A sustainable blue economy may not be possible in Tanzania without cutting emissions.

Balancing blue growth with the conservation of wild species and habitats is a key challenge for global ocean management. This is exacerbated in Global South nations, such as Tanzania, where climate-driven ocean change requires delicate marine spatial planning (MSP) trade-offs to ensure climate resilience of marine resources relied upon by coastal communities. Here, we identified challenges and opportunities that climate change presents to the near-term spatial management of Tanzania's artisanal fishing sector, marine protected areas and seaweed farming. Specifically, spatial meta-analysis of climate modelling for the region was carried out to estimate the natural distribution of climate resilience in the marine resources that support these socially important sectors. We estimated changes within the next 20 and 40 years, using modelling projections forced under global emissions trajectories, as well as a wealth of GIS and habitat suitability data derived from globally distributed programmes. Multi-decadal analyses indicated that long-term climate change trends and extreme weather present important challenges to the activity of these sectors, locally and regionally. Only in few instances did we identify areas exhibiting climate resilience and opportunities for sectoral expansion. Including these climate change refugia and bright spots in effective ocean management strategies may serve as nature-based solutions: promoting adaptive capacity in some of Tanzania's most vulnerable economic sectors; creating wage-gaining opportunities that promote gender parity; and delivering some economic benefits of a thriving ocean where possible. Without curbs in global emissions, however, a bleak future may emerge for globally valuable biodiversity hosted in Tanzania, and for its coastal communities, despite the expansion of protected areas or curbs in other pressures. Growing a sustainable ocean economy in this part of the Global South remains a substantial challenge without global decarbonization.

A Direct Comparison of Peptide Drug Delivery Systems Based on the Use of Hybrid Calcium Phosphate/Chitosan Nanoparticles versus Unmixed Calcium Phosphate or Chitosan Nanoparticles In Vitro and In Vivo.

Nanocarriers provide a number of undeniable advantages that could improve the bioavailability of active agents for human, animal, and plant cells. In this study, we compared hybrid nanoparticles (HNPs) consisting of a calcium phosphate core coated with chitosan with unmixed calcium phosphate (CaP) and chitosan nanoparticles (CSNPs) as carriers of a model substrate, enalaprilat. This tripeptide analog is an inhibitor of angiotensin-converting enzyme and was chosen by its ability to lower intraocular pressure (IOP). In particular, we evaluated the physicochemical characteristics of the particles using dynamic light scattering (DLS) and scanning electron microscopy (SEM) and analyzed their ability to incorporate and release enalaprilat. HNPs exhibited the highest drug loading capacity and both HNPs and CSNPs demonstrated slow drug release. The comparison of the physiological effects of enalaprilat-loaded CaP particles, HNPs, and CSNPs in terms of their impact on IOP in rabbits revealed a clear advantage of hybrid nanoparticles over both inorganic and chitosan nanoparticles. These results could have important mechanistic implications for developing nano-based delivery systems for other medical, veterinary, and agricultural applications.

Cerebrospinal fluid indices as predictors of treatment response in autoimmune encephalitis.

BACKGROUND: Cerebrospinal fluid (CSF) indices reflecting intrathecal antibody production and blood-brain barrier impairment are not routinely assessed in patients with autoimmune encephalitis (AE). We aimed to study CSF indices and their association with the prognosis of AE. METHODS: This retrospective cohort study conducted at Amrita Institute of Medical Sciences (AIMS), Kochi, India, included 60 patients aged more than 18 years with definite/probable/possible AE admitted to the Department of Neurology from August 2016 to November 2021. We introduced a classification of treatment response based on modified Rankin Scale change over time and treatment modalities. RESULTS: In our cohort of 60 patients (six [10%] seropositive cases), a good rapid treatment response was associated with CSF white blood cell count of more than 4 cells/mm3 (OR, 4.57; 95% CI 1.31-15.96; P = .02) and positive immunoglobulin G (IgG) Local Synthesis (OR, 7.27; 95% CI 1.56-33.86; P = .01). Albumin Index had association with a poor Glasgow Coma Scale score at the nadir of the disease (OR, 1.17; 95% CI 1.01-1.34; P = .04). Similar results were yielded in the seronegative cohort. IgG Local Synthesis appeared to be a strong predictor for good rapid treatment response in both univariate and multivariate (adjusted OR, 28.71; 95% CI 2.12-389.22; P= .01) analysis. Time to immunotherapy was reversely correlated with good response overall (in the cohort with outliers removed [N = 49]: unadjusted OR 0.97, 95% CI 0.95-0.99; P= .01; adjusted OR 0.97; 95% CI 0.95-0.99; P= .008). CONCLUSION: CSF indices reflecting intrathecal antibody production and blood-brain barrier impairment appear to be promising predictors of disease severity and therapeutic response in patients with autoimmune encephalitis.

