, while the movement area within the avalanche path changes was large, as were the different categories of avalanches and their different movement characteristic values. Overall, wet snow avalanches are more hazardous, and the impact force is larger. The new snow avalanches start in a short period, the sliding rate is fast, and the avalanche sliding surface (full-snow surface and face-snow) of the difference is mainly manifested in the differences in the value of the flow height.

Careful feedback active noise and vibration control algorithm robust to large secondary path changes

Feedback active noise and vibration control (ANVC) reduces narrowband noise and vibration when there is no reference signal. However, most ANVC algorithms require a secondary path (plant) model and can become unstable when this model is inaccurate. This work proposes an algorithm less sensitive to plant modeling errors and can cope with large and fast plant changes. This is achieved by modeling the plant and the noise using an autoregressive exogenous input (ARX) model. This model allows obtaining the expected values of the future residual noise and determining the optimal control signal. Since the model coefficient uncertainty (variance) is considered when calculating the expected value, the resulting controller is a careful controller. This allows solving problems due to significant model estimation errors when information is insufficient to estimate the full ARX model.

Eye Muscle MRI in Myasthenia Gravis and Other Neuromuscular Disorders.

MRI of extra-ocular muscles (EOM) in patients with myasthenia gravis (MG) could aid in diagnosis and provide insights in therapy-resistant ophthalmoplegia. We used quantitative MRI to study the EOM in MG, healthy and disease controls, including Graves' ophthalmopathy (GO), oculopharyngeal muscular dystrophy (OPMD) and chronic progressive external ophthalmoplegia (CPEO). Twenty recently diagnosed MG (59±19yrs), nineteen chronic MG (51±16yrs), fourteen seronegative MG (57±9yrs) and sixteen healthy controls (54±13yrs) were included. Six CPEO (49±14yrs), OPMD (62±10yrs) and GO patients (44±12yrs) served as disease controls. We quantified muscle fat fraction (FF), T2water and volume. Eye ductions and gaze deviations were assessed by synoptophore and Hess-charting. Chronic, but not recent onset, MG patients showed volume increases (e.g. superior rectus and levator palpebrae [SR+LPS] 985±155 mm3 compared to 884±269 mm3 for healthy controls, p < 0.05). As expected, in CPEO volume was decreased (e.g. SR+LPS 602±193 mm3, p < 0.0001), and in GO volume was increased (e.g. SR+LPS 1419±457 mm3, p < 0.0001). FF was increased in chronic MG (e.g. medial rectus increased 0.017, p < 0.05). In CPEO and OPMD the FF was more severely increased. The severity of ophthalmoplegia did not correlate with EOM volume in MG, but did in CPEO and OPMD. No differences in T2water were found. We observed small increases in EOM volume and FF in chronic MG compared to healthy controls. Surprisingly, we found no atrophy in MG, even in patients with long-term ophthalmoplegia. This implies that even long-term ophthalmoplegia in MG does not lead to secondary structural myopathic changes precluding functional recovery.

Management of Branch Retinal Vein Occlusion (BRVO) in Ayurveda - A Case Study

Retina is the innermost tunic of the Eyeball; it is thin, delicate and transparent membrane. It is the most highly developed tissue of the Eye. Retinal arteriole and Vein share an adventitial sheath and because of Arteriolosclerosis thickening of arteriole is associated with compression of the Vein and this intern causes secondary changes including Venous endothelial cell loss, Thrombus formation and Occlusion.[1] These changes appear in both arteriole and vein that contribute to Retinal Vein Occlusions. Branch Retinal Vein Occlusion caused when a single branch of the central vein is blocked due to an embolism and spasm. Retinal Vein Occlusion is the second most common retinal disease after Diabetic Retinopathy. BRVO has a good prognosis of 50 to 60% of eyes are reported to have an improved Visual Acuity or better.

Effects of different ohmic heating treatments on parvalbumin structure and reduction of allergenicity in Japanese eel (Anguilla japonica)

We investigated the effects of ohmic heating (OH) on the structural properties and allergenicity of parvalbumin (PV). Compared to other heating methods (water bath heating (WH), OH combined with WH, and OH combined with air thermostatic heating (AH)), pure OH heating expended the least time and total energy. PV sensitization was reduced by approximately 65% by pure OH heating. SDS-PAGE, tricine–SDS-PAGE, and western blotting analyses revealed a molecular weight of sensitized β-PV of about 12 kDa. Band intensity decreased with increasing OH time, and significant changes were observed in amino acid content, secondary structure, microstructure, and dielectric properties. Reducing PV, allergenicity through protein unfolding and secondary structural changes, thereby possibly reducing the allergenicity of eel, provides a theoretical basis for developing hypoallergenic products.

