Fabrication of 1D particle structures outside a liquid environment using electric and capillary interactions: From fundamentals to applications

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Urocortin, a CRF-like peptide, restores key indicators of damage in the substantia nigra in a neuroinflammatory model of Parkinson's disease

We have recently observed that the corticotrophin releasing hormone (CRF) related peptide urocortin (UCN) reverses key features of nigrostriatal damage in the hemiparkinsonian 6-hydroxydopamine lesioned rat. Here we have studied whether similar effects are also evident in the lipopolysaccaride (LPS) neuroinflammatory paradigm of Parkinson's disease (PD). To do this we have measured restoration of normal motor behaviour, retention of nigral dopamine (DA) and also tyrosine hydroxylase (TH) activity. Fourteen days following intranigral injections of LPS and UCN, rats showed only modest circling after DA receptor stimulation with apomorphine, in contrast to those given LPS and vehicle where circling was pronounced. In separate experiments, rats received UCN seven days following LPS, and here apomorphine challenge caused near identical circling intensity to those that received LPS and UCN concomitantly. In a similar and consistent manner with the preservation of motor function, UCN 'protected' the nigra from both DA depletion and loss of TH activity, indicating preservation of DA cells. The effects of UCN were antagonised by the non-selective CRF receptor antagonist α-helical CRF and were not replicated by the selective CRF2 ligand UCN III. This suggests that UCN is acting via CRF1 receptors, which have been shown to be anti-inflammatory in the periphery. Our data therefore indicate that UCN is capable of maintaining adequate nigrostriatal function in vivo, via CRF1 receptors following a neuro-inflammatory challenge. This has potential therapeutic implications in PD

Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>It has recently become apparent that neuroinflammation may play a significant role in Parkinson's disease (PD). This is also the case in animal paradigms of the disease. The potential neuroprotective action of the glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4 (EX-4), which is protective against cytokine mediated apoptosis and may stimulate neurogenesis, was investigated In paradigms of PD.</p> <p>Methods</p> <p>Two rodent 'models' of PD, 6-hydroxydopamine (6-OHDA) and lipopolysaccaride (LPS), were used to test the effects of EX-4. Rats were then investigated <it>in vivo </it>and <it>ex vivo </it>with a wide range of behavioural, neurochemical and histological tests to measure integrity of the nigrostriatal system.</p> <p>Results</p> <p>EX-4 (0.1 and 0.5 μg/kg) was given seven days after intracerebral toxin injection. Seven days later circling behaviour was measured following apomorphine challenge. Circling was significantly lower in rats given EX-4 at both doses compared to animals given 6-OHDA/LPS and vehicle. Consistent with these observations, striatal tissue DA concentrations were markedly higher in 6-OHDA/LPS + EX-4 treated rats versus 6-OHDA/LPS + vehicle groups, whilst assay of L-DOPA production by tyrosine hydroxylase was greatly reduced in the striata of 6-OHDA/LPS + vehicle rats, but this was not the case in rats co-administered EX-4. Furthermore nigral TH staining recorded in 6-OHDA/LPS + vehicle treated animals was markedly lower than in sham-operated or EX-4 treated rats. Finally, EX-4 clearly reversed the loss of extracellular DA in the striata of toxin lesioned freely moving rats.</p> <p>Conclusion</p> <p>The apparent ability of EX-4 to arrest progression of, or even reverse nigral lesions once established, suggests that pharmacological manipulation of the GLP-1 receptor system could have substantial therapeutic utility in PD. Critically, in contrast to other peptide agents that have been demonstrated to possess neuroprotective properties in pre-clinical models of PD, EX-4 is in current clinical use in the management of type-II diabetes and freely crosses the blood brain barrier; hence, assessment of the clinical efficacy of EX-4 in patients with PD could be pursued without delay.</p

Information Security of the State Under Conditions of Hybrid Warfare: Mechanisms of Ensuring

Taking into account the tendencies of democratization and informatization of all sectors of the economy and spheres of public administration, and, accordingly, the increase in information risks, the vast majority of countries in the world today go through a series of stages of ensuring information security. Despite the legislatively established powers of the relevant state authorities and local self-government in this area, the issues of defining their competence and effective interaction are real and effective guarantees of preventing a variety of information threats to national security as in this case effective and timely ways of eliminating existing dangers are provided. Given that large-scale invasions and hybrid wars can cause catastrophic harm and undermine public confidence in the government, the state must make quick decisions. Consequently, establishing an effective mechanism for ensuring information security has become more relevant than ever nowadays. The purpose of the academic paper is to clarify the theoretical fundamentals, as well as the components, directions and other critical practical aspects of the process of ensuring the state’s information security under conditions of hybrid warfare. Methodology. In the course of the research, abstraction, idealization, system-structural, comparative, logical-linguistic methods, analysis, synthesis, induction, deduction were used to process scientific information on issues of the state’s information security. Results. Based on the research results, the features of the process of ensuring the state’s information security in a hybrid war were studied and certain practical aspects of this issue were clarified

