Репозиторий Университета

Glycogen synthase kinase 3 (GSK3) has been linked to the mechanisms of stress, mood regulation, and the effects of antidepressants. The functions of the GSK3β isoform have been extensively investigated, but little is known about the α-isoform, although they may functionally related. In a recently established modified swim test with a third delayed swim exposure, brain GSK3β mRNA expression positively correlated with floating behavior on the third test. A two-week-long pretreatment regime with imipramine (7.5mg/kg/day) or thiamine (200mg/kg/day), which is known to have antidepressant properties, reduced the GSK3β over-expression and decreased floating behavior on Day 5. GSK3α mRNA levels were measured in the hippocampus and prefrontal cortex on Days 1, 2 and 5. GSK3α expression was decreased in the prefrontal cortex on Day 2 and increased on Day 5. In this model, GSK3α mRNA changes were prevented by imipramine or thiamine treatment. There was a significant correlation between the expression of the two isoforms in the prefrontal cortex on Day 2 in untreated group. These results provide the first evidence for the potential involvement of GSK3α in depressive-like behaviours and as a target of anti-depressant therapy. Furthermore, the correlations suggest some cross-talk may exist between the two GSK3 isoforms.

A high-calorie diet (HCD) induces two mutually exacerbating effects contributing to diet-induced obesity (DIO): impaired glucose metabolism and increased food consumption. A link between the metabolic and behavioral manifestations is not well understood yet. We hypothesized that chronic inflammation induced by HCD plays a key role in linking together the two components of diet-induced pathology. Based on this hypothesis, we tested if a plasmid (DNA vaccine) encoding p62 (SQSTM1) would alleviate DIO including its metabolic and/or food consumption abnormalities. Previously we reported that injections of the p62 plasmid reduce chronic inflammation during ovariectomy-induced osteoporosis. Here we found that the p62 plasmid reduced levels of pro-inflammatory cytokines IL-1β, IL-12, and INFγ and increased levels of anti-inflammatory cytokines IL-4, IL-10 and TGFβ in HCD-fed animals. Due to this anti-inflammatory response, we further tested whether the plasmid can alleviate HCD-induced obesity and associated metabolic and feeding impairments. Indeed, p62 plasmid significantly reversed effects of HCD on the body mass index (BMI), levels of glucose, insulin and glycosylated hemoglobin (HbA1c). Furthermore, p62 plasmid partially restored levels of the satiety hormone, serotonin, and tryptophan, simultaneously reducing activity of monoamine oxidase (MAO) in the brain affected by the HCD. Finally, the plasmid partially reversed increased food consumption caused by HCD. Therefore, the administering of p62 plasmid alleviates both metabolic and behavioral components of HCD-induced obesity.

Elenagen is a plasmid encoding p62/SQSTM1, the first DNA vaccine possessing two mutually complementing mechanisms of action: it elicits immune response against p62 and mitigates systemic chronic inflammation. Previously, Elenagen demonstrated anti-tumor efficacy and safety in rodent tumor models and spontaneous tumors in dogs. This multicenter I/IIa trial evaluated safety and clinical activity of Elenagen in patients with advanced solid tumors. Fifteen patients were treated with escalating doses of Elenagen (1-5 mg per doses, 5 times weekly) and additional 12 patients received 1 mg dose. Ten patients with breast and ovary cancers that progressed after Elenagen were then treated with conventional chemotherapy. Adverse events (AE) were of Grade 1; no severe AE were observed. Cumulatively twelve patients (44%) with breast, ovary, lung, renal cancer and melanoma achieved stable disease for at least 8 wks, with 4 of them (15%) had tumor control for more than 24 wks, with a maximum of 32 wks. The patients with breast and ovary cancers achieved additional tumor stabilization for 12-28 wks when treated with chemotherapy following Elenagen treatment. Therefore, Elenagen demonstrated good safety profile and antitumor Oncotarget 2 www.impactjournals.com/oncotarget

(PDF) Safety and efficacy of p62 DNA vaccine ELENAGEN in a first-in-human trial in patients with advanced solid tumors. Available from: https://www.researchgate.net/publication/316148229_Safety_and_efficacy_of_p62_DNA_vaccine_ELENAGEN_in_a_first-in-human_trial_in_patients_with_advanced_solid_tumors [accessed Dec 25 2018].