Identifying structural and dynamic changes during the Biliverdin Reductase B catalytic cycle.

Biliverdin Reductase B (BLVRB) is an NADPH-dependent reductase that catalyzes the reduction of multiple substrates and is therefore considered a critical cellular redox regulator. In this study, we sought to address whether both structural and dynamics changes occur between different intermediates of the catalytic cycle and whether these were relegated to just the active site or the entirety of the enzyme. Through X-ray crystallography, we determined the apo BLVRB structure for the first time, revealing subtle global changes compared to the holo structure and identifying the loss of a critical hydrogen bond that "clamps" the R78-loop over the coenzyme. Amide and Cα chemical shift perturbations were used to identify environmental and secondary structural changes between intermediates, with more distant global changes observed upon coenzyme binding compared to substrate interactions. NMR relaxation rate measurements provided insights into the dynamic behavior of BLVRB during the catalytic cycle. Specifically, the inherently dynamic R78-loop that becomes ordered upon coenzyme binding persists through the catalytic cycle while similar regions experience dynamic exchange. However, the dynamic exchange processes were found to differ through the catalytic cycle with several groups of residues exhibiting similar dynamic responses. Finally, both local and distal structural and dynamic changes occur within BLVRB that are dependent solely on the oxidative state of the coenzyme. Thus, through a comprehensive analysis here, this study revealed structural and dynamic alterations in BLVRB through its catalytic cycle that are not simply relegated to the active site, but instead, are allosterically coupled throughout the enzyme.

On the Role of a Conserved Tryptophan in the Chromophore Pocket of Cyanobacteriochrome

The cyanobacteriochrome Slr1393 can be photoconverted between a red (Pr) and green absorbing form (Pg). The recently determined crystal structures of both states suggest a major movement of Trp496 from a stacking interaction with ring D of the phycocyanobilin (PCB) chromophore in Pr to a position outside the chromophore pocket in Pg. Here, we investigated the role of this amino acid during photoconversion in solution using engineered protein variants in which Trp496 was substituted by natural and non-natural amino acids. These variants and the native protein were studied by various spectroscopic techniques (UV–vis absorption, fluorescence, IR, NIR and UV resonance Raman) complemented by theoretical approaches. Trp496 is shown to affect the electronic transition of PCB and to be essential for the thermal equilibrium between Pr and an intermediate state O600. However, Trp496 is not required to stabilize the tilted orientation of ring D in Pr, and does not play a role in the secondary structure changes of Slr1393 during the Pr/Pg transition. The present results confirm the re-orientation of Trp496 upon Pr → Pg conversion, but do not provide evidence of a major change in the microenvironment of this residue. Structural models indicate the penetration of water molecules into the chromophore pocket in both Pr and Pg states and thus water-Trp contacts, which can readily account for the subtle spectral changes between Pr and Pg. Thus, we conclude that reorientation of Trp496 during the Pr-to-Pg photoconversion in solution is not associated with a major change in the dielectric environment in the two states.

Abstract P2189: Role Of Innate Immune Response And Mitochondrial Ros In The Cardiac And Pulmonary Sequelae Of Covid-19

Intro: Cardiac risk rises during acute SARS-CoV-2 infection and in long COVID syndrome, but the mechanisms behind COVID-19-linked arrhythmias are unknown. Here, we test the hypothesis that innate immune activation and mitochondrial ROS contribute to cardiac conduction abnormalities and pulmonary dysfunction in a COVID-19 hamster model. Results: ECGs and subpleural pressures were recorded by radiotelemetry over a 4-week timespan after SARS-CoV-2 infection. Multiple cardiac arrhythmias were observed, including bradycardia, sinus pauses, and atrioventricular block (AVB). RR intervals and sinus arrhythmia (RR&gt; mean+100ms, RR100) increased transiently 3-5 days after SARS-CoV-2 infection (baseline/peak: RR, 167±3ms/241±7ms; RR100, 5.5±0.4min -1 /22.7±3.0min -1 ) and returned to levels ≤ baseline by 7 dpi. After the acute phase, these measures increased above baseline over 3 weeks (at 28dpi: RR, 190±2ms, p&lt;0.05; RR100, 13.4±1.0 min -1 , p&lt;0.01). AVB count peaked at 3.1±0.1 min -1 at 1 dpi and gradually decreased to 0.4±0.2 min -1 by 28 dpi (vs. 0.004±0.002 at 0 dpi, p&lt;0.05). These parameters did not change in Mock-infected controls. RT-PCR showed that RIG-I, CXCL-10, OAS1, IL-1b and CCL-2 expression increased 18, 7, 2, 3, and 2-fold, respectively, over Mock controls at 4 dpi. IF analysis of the His-bundle region showed increased abundance of inflammatory IBA-1 + macrophages and decreased anti-inflammatory CD163 + macrophages. Ruxolitinib (Jak/Stat inhibitor) or mitochondrial antioxidant (mitoTEMPO) treatments were administered via implanted osmotic pumps. Subpleural pressure recordings indicated that infection induced tachypnea peaking at 7 dpi (272±11 versus 81±17 breaths/min at 0 dpi, p&lt;0.0001), which was attenuated by either treatment (peak: mitoTEMPO, 170±10; Ruxo,184±14). MitoTEMPO, but not Ruxolitinib, suppressed the increases in RR, RR100, and AVB during the acute phase and prevented the secondary changes in these measures in the post-acute phase (up to 28 dpi). Conclusions: The hamster model recapitulates a subset of arrhythmias observed in COVID-19 patients. Jak/Stat inhibition or mitoTEMPO treatment both mitigated acute respiratory distress, but only the latter suppressed arrhythmias during the acute and late phases of COVID-19.