Hygienic assessment of planning decisions for the cities with different city-forming base by the state of the environmental pollution and risk to the health of the population

Мета роботи – розробити гігієнічні підходи до оцінки планувальних рішень міст з різною містоутворюючою системою за станом забруднення навколишнього середовища та ризиком для здоров’я населення. Методи досліджень: використовували комплекс загальнонаукових і спеціальних методів дослідження: бібліосемантичні (для аналізу нормативно-правового регулювання та наукової літератури у сфері містобудування), теоретичні (оцінка ретроспективних даних наукових досліджень щодо гігієни планування населених місць), аналітичні (розробка методики гігієнічної оцінки проектів будівництва об’єктів різного призначення); санітарно-епідеміологічної експертизи проектів генпланів міст та СЗЗ для об’єктів різного класу небезпеки; епідеміологічні та медико-статистичні методи дослідження; для оцінки небезпеки впливу хімічних забруднювачів атмосферного повітря міст на населення застосовували методологію оцінки ризику. Результати. Досліджувались міста з урахуванням характеру основних галузей господарства, які формують їх містоутворюючу базу, а також особливостей планувальної структури міст, що дозволяють виокремити сельбищні території, які знаходяться під значним впливом промислових об’єктів, та поза їх впливом. Отримані дані дозволяють розробляти заходи із корегування стану довкілля та обґрунтовано вирішувати питання генеральних планів забудови території міст з урахуванням специфіки розбудови профілюючих промислових комплексів для прийняття управлінських рішень на місцях, їх впровадження для створення безпечних умов життєдіяльності людини. Суттєвого значення набули процеси реструктуризації основних галузей важкої індустрії, розукрупнення і перепрофілювання великих промислових комплексів і підприємств та інтенсивний розвиток відносно невеликих виробничих об’єктів. У зв’язку з дефіцитом земельних ресурсів в найкрупніших містах і мегаполісах питання розташування існуючих АЗС і проектування перспективної житлової забудови, наближеної до них, а також розташування проектованих АЗС в умовах сельбищної забудови, що вже склалась, на фоні стрімкої автомобілізації сучасного суспільства набувають все більшого значення і потребують законодавчого врегулювання щодо унормування СЗЗ для сучасних АЗС з урахуванням не тільки гігієнічних вимог, а ще вимог пожежонебезпеки. We developed the hygienic approaches to the assessment of planning decisions of the cities with different city-forming systems in terms of environmental pollution and risk to the health of the population

Dysregulation of glucose metabolism is an early event in sporadic Parkinson's disease

AbstractUnlike most other cell types, neurons preferentially metabolize glucose via the pentose phosphate pathway (PPP) to maintain their antioxidant status. Inhibiting the PPP in neuronal cell models causes cell death. In rodents, inhibition of this pathway causes selective dopaminergic cell death leading to motor deficits resembling parkinsonism. Using postmortem human brain tissue, we characterized glucose metabolism via the PPP in sporadic Parkinson's disease (PD), Alzheimer's disease (AD), and controls. AD brains showed increased nicotinamide adenine dinucleotide phosphate (NADPH) production in areas affected by disease. In PD however, increased NADPH production was only seen in the affected areas of late-stage cases. Quantifying PPP NADPH-producing enzymes glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase by enzyme-linked immunosorbent assay, showed a reduction in the putamen of early-stage PD and interestingly in the cerebellum of early and late-stage PD. Importantly, there was no decrease in enzyme levels in the cortex, putamen, or cerebellum of AD. Our results suggest that down-regulation of PPP enzymes and a failure to increase antioxidant reserve is an early event in the pathogenesis of sporadic PD

Dopamine-dependent tuning of striatal inhibitory synaptogenesis.