The formation of hydrophilic pores in lipid bilayer during phase transition is described using Smolukhowski's equation with an additional term of the hydrophobic pore source. This term is added to account for defects in lipid packing during phase transition. We assume that the temporal sequence of the pores is a stochastic process, a non -stationary second- order Erlang flow. Flow characteristics depend on the equation solution and determine the formation times of the hydrophilic pore. The calculated distribution of the durations of intervals between hydrophilic pore formations is in a good agree ment with experimental data published before. In terms of this model we describe the influence of poly (ethylene glycol) on the pore formation frequency.

Background: Colonic microbiome is thought to be involved in auto-immune multiple sclerosis (MS). Interactions between diet and the colonic microbiome in MS are unknown. Methods: We compared the composition of the colonic microbiota quantitatively in 25 MS patients and 14 healthy controls.Fluorescence in situ hybridization (FISH) with 162 ribosomal RNA derived bacterial FISH probes was used. Ten of the MS patients received a ketogenic diet for 6 months. Changes in concentrations of 35 numerically substantial bacterial groups were monitored at baseline and at 2, 12, and 23/24 weeks. Results: No MS typical microbiome pattern was apparent.The total concentrations and diversity of substantial bacterial groups were reduced in MS patients (P < 0.001). Bacterial groups detected with EREC (mainly Roseburia), Bac303 (Bacteroides), and Fprau (Faecalibacterium prausnitzii) probes were diminished the most. The individual changes were multidirectional and inconsistent. The effects of a ketogenic diet were biphasic. In the short term, bacterial concentrations and diversity were further reduced. They started to recover at week 12 and exceeded significantly the baseline values after 23–24 weeks on the ketogenic diet. Conclusions: Colonic biofermentative function is markedly impaired in MS patients.The ketogenic diet normalized concentrations of the colonic microbiome after 6 months.

Our investigation of 1004 faecal specimens from European bats for picornaviruses by broadly reactive nested reverse transcription-PCR found picornaviral RNA in 28 samples (2.8 %). Phylogenetic analysis of the partial 3D genomic region suggested that one bat virus belonged to the species Enterovirus G (EV-G, formerly Porcine enterovirus B). Bat infection was supported by relatively high EV-G concentrations of 1.1×106 RNA copies per gram of faeces. All other bat viruses belonged either to the bat-associated genus Mischivirus, or to an unclassified Picornaviridae group distantly related to the genus Sapelovirus. Members of this unclassified sapelovirus-related group had RNA secondary structures in their 3′-nontranslated regions that were typical of enteroviruses and that resembled structures that occur in bat-associated coronaviruses, suggesting ancient recombination events. Based on sequence distances, several picornaviruses from European and Chinese bats were likely conspecific, suggesting connectivity of virus populations. Due to their high mutation rates and their diversity, picornaviruses may be useful tools for studies of bat and virus ecology.

Цель данного исследования — изучение функциональных последствий эстетической ринопластики. Авторы на достаточно большом объеме клинического материала (253 пациента) сравнили результаты операций в зависимости от хирургического доступа, объема и техники вмешательства и выявили, что постринопластические нарушения носового дыхания достоверно чаще встречаются после «эндоназального» хирургического доступа, чем после «открытой» ринопластики (75% против 68%), функциональный результат вмешательства существенно лучше при одноэтапном проведении риносептопластики и внутриносового вмешательства (конхопластика, синусотомия) (СОП 629±98 см3/с против 397±65 см3/с по объективной оценке, p<0,05) и применение во время первичной ринопластики структуросохраняющих приемов (расширяющие трансплантаты, расширяющие лоскуты, укрепляющие трансплантаты) позволяет уменьшить выраженность и частоту функциональных нарушений в отдаленные сроки наблюдения (СОП 550±85 см3/с против 303±50 см3/с по объективной оценке, p<0,05).