Holmium-Containing Metal-Organic Frameworks as Modifiers for PEBA-Based Membranes.

Recently, there has been an active search for new modifiers to create hybrid polymeric materials for various applications, in particular, membrane technology. One of the topical modifiers is metal-organic frameworks (MOFs), which can significantly alter the characteristics of obtained mixed matrix membranes (MMMs). In this work, new holmium-based MOFs (Ho-MOFs) were synthesized for polyether block amide (PEBA) modification to develop novel MMMs with improved properties. The study of Ho-MOFs, polymers and membranes was carried out by methods of X-ray phase analysis, scanning electron and atomic force microscopies, Fourier transform infrared spectroscopy, low-temperature nitrogen adsorption, dynamic and kinematic viscosity, static and dynamic light scattering, gel permeation chromatography, thermogravimetric analysis and contact angle measurements. Synthesized Ho-MOFs had different X-ray structures, particle forms and sizes depending on the ligand used. To study the effect of Ho-MOF modifier on membrane transport properties, PEBA/Ho-MOFs membrane retention capacity was evaluated in vacuum fourth-stage filtration for dye removal (Congo Red, Fuchsin, Glycine thymol blue, Methylene blue, Eriochrome Black T). Modified membranes demonstrated improved flux and rejection coefficients for dyes containing amino groups: Congo Red, Fuchsin (PEBA/Ho-1,3,5-H3btc membrane possessed optimal properties: 81% and 68% rejection coefficients for Congo Red and Fuchsin filtration, respectively, and 0.7 L/(m2s) flux).

Mitochondrial Oxidative Stress and Mitophagy Activation Contribute to TNF-Dependent Impairment of Myogenesis.

Many muscular pathologies are associated with oxidative stress and elevated levels of the tumor necrosis factor (TNF) that cause muscle protein catabolism and impair myogenesis. Myogenesis defects caused by TNF are mediated in part by reactive oxygen species (ROS), including those produced by mitochondria (mitoROS), but the mechanism of their pathological action is not fully understood. We hypothesized that mitoROS act by triggering and enhancing mitophagy, an important tool for remodelling the mitochondrial reticulum during myogenesis. We used three recently developed probes-MitoTracker Orange CM-H2TMRos, mito-QC, and MitoCLox-to study myogenesis in human myoblasts. Induction of myogenesis resulted in a significant increase in mitoROS generation and phospholipid peroxidation in the inner mitochondrial membrane, as well as mitophagy enhancement. Treatment of myoblasts with TNF 24 h before induction of myogenesis resulted in a significant decrease in the myoblast fusion index and myosin heavy chain (MYH2) synthesis. TNF increased the levels of mitoROS, phospholipid peroxidation in the inner mitochondrial membrane and mitophagy at an early stage of differentiation. Trolox and SkQ1 antioxidants partially restored TNF-impaired myogenesis. The general autophagy inducers rapamycin and AICAR, which also stimulate mitophagy, completely blocked myogenesis. The autophagy suppression by the ULK1 inhibitor SBI-0206965 partially restored myogenesis impaired by TNF. Thus, suppression of myogenesis by TNF is associated with a mitoROS-dependent increase in general autophagy and mitophagy.

Chitosan-Covered Calcium Phosphate Particles Co-Loaded with Superoxide Dismutase 1 and ACE Inhibitor: Development, Characterization and Effect on Intraocular Pressure.