CHRONIC CEREBRAL ISCHEMIA. MODERN VIEW OF THE PROBLEM

Introduction. Chronic cerebral ischemia (CCI) is considered a syndrome that develops as a result of a slowly progressive reduction in cerebral blood flow. This reduction occurs due to the gradual accumulation of ischemic and secondary degenerative changes in the brain, which are caused by repeated ischemic episodes resulting from the development of atherosclerosis and arterial hypertension. These changes lead to impairment of brain functions, manifested by progressive neurological, neuropsychological, and mental disorders.&#x0D; The aim. To analyze the problems of pathogenesis, diagnosis, and treatment of CCI from the sources of modern literature in order to optimize the treatment of this group of patients.&#x0D; Materials and methods. Bibliosemantic, comparative and method of system analysis.&#x0D; Results. The pathogenetic mechanisms underlying CCI remain controversial due to the heterogeneity of causes and the complexity of the neuropathology associated with the disease. However, one common reason that can be named is dysregulation of cerebral blood flow, that results in chronic cerebral hypoperfusion, which can lead to the development of vascular cognitive impairment and dementia. Detection of biological markers in the patients' blood in combination with neuropsychological testing, neurophysiological (CEP P300, EEG) and neuroimaging (CT, MRI, Doppler Ultrasound of the head and neck) methods, which confirms the morphological substrate of vascular disease (leukoareosis, focal changes, multi-infarct condition, cerebral atrophy) and provides the possibility of choosing an effective pathogenetically-justified treatment.&#x0D; Conclusions. The rating of effectiveness of treatment in CCI is complicated considering difficulties in the selection of the efficiency criteria due to the significant differences in the methodology and research formats, as well as problem of a significant medication-related burden in the case of comorbidities. In this regard, the main direction in therapy is combined neuroprotection, which allows to optimize the possibilities of this strategy and to increase its clinical significance in angioneurology.

Hypertrophic Cardiomyopathy: Genetic Foundations, Outcomes, Interconnections, and Their Modifiers.

Hypertrophic cardiomyopathy (HCM) is the most prevalent heritable cardiomyopathy. HCM is considered to be caused by mutations in cardiac sarcomeric protein genes. Recent research suggests that the genetic foundation of HCM is much more complex than originally postulated. The clinical presentations of HCM are very variable. Some mutation carriers remain asymptomatic, while others develop severe HCM, terminal heart failure, or sudden cardiac death. Heterogeneity regarding both genetic mutations and the clinical course of HCM hinders the establishment of universal genotype-phenotype correlations. However, some trends have been identified. The presence of a mutation in some genes encoding sarcomeric proteins is associated with earlier HCM onset, more severe left ventricular hypertrophy, and worse clinical outcomes. There is a diversity in the mechanisms implicated in the pathogenesis of HCM. They may be classified into groups, but they are interrelated. The lack of known supplementary elements that control the progression of HCM indicates that molecular mechanisms that exist between genotype and clinical presentations may be crucial. Secondary molecular changes in pathways implicated in HCM pathogenesis, post-translational protein modifications, and epigenetic factors affect HCM phenotypes. Cardiac loading conditions, exercise, hypertension, diet, alcohol consumption, microbial infection, obstructive sleep apnea, obesity, and environmental factors are non-molecular aspects that change the HCM phenotype. Many mechanisms are implicated in the course of HCM. They are mostly interconnected and contribute to some extent to final outcomes.