Цель. Улучшение результатов лечения пациентов, страдающих циррозом печени, путем внутрипеченочного введения криопреципитата, стимулирующего регенерацию органа. Материал и методы. В исследование включено 72 пациента, страдающих циррозом печени вирусной (НСV и НВV) и токсической этиологии. Цирроз печени класса А и В по Child-Pugh до введения криопреципитата был у 32 (44%) пациентов, класса С у 40 (56%). Криопреципитат вводили чрескожно в печень пункционным методом под ультразвуковым контролем. Оценивали динамику клинико-лабораторных показателей, параметры портального кровотока у всех пациентов, изменения в морфологической картине биопсийного материала печени у 42 (58%) и показатели иммунного статуса у 38 (53%) пациентов до и после введения криопреципитата. Результаты. После стимуляции регенерации печени криопреципитатом у большинства пациентов отмечено уменьшение выраженности клинических и лабораторных проявлений цирроза печени как через 3, так и через 6 и 12 месяцев после введения криопреципитата. Цирроз печени класса С через год регистрировался у 7 пациентов (до стимуляции у 40). Через 12 месяцев у 65 (90%) достоверно уменьшился диаметр воротной и селезеночной вен. У 11 (15%) пациентов снизился индекс застоя, у 18 (25%) сплено-портальный индекс. У 40 (95%) из 42 больных при морфологическом исследовании биоптата печени спустя год после проведенного лечения была выявлена положительная динамика (снижение воспалительно-клеточной инфильтрации, дистрофических изменений, у 29 (69%) уменьшение выраженности ступенчатого некроза гепатоцитов. Заключение. Введение криопреципитата в печень под ультразвуковым контролем является безопасным, так как позволяет избежать травмирования крупных внутрипеченочных сосудов. Криопреципитат оказывает стимулирующее действие на регенерацию печени, что улучшает ее функциональную активность и позволяет продлить время до трансплантации печени.

Aim: To develop minimally invasive and safe endoscopic access to thyroid gland. Material and methods: Transoral pre-mandibular video-assisted gas-free access to thyroid gland was developed in experimental study that included 19 human cadavers. Stereometric modeling defined the evaluation criteria including the form of basal arch of lower jaw and its height. There was no conflict of instruments in working chamber under platysma. Additional trocar was deployed to resolve the conflict between working parts of instruments during thyroid gland mobilization. The angle of operative action between the instruments is close to 90°. Trocar hole is used for drainage. Results: The access provides good visualization of recurrent laryngeal nerve, upper and lower thyroid arteries and parathyroid gland. It is less traumatic compared with other extra-cervical accesses to thyroid glands.

There is conflicting evidence on the protective role of breastfeeding in relation to the development of allergic sensitisation and allergic disease. Studies vary in methodology and definition of outcomes, which lead to considerable heterogeneity. Human milk composition varies both within and between individuals, which may partially explain conflicting data. It is known that human milk composition is very complex and contains variable levels of immune active molecules, oligosaccharides, metabolites, vitamins and other nutrients and microbial content. Existing evidence suggests that modulation of human breast milk composition has potential for preventing allergic diseases in early life. In this review, we discuss associations between breastfeeding/human milk composition and allergy development.

(PDF) Human Milk and Allergic Diseases: An Unsolved Puzzle. Available from: https://www.researchgate.net/publication/319178514_Human_Milk_and_Allergic_Diseases_An_Unsolved_Puzzle [accessed Dec 25 2018].

    With increased international travel over the world the need for safe and effective chemoprophylaxis for malaria is as great as ever. The choice of regimen is difficult, as effectiveness should be weighted against potential adverse effects. Although, some studies have reported high prophylactic efficacy of primaquine, there is no comprehensive evidence comparing its prophylactic effectiveness as well as toxicity. To fill the gap, this systematic review and meta-analysis study was carried out.

Despite recent advances, our knowledge of potential and rare human pathogens is far from exhaustive. Current molecular diagnostic tools mainly rely on the specific amplification of marker sequences and may overlook infections caused by unknown and rare pathogens. Using high-throughput sequencing (HTS) can solve this problem; but, due to the extremely low fraction of pathogen genetic material in clinical samples, its application is only cost-effective in special, rather than routine, cases. In this study, we present a method for the semi-specific enrichment of viral conservative sequences in a HTS library by hybridization in solution with genus-specific degenerate biotinylated oligonucleotides. Nucleic acids of the test viruses (yellow fever virus and Japanese encephalitis virus) were enriched by solution hybrid selection using pan-flavivirus oligonucleotides. Moreover, enterovirus (family: Picornaviridae, genus: Enterovirus) sequences were successfully enriched using foot-and-mouth disease virus (family: Picornaviridae, genus: Aphthovirus) oligonucleotide. The enrichment factor relative to the background nucleic acid was about 1,000-fold. As hybridization has less stringent oligonucleotide match requirements than PCR, few oligonucleotides are sufficient to cover the potential sequence variation in the whole genus and may even enrich nucleic acids of viruses of other related genera. Efficient enrichment of viral sequences makes its use in diagnostics cost-efficient.