Improvement of the efficiency of drug penetration into the eye tissues is still an actual problem in ophthalmology. One of the most promising solutions is drug encapsulation in carriers capable of overcoming the cornea/sclera tissue barrier. Formulations on the base of antioxidant enzyme, superoxide dismutase 1 (SOD1), and an inhibitor of angiotensin-converting enzyme, enalaprilat, were prepared by simultaneous inclusion of both drugs into calcium phosphate (CaP) particles in situ with subsequent covering of the particles with 5 kDa chitosan. The formulations obtained were characterized by dynamic light scattering and scanning electron microscopy. Hybrid CaP-chitosan particles co-loaded with SOD1 and enalaprilat had a mean hydrodynamic diameter of 120-160 nm and ζ-potential +20 ± 1 mV. The percentage of the inclusion of SOD1 and enalaprilat in hybrid particles was 30% and 56%, respectively. The ability of SOD1 and enalaprilat to reduce intraocular pressure (IOP) was examined in vivo in normotensive Chinchilla rabbits. It was shown that topical instillations of SOD1/enalaprilat co-loaded hybrid particles were much more effective in decreasing IOP compared to free enzyme or free enalaprilat and even to the same particles that contained a single drug. Thus, the proposed formulations demonstrate potential as prospective therapeutic agents for the treatment of glaucoma.

Chitosan-covered calcium phosphate particles as a drug vehicle for delivery to the eye.

Formulations on the base of an inhibitor of angiotensin-converting enzyme, enalaprilat, were prepared by the inclusion of the drug into calcium phosphate (CaP)-particles in situ, followed by the covering of the particles with 5 kDa chitosan or 72 kDa glycol chitosan and cross-linking with sodium tripolyphosphate. Physicochemical characterization of the resulted hybrid particles was conducted using dynamic light scattering, as well as scanning and transmission electron microscopy. Enalaprilat-containing particles had a mean hydrodynamic diameter 180 nm and 260 nm and ζ-potential +7 mV and +16 mV for 5 kDa and 72 kDa chitosans, respectively. In vivo studies showed that enalaprilat within particles stayed longer in the tear fluid after single instillation and caused a significantly pronounced and prolonged decrease of intraocular pressure in rabbits, especially in the case of CaP-particles, covered by glycol chitosan. Thus, such formulations demonstrate potential as prospective therapeutic agents for the treatment of eye diseases.

Nanotechnology for Topical Drug Delivery to the Anterior Segment of the Eye.

Topical drug delivery is one of the most challenging aspects of eye therapy. Eye drops are the most prevalent drug form, especially for widely distributed anterior segment eye diseases (cataracts, glaucoma, dry eye syndrome, inflammatory diseases, etc.), because they are convenient and easy to apply by patients. However, conventional drug formulations are usually characterized by short retention time in the tear film, insufficient contact with epithelium, fast elimination, and difficulties in overcoming ocular tissue barriers. Not more than 5% of the total drug dose administered in eye drops reaches the interior ocular tissues. To overcome the ocular drug delivery barriers and improve drug bioavailability, various conventional and novel drug delivery systems have been developed. Among these, nanosize carriers are the most attractive. The review is focused on the different drug carriers, such as synthetic and natural polymers, as well as inorganic carriers, with special attention to nanoparticles and nanomicelles. Studies in vitro and in vivo have demonstrated that new formulations could help to improve the bioavailability of the drugs, provide sustained drug release, enhance and prolong their therapeutic action. Promising results were obtained with drug-loaded nanoparticles included in in situ gel.

Identifying Early Vascular Ageing in Patients With Metabolic Syndrome: Unresolved Issues and a Proposed Novel VAmets Score.

PURPOSE: To identify the features of early vascular ageing (EVA) in patients with metabolic syndrome (MetS), to assess the accuracy of existing methods for determining vascular age in MetS, and to derive a new score (VAmets) for the calculation of vascular age and predicting EVA in patients with MetS. METHODS: Prospective open cohort study using routinely collected data from general practice. A total of 750 patients (age, 35-80 yrs old) with MetS were examined. EVA syndrome was detected in 484 patients with MetS and carotid-femoral pulse wave velocity (cfPWV) values exceeding average expected for age values by 2 or more standard deviations (SD). RESULTS: The presence of type 2 diabetes and insulin resistance (IR) were associated with greater risk of EVA in MetS patients; the odds ratios were 2.75 (95% confidence interval [CI]: 2.34, 3.35) and 1.57 (95% CI: 1.16, 2.00), respectively. In addition, the risk of EVA increased by 76% with an increase in homeostatic model assessment ofinsulin resistance (HOMA-IR) by 1 unit, by 17% with an increase in high-sensitivity C-reactive protein (hs-CRP) by 1 mg/L, by 4% with an increase in diastolic blood pressure (DBP) by 1 mmHg, and by 1% with each (1) µmol/L increase in the level of uric acid (UA). The area under the curve (AUC) for predicting EVA in patients with MetS was 0.949 (95% CI: 0.936-0.963), 0.630 (95% CI: 0.589-0.671), 0.697 (95% CI: 0.659-0.736) and 0.686 (95% CI: 0.647-0.726), for vascular age calculated from carotid-femoral pulse wave velocity (cfPWV), Systematic COronary Risk Evaluation (SCORE) scale, QRESEARCH cardiovascular risk algorithm (QRISK-3) scale, and Framingham scale, respectively. Diabetes mellitus and clinical markers of IR (yes/no), HOMA-IR and UA level were used to develop a new VAmets score for EVA prediction providing a total accuracy of 0.830 (95% CI: 0.799-0.860). Based on the results of the study, a VAmets calculator was developed for diagnosing EVA in patients with MetS. (The calculator is available online at https://apps.medhub.pro/evams/) CONCLUSION: Carotid-femoral pulse wave velocity is at present the most widely studied index of arterial stiffness and fulfils most of the stringent criteria for a clinically useful biomarker of EVA in patients with MetS. There are parallel efforts for the effective identification and integration of a simple clinical score into clinical practice. Our score (VAmets) may accurately identify patients with MetS and EVA on the basis of widely available clinical variables and classic cardiovascular risk factors, and may assist in prioritising the calculation and use of vascular age in routine care.

Analysis of genes regulated by DUX4 via oxidative stress reveals potential therapeutic targets for treatment of facioscapulohumeral dystrophy.

Muscles of patients with facioscapulohumeral dystrophy (FSHD) are characterized by sporadic DUX4 expression and oxidative stress which is at least partially induced by DUX4 protein. Nevertheless, targeting oxidative stress with antioxidants has a limited impact on FSHD patients, and the exact role of oxidative stress in the pathology of FSHD, as well as its interplay with the DUX4 expression, remain unclear. Here we set up a screen for genes that are upregulated by DUX4 via oxidative stress with the aim to target these genes rather than the oxidative stress itself. Immortalized human myoblasts expressing DUX4 (MB135-DUX4) have an increased level of reactive oxygen species (ROS) and exhibit differentiation defects which can be reduced by treating the cells with classic (Tempol) or mitochondria-targeted antioxidants (SkQ1). The transcriptome analysis of antioxidant-treated MB135 and MB135-DUX4 myoblasts allowed us to identify 200 genes with expression deregulated by DUX4 but normalized upon antioxidant treatment. Several of these genes, including PITX1, have been already associated with FSHD and/or muscle differentiation. We confirmed that PITX1 was indeed deregulated in MB135-DUX4 cells and primary FSHD myoblasts and revealed a redox component in PITX1 regulation. PITX1 silencing partially reversed the differentiation defects of MB135-DUX4 myoblasts. Our approach can be used to identify and target redox-dependent genes involved in human diseases.

Interannual monsoon wind variability as a key driver of East African small pelagic fisheries.

Small pelagic fisheries provide food security, livelihood support and economic stability for East African coastal communities-a region of least developed countries. Using remotely- sensed and field observations together with modelling, we address the biophysical drivers of this important resource. We show that annual variations of fisheries yield parallel those of chlorophyll-a (an index of phytoplankton biomass). While enhanced phytoplankton biomass during the Northeast monsoon is triggered by wind-driven upwelling, during the Southeast monsoon, it is driven by two current induced mechanisms: coastal "dynamic uplift" upwelling; and westward advection of nutrients. This biological response to the Southeast monsoon is greater than that to the Northeast monsoon. For years unaffected by strong El-Niño/La-Niña events, the Southeast monsoon wind strength over the south tropical Indian Ocean is the main driver of year-to-year variability. This has important implications for the predictability of fisheries yield, its response to climate change, policy and resource management.

One-year Results of a Factorial Randomized Trial of Aspirin versus Placebo and Clonidine versus Placebo in Patients Having Noncardiac Surgery.