Dopaminergic projections to the striatum, crucial for the correct functioning of this brain region in adulthood, are known to be established early in development, but their role is currently uncharacterized. We demonstrate here that dopamine, by activating D(1)- and/or D(2)-dopamine receptors, decreases the number of functional GABAergic synapses formed between the embryonic precursors of the medium spiny neurons, the principal output neurons of the striatum, with associated changes in spontaneous synaptic activity. Activation of these receptors reduces the size of postsynaptic GABA(A) receptor clusters and their overall cell-surface expression, without affecting the total number of clusters or the size or number of GABAergic nerve terminals. These changes result from an increased internalization of GABA(A) receptors, and are mediated by distinct signaling pathways converging at the level of GABA(A) receptors to cause a transient PP2A/PP1-dependent dephosphorylation. Thus, tonic D(1)- and D(2)-receptor activity limits the extent of collateral inhibitory synaptogenesis between medium spiny neurons, revealing a novel role of dopamine in controlling the development of intrinsic striatal microcircuits

Investigations of proximity-induced superconductivity in the topological insulator Bi2Te3 by microRaman spectroscopy

We used the topological insulator (TI) Bi2Te3 and a high-temperature superconductor (HTSC) hybrid device for investigations of proximity-induced superconductivity (PS) in the TI. Application of the superconductor YBa2Cu3O7- δ (YBCO) enabled us to access higher temperature and energy scales for this phenomenon. The HTSC in the hybrid device exhibits emergence of a pseudogap state for T > Tc that converts into a superconducting state with a reduced gap for T < Tc. The conversion process has been reflected in Raman spectra collected from the TI. Complementary charge transport experiments revealed emergence of the proximity-induced superconducting gap in the TI and the reduced superconducting gap in the HTSC, but no signature of the pseudogap. This allowed us to conclude that Raman spectroscopy reveals formation of the pseudogap state but cannot distinguish the proximity-induced superconducting state in the TI from the superconducting state in the HTSC characterised by the reduced gap. Results of our experiments have shown that Raman spectroscopy is a complementary technique to classic charge transport experiments and is a powerful tool for investigation of the proximity-induced superconductivity in the Bi2Te3

Exendin-4 Ameliorates Motor Neuron Degeneration in Cellular and Animal Models of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by a progressive loss of lower motor neurons in the spinal cord. The incretin hormone, glucagon-like peptide-1 (GLP-1), facilitates insulin signaling, and the long acting GLP-1 receptor agonist exendin-4 (Ex-4) is currently used as an anti-diabetic drug. GLP-1 receptors are widely expressed in the brain and spinal cord, and our prior studies have shown that Ex-4 is neuroprotective in several neurodegenerative disease rodent models, including stroke, Parkinson's disease and Alzheimer's disease. Here we hypothesized that Ex-4 may provide neuroprotective activity in ALS, and hence characterized Ex-4 actions in both cell culture (NSC-19 neuroblastoma cells) and in vivo (SOD1 G93A mutant mice) models of ALS. Ex-4 proved to be neurotrophic in NSC-19 cells, elevating choline acetyltransferase (ChAT) activity, as well as neuroprotective, protecting cells from hydrogen peroxide-induced oxidative stress and staurosporine-induced apoptosis. Additionally, in both wild-type SOD1 and mutant SOD1 (G37R) stably transfected NSC-19 cell lines, Ex-4 protected against trophic factor withdrawal-induced toxicity. To assess in vivo translation, SOD1 mutant mice were administered vehicle or Ex-4 at 6-weeks of age onwards to end-stage disease via subcutaneous osmotic pump to provide steady-state infusion. ALS mice treated with Ex-4 showed improved glucose tolerance and normalization of behavior, as assessed by running wheel, compared to control ALS mice. Furthermore, Ex-4 treatment attenuated neuronal cell death in the lumbar spinal cord; immunohistochemical analysis demonstrated the rescue of neuronal markers, such as ChAT, associated with motor neurons. Together, our results suggest that GLP-1 receptor agonists warrant further evaluation to assess whether their neuroprotective potential is of therapeutic relevance in ALS

The ongoing pursuit of neuroprotective therapies in Parkinson disease

Many agents developed for neuroprotective treatment of Parkinson disease (PD) have shown great promise in the laboratory, but none have translated to positive results in patients with PD. Potential neuroprotective drugs, such as ubiquinone, creatine and PYM50028, have failed to show any clinical benefits in recent high-profile clinical trials. This 'failure to translate' is likely to be related primarily to our incomplete understanding of the pathogenic mechanisms underlying PD, and excessive reliance on data from toxin-based animal models to judge which agents should be selected for clinical trials. Restricted resources inevitably mean that difficult compromises must be made in terms of trial design, and reliable estimation of efficacy is further hampered by the absence of validated biomarkers of disease progression. Drug development in PD dementia has been mostly unsuccessful; however, emerging biochemical, genetic and pathological evidence suggests a link between tau and amyloid-β deposition and cognitive decline in PD, potentially opening up new possibilities for therapeutic intervention. This Review discusses the most important 'druggable' disease mechanisms in PD, as well as the most-promising drugs that are being evaluated for their potential efficiency in treatment of motor and cognitive impairments in PD