(PDF) Enrichment of Viral Nucleic Acids by Solution Hybrid Selection with Genus Specific Oligonucleotides. Available from: https://www.researchgate.net/publication/319337364_Enrichment_of_Viral_Nucleic_Acids_by_Solution_Hybrid_Selection_with_Genus_Specific_Oligonucleotides [accessed Dec 25 2018].

The cell-to-cell transport of many plant viruses through plasmodesmata requires viral movement proteins (MPs) encoded by a ‘triple gene block’ (TGB) and termed TGB1, TGB2 and TGB3. TGB3 is a small integral membrane protein that contains subcellular targeting signals and directs both TGB2 and the helicase domain-containing TGB1 protein to plasmodesmata-associated structures. Recently, we described a ‘binary movement block’ (BMB) coding for two MPs, BMB1 and BMB2. The BMB2 protein associates with endoplasmic reticulum (ER) membranes, accumulates at plasmodesmata-associated membrane bodies and directs the BMB1 helicase to these structures. TGB3 transport to cell peripheral bodies was previously shown to bypass the secretory pathway and involve a non-conventional mechanism. Here, we provide evidence that the intracellular transport of both poa semilatent virus TGB3 and hibiscus green spot virus BMB2 to plasmodesmata-associated sites can occur via lateral translocation along the ER membranes. Agrobacterium-mediated transient co-expression in Nicotiana benthamiana leaves revealed that green fluorescent protein (GFP)-fused actin-binding domains of Arabidopsis fimbrin (ABD2–GFP) and mouse talin (TAL–GFP) inhibited the subcellular targeting of TGB3 and BMB2 to plasmodesmata-associated bodies, which resulted in TGB3 and BMB2 accumulation in the cytoplasm in association with aberrant ER structures. Inhibition of COPII budding complex formation by the expression of a dominant-negative mutant of the small GTPase Sar1 had no detectable effect on BMB2 subcellular targeting, which therefore could occur without exit from the ER in COPII transport vesicles. Collectively, the presented data support the current view that plant viral MPs exploit the ER:actin network for their intracellular transport.

Western Siberia is the region with little information on the prevalence of hepatitis C virus (HCV) infection, genotypic diversity of HCV isolates and risk factors. A molecular epidemiological survey was conducted to clarify these issues. Four groups of volunteers were included in a cross-sectional study (n = 500 in each group): health care workers; daycare patients from a hospital for drug users, daycare patients from an AIDS prevention and control center; and persons admitted to a local general practice clinic for any reason (outpatients). The anti-HCV IgG prevalence was 4.6% in health care workers, 48.0% in a narcological center, 35.8% in AIDS center, and 5.6% in outpatients. HCV RNA was found in 79.3%-86.3% of seropositives. A total of 388 HCV isolates were genotyped by direct sequencing and phylogenetic analysis of the 5'-UTR and NS5B regions of HCV genome. The genotypes distribution was: 1b--50.3%, 2a--4.4%, 2c--0.3%, 3a--44.8%. One isolate (0.3%) could not be typed unambiguously. This genotypic diversity is intermediate between that of European Russia and China. Genotype 1 prevailed in an older age group (75% among 51-60 years old), and genotype 3 was most prevalent in young people (51.4% in 16-20 years old). A statistically significant (P < 0.05) increase in risk was found in intravenous drug users (odds ratio (OR) = 77.5), unemployed persons (OR = 16.3), persons having >4 sexual partners during lifetime (OR = 4.3), and male homosexuals (OR = 6.6).

The TRPV1 receptor plays a significant role in many biological processes, such as perception of external temperature (above 43°C), inflammation development, and thermoregulation. Activation of TRPV1 leads to the pain occurrence and decrease in the body temperature, while inhibition of this receptor can lead to an increase in the temperature. The TRPV1 peptide modulators from sea anemone Heteractis crispa extract (APHC1 and APHC3) have been previously characterized as molecules, which generated a pronounced analgesic effect and a decrease in the body temperature in experimental animals. Using the combined APHC1 and APHC3 amino acid sequences, we have prepared a hybrid peptide molecule named A13 that contains all residues potentially important for the activity of the peptide precursors. Biological tests on animals have shown that the hybrid molecule not only combines the analgesic properties of both peptides but, unlike the peptide precursors, also raises the body temperature of experimental animals.