BACKGROUND: The authors previously reported that perioperative aspirin and/or clonidine does not prevent a composite of death or myocardial infarction 30 days after noncardiac surgery. Moreover, aspirin increased the risk of major bleeding and clonidine caused hypotension and bradycardia. Whether these complications produce harm at 1 yr remains unknown. METHODS: The authors randomized 10,010 patients with or at risk of atherosclerosis and scheduled for noncardiac surgery in a 1:1:1:1 ratio to clonidine/aspirin, clonidine/aspirin placebo, clonidine placebo/aspirin, or clonidine placebo/aspirin placebo. Patients started taking aspirin or placebo just before surgery; those not previously taking aspirin continued daily for 30 days, and those taking aspirin previously continued for 7 days. Patients were also randomly assigned to receive clonidine or placebo just before surgery, with the study drug continued for 72 h. RESULTS: Neither aspirin nor clonidine had a significant effect on the primary 1-yr outcome, a composite of death or nonfatal myocardial infarction, with a 1-yr hazard ratio for aspirin of 1.00 (95% CI, 0.89 to 1.12; P = 0.948; 586 patients [11.8%] vs. 589 patients [11.8%]) and a hazard ratio for clonidine of 1.07 (95% CI, 0.96 to 1.20; P = 0.218; 608 patients [12.1%] vs. 567 patients [11.3%]), with effect on death or nonfatal infarction. Reduction in death and nonfatal myocardial infarction from aspirin in patients who previously had percutaneous coronary intervention at 30 days persisted at 1 yr. Specifically, the hazard ratio was 0.58 (95% CI, 0.35 to 0.95) in those with previous percutaneous coronary intervention and 1.03 (95% CI, 0.91to 1.16) in those without (interaction P = 0.033). There was no significant effect of either drug on death, cardiovascular complications, cancer, or chronic incisional pain at 1 yr (all P > 0.1). CONCLUSIONS: Neither perioperative aspirin nor clonidine have significant long-term effects after noncardiac surgery. Perioperative aspirin in patients with previous percutaneous coronary intervention showed persistent benefit at 1 yr, a plausible sub-group effect.

In search for the sources of plastic marine litter that contaminates the Easter Island Ecoregion.

Subtropical gyres are the oceanic regions where plastic litter accumulates over long timescales, exposing surrounding oceanic islands to plastic contamination, with potentially severe consequences on marine life. Islands' exposure to such contaminants, littered over long distances in marine or terrestrial habitats, is due to the ocean currents that can transport plastic over long ranges. Here, this issue is addressed for the Easter Island ecoregion (EIE). High-resolution ocean circulation models are used with a Lagrangian particle-tracking tool to identify the connectivity patterns of the EIE with industrial fishing areas and coastline regions of the Pacific basin. Connectivity patterns for "virtual" particles either floating (such as buoyant macroplastics) or neutrally-buoyant (smaller microplastics) are investigated. We find that the South American shoreline between 20°S and 40°S, and the fishing zone within international waters off Peru (20°S, 80°W) are associated with the highest probability for debris to reach the EIE, with transit times under 2 years. These regions coincide with the most-densely populated coastal region of Chile and the most-intensely fished region in the South Pacific. The findings offer potential for mitigating plastic contamination reaching the EIE through better upstream waste management. Results also highlight the need for international action plans on this important issue.

Lesión miocárdica tras la cirugía no cardiaca: ¿el dabigatrán puede ser un primer paso para su tratamiento? / Myocardial injury after noncardiac surgery. Could dabigatran be a first step in its management?

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DUX4 Pathological Expression: Causes and Consequences in Cancer.

DUX4, a double homeobox transcription factor, has been mostly studied in facioscapulohumeral dystrophy (FSHD), a pathology linked to a deletion of subtelomeric repeats on chromosome 4q. More recently, however, the gene has been associated with various sarcomas and haematological malignancies. Drugs developed for FSHD could be tested on cancer cells to develop efficient treatment strategies for both pathologies.

Real-world study of efficacy, risk management and reasons for discontinuation of natalizumab for treatment of multiple sclerosis in Russia.

BACKGROUND: NTZ is approved in Russia for the treatment of highly active relapsing remitting multiple sclerosis and is reimbursed via federal budget program. However, no data about NTZ treatment in Russia and the effect of federal reimbursement have been performed so far. OBJECTIVE: To characterize the population of patients receiving natalizumab and assess the efficacy and risk-management plan (RMP) implementation of NTZ therapy in routine clinical practice in Russia. METHODS: We analyzed data for 334 patients, who received at least one infusion of NTZ. Relapse rate, MRI activity, NEDA-3 status after 2 years were assessed. Anti-JC virus antibodies status and RMP implementation were evaluated. Drop-out rate and reasons for therapy discontinuation were analyzed. RESULTS: Patients switched to natalizumab in Russia are mainly female (63%), with median EDSS score of 3.5 and high disease activity: 93% had at least 1 relapse and 58% had both T1Gd+ and new T2 lesion a year before therapy initiation. Introduction of federal reimbursement allowed patients with less relapses to start therapy with natalizumab. The only predictor of 6-month progression was EDSS score at the baseline of therapy (HR = 2.1375, 95%CI 1.0026-4.5570, p = 0.0492). 82% patients reached NEDA-3 at 24 month of therapy. 25% of patients discontinued NTZ for reasons: tolerability (14.5%), JCV antibody status (61%), and patient's decision (17%). RMP was implemented in only 36% patients. CONCLUSION: Natalizumab appeared to have high efficacy in Russian clinical practice. Federal reimbursement allowed less active patients to start natalizumab. More efforts should be done to improve RMP implementation.

Genetic differences between primary progressive and relapsing-remitting multiple sclerosis: The impact of immune-related genes variability.

BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune disease of CNS with a highly heterogeneous clinical course. The role of the genetic variability in determination of MS course is not yet well established. We aimed to estimate the impact of immune-related genes variability in the genetic architecture of two clinically different MS courses - primary progressive (PPMS) and relapsing-remitting (RRMS). METHODS: We performed the association analysis of 31 immune-related genes' variants in pairwise comparisons of 110 PPMS patients, 564 RRMS patients and 424 healthy individuals (HI). RESULTS: HLA-DRB1*11 and *15, IL7RA rs6897932*C/C, CXCR5 rs523604*A/A, and CLEC16A rs6498169*G/G were found as MS-associated variants common for PPMS and RRMS. HLA-DRB1*07, IL4 rs2243250*C/C, IRF5 rs4728142*A/A, and IFNAR2 rs2248202*C were PPMS- associated when compared to HI and RRMS, while HLA-DRB1*09 and IL6 rs1800795*C were RRMS-associated when compared to HI and PPMS. In multiple logistic regression and ROC curve analyses composite regression models were characterized by area under the curve values of 0.769, 0.726, and 0.679 in comparisons "PPMS vs HI", "RRMS vs HI", and "PPMS vs RRMS", respectively. CONCLUSION: We revealed genetic variants associated with PPMS, among which both variants common for two MS courses and distinguishing PPMS and RRMS were found. Observed genetic features of two MS courses may underlie different impact of autoimmune inflammatory processes in development of PPMS and RRMS, however additional studies on larger PPMS samples are strictly needed.

MiRNAs from DLK1-DIO3 Imprinted Locus at 14q32 are Associated with Multiple Sclerosis: Gender-Specific Expression and Regulation of Receptor Tyrosine Kinases Signaling.

Relapsing-remitting multiple sclerosis (RRMS) is the most prevalent course of multiple sclerosis. It is an autoimmune inflammatory disease of the central nervous system. To investigate the gender-specific involvement of microRNAs (miRNAs) in RRMS pathogenesis, we compared miRNA profiles in peripheral blood mononuclear cells separately in men and women (eight RRMS patients versus four healthy controls of each gender) using high-throughput sequencing. In contrast to women, six downregulated and 26 upregulated miRNAs (padj < 0.05) were identified in men with RRMS. Genes encoding upregulated miRNAs are co-localized in DLK1-DIO3 imprinted locus on human chromosome 14q32. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis was performed in independent groups of men (16 RRMS patients and 10 healthy controls) and women (20 RRMS patients and 10 healthy controls). Increased expression of miR-431, miR-127-3p, miR-379, miR-376c, miR-381, miR-410 and miR-656 was again demonstrated in male (padj < 0.05), but not in female RRMS patients. At the same time, the expression levels of these miRNAs were lower in healthy men than in healthy women, whereas in RRMS men they increased and reached or exceeded levels in RRMS women. In general, we demonstrated that expression levels of these miRNAs depend both on "health⁻disease" status and gender. Network-based enrichment analysis identified that receptor tyrosine kinases-activated pathways were enriched with products of genes targeted by miRNAs from DLK1-DIO3 locus. These results suggest the male-specific involvement of these miRNAs in RRMS pathogenesis via regulation of PI3K/Akt signaling.