Autophagy Modulation for Alzheimer’s Disease Therapy

Autophagy is an essential and conserved lysosomal degradation pathway that controls the quality of cytoplasm by eliminating the intracellular aggregated proteins and damaged organelles. Autophagy works in mammalian target of rapamycin (mTOR)-dependent pathway or mTOR-independent pathway to keep the neuronal homeostasis. Mounting evidence has implicated the importance of defective autophagy in the pathogenesis of aging and neurodegenerative diseases, especially in Alzheimer’s disease (AD). It has also demonstrated a neuroprotective role of autophagy in mediating the degradation of amyloid beta and tau which are major factors of AD. Amounts of molecules function in either mTOR-dependent pathway or mTOR-independent pathway to induce autophagy, which maybe a potential treatment for AD. In this review, we summarize the latest studies concerning the role of autophagy in AD and explore autophagy modulation as a potential therapeutic strategy for AD. However, to date, little of the researches on autophagy have been performed to investigate the modulation in AD; more investigations need to be confirmed in the future.     

Modulation effect of filamentous phage on α-synuclein aggregation

Conversion of soluble peptides and proteins into amyloid fibrils and/or intermediate oligomers is believed to be the central event in the pathogenesis of most human neurodegenerative diseases, including Parkinson’s disease (PD). Here we describe the modulating effect of filamentous phages on aggregation of α-synuclein (AS) in vitro and in a PD cellular model. Filamentous phages, well understood at both structural and genetic levels, have a nanotubular appearance, showing conformational similarities to amyloid fibrils. Since filamentous phages can infect only bacteria and have no tropism to mammalian cells, we utilized the f88 system to present a peptide containing a cyclic RGD (arg-gly-asp), which enabled phage internalization into the cells. Detection of intracellular AS oligomers, in differentiated SH-SY5Y cells, stably transfected with wild type AS gene, was performed using Western blot and ELISA measurements. Data presented here show reduced levels of AS soluble aggregates in phage treated cells compared to non-treated cells, suggesting new therapeutics for PD.     

The Modulation and Control of the Gecko''''s Foot Movement

1IntroductionAttachment is still a difficult problem in wall-climbing robotics.There are two main types ofattachment mechanisms for wall climbing robots.One issuction,which has major drawbacks.The mechanismrequires the contacting surface being smooth,otherwise itwill be ineffective.This limits adhesion of the suctioncup to relatively smooth,non-porous,non-crackedsurfaces.Another issue associated with suction adhesionis that this method requires time to develop enoughvacuum to generate suffici…     

Modulation of human interferon-γ biosynthesis by antisense oligodeoxynucleotides

We investigated the inhibition of human interferon-γ (HuIFN-γ) production in cultures of lymphocytes with the use of the antisense strategy. Out of a series of antisense oligodeoxynucleotides (ODN) complementary to different regions of the HuIFN-γ gene, a 16-mer specific for a sequence including the translation initiation codon was the most effective. Here we describe a detailed protocol for the isolation of lymphocytes from buffy coats, the rational design of antisense ODN, and the monitoring of HuIFN-γ production of the antisense ODN-treated cells.     

Is Autonomic Modulation Different between European and Chinese Astronauts?

Purpose

The objective was to investigate autonomic control in groups of European and Chinese astronauts and to identify similarities and differences.

Methods

Beat-to-beat heart rate and finger blood pressure, brachial blood pressure, and respiratory frequency were measured from 10 astronauts (five European taking part in three different space missions and five Chinese astronauts taking part in two different space missions). Data recording was performed in the supine and standing positions at least 10 days before launch, and 1, 3, and 10 days after return. Cross-correlation analysis of heart rate and systolic pressure was used to assess cardiac baroreflex modulation. A fixed breathing protocol was performed to measure respiratory sinus arrhythmia and low-frequency power of systolic blood pressure variability.

Results

Although baseline cardiovascular parameters before spaceflight were similar in all astronauts in the supine position, a significant increase in sympathetic activity and a decrease in vagal modulation occurred in the European astronauts when standing; spaceflight resulted in a remarkable vagal decrease in European astronauts only. Similar baseline supine and standing values for heart rate, mean arterial pressure, and respiratory frequency were shown in both groups. Standing autonomic control was based on a balance of higher vagal and sympathetic modulation in European astronauts.

Conclusion

Post-spaceflight orthostatic tachycardia was observed in all European astronauts, whereas post-spaceflight orthostatic tachycardia was significantly reduced in Chinese astronauts. The basis for orthostatic intolerance is not apparent; however, many possibilities can be considered and need to be further investigated, such as genetic diversities between races, astronaut selection, training, and nutrition, etc.     

Inflammatory Mediators and Modulation of Blood–Brain Barrier Permeability

1. Unlike some interfaces between the blood and the nervous system (e.g., nerve perineurium), the brain endothelium forming the blood–brain barrier can be modulated by a range of inflammatory mediators. The mechanisms underlying this modulation are reviewed, and the implications for therapy of the brain discussed.2. Methods for measuring blood–brain barrier permeability in situ include the use of radiolabeled tracers in parenchymal vessels and measurements of transendothelial resistance and rate of loss of fluorescent dye in single pial microvessels. In vitro studies on culture models provide details of the signal transduction mechanisms involved.3. Routes for penetration of polar solutes across the brain endothelium include the paracellular tight junctional pathway (usually very tight) and vesicular mechanisms. Inflammatory mediators have been reported to influence both pathways, but the clearest evidence is for modulation of tight junctions.4. In addition to the brain endothelium, cell types involved in inflammatory reactions include several closely associated cells including pericytes, astrocytes, smooth muscle, microglia, mast cells, and neurons. In situ it is often difficult to identify the site of action of a vasoactive agent. In vitro models of brain endothelium are experimentally simpler but may also lack important features generated in situ by cell:cell interaction (e.g. induction, signaling).5. Many inflammatory agents increase both endothelial permeability and vessel diameter, together contributing to significant leak across the blood–brain barrier and cerebral edema. This review concentrates on changes in endothelial permeability by focusing on studies in which changes in vessel diameter are minimized.6. Bradykinin (Bk)² increases blood–brain barrier permeability by acting on B₂ receptors. The downstream events reported include elevation of [Ca²⁺]_i, activation of phospholipase A₂, release of arachidonic