Acid-sensing ion channels (ASICs) ASIC3 expressed mainly in peripheral sensory neurons play an important role in pain perception and inflammation development. In response to acidic stimuli, they can generate a unique biphasic current. At physiological pH 7.4, human ASIC3 isoform (hASIC3) is desensitized and able to generate only a sustained current. We found endogenous isoquinoline alkaloids (EIAs), which restore hASIC3 from desensitization and recover the transient component of the current. Similarly, rat ASIC3 isoform (rASIC3) can also be restored from desensitization (at pH < 7.0) by EIAs with the same potency. At physiological pH and above, EIAs at high concentrations were able to effectively activate hASIC3 and rASIC3. Thus, we found first endogenous agonists of ASIC3 channels that could both activate and prevent or reverse desensitization of the channel. The decrease of EIA levels could be suggested as a novel therapeutic strategy for treatment of pain and inflammation.

Marital status is an independent prognostic factor for various cancer types. The present study used the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute (NCI) to analyze the impact of marital status on renal cancer patient survival outcomes. We identified a total of 62,405 eligible patients (23,800 women and 38,605 men). Overall 5-year renal cancer cause-specific survival (CSS) was 80.3% in the married group, 69.2% in the widowed group, 78.9% in the single group, and 76.5% in the divorced/separated group. The widowed patient group had the highest female/male ratio, more distant metastases, and fewer high-grade (III/IV) tumors. Most widowed patients (90.4%) were elderly (>60 years old). In our study, male renal cancer patients benefited more from marriage than females. We also found that white married patients had better survival outcomes than other white patient groups, but black unmarried and married patients exhibited similar survival outcomes. Our results show that, in general, unmarried patients have higher rates of cancer-specific mortality and highlight the importance of psychological intervention for cancer patients during treatment.

Perioperative corneal abrasion is a common ophthalmic complication detectable in patients undergoing general anesthesia. In this study, using experimental perioperative corneal abrasion in animals (rabbits) correlations have been found between development of corneal abrasion and proteomic changes in the tear film. The process of accumulation of pathological changes in the cornea begins after 1 h of general anesthesia while after 3–6 h of general anesthesia clinically manifested abrasions have been recognized. The development of corneal abrasions was associated with different changes in the content of the major proteins of the tear film. Analysis of the tear proteome points to suppressed lachrymal gland functioning, and suggests that serotransferrin, serum albumin and annexin A1 may be applicable as potential tear markers of the ophthalmic complication. The biochemical changes in the tear film included the rapid decrease in total antioxidant activity and activity of superoxide dismutase, as well as the decrease in interleukin-4 and the increase in interleukin-6 content thus indicating development of oxidative and pro-inflammatory responses. These findings suggest that antioxidant and anti-inflammatory therapy is a prospective approach for prevention/treatment of perioperative corneal abrasions. The observed anesthesia-induced effects should be taken into consideration in any study of ocular surface diseases employing anesthetized animals.

Anti-neutrophil cytoplasmic antibodies (ANCAs) are valuable laboratory markers used for the diagnosis of well-defined types of small-vessel vasculitis, including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). According to the 1999 international consensus on ANCA testing, indirect immunofluorescence (IIF) should be used to screen for ANCAs, and samples containing ANCAs should then be tested by immunoassays for proteinase 3 (PR3)-ANCAs and myeloperoxidase (MPO)-ANCAs. The distinction between PR3-ANCAs and MPO-ANCAs has important clinical and pathogenic implications. As dependable immunoassays for PR3-ANCAs and MPO-ANCAs have become broadly available, there is increasing international agreement that high-quality immunoassays are the preferred screening method for the diagnosis of ANCA-associated vasculitis. The present Consensus Statement proposes that high-quality immunoassays can be used as the primary screening method for patients suspected of having the ANCA-associated vaculitides GPA and MPA without the categorical need for IIF, and presents and discusses evidence to support this recommendation.

Cryofibrinogen is an abnormal protein that forms precipitate only in plasma. Cryofibrinogenaemia (CF) can be detected both in healthy persons and patients with autoimmune diseases, cancer and infections. Essential CF is frequently asymptomatic, although in a proportion of patients it is associated with skin lesions and systemic manifestations and can lead to refractory skin ulcers and gangrene or thrombotic events. Identification of CF in plasma is simple, but establishing a definite diagnosis may be a challenge due to a lack of accepted diagnostic criteria. Several treatment options have been suggested for patients with symptomatic CF, although their efficacy has been shown only in uncontrolled series or case reports. A variety of possible approaches to drug treatment poses additional problems for the physician. Treatment for secondary CF usually relies on effective management of the underlying disease. The clinical significance of CF and its true prevalence are apparently underestimated and should be further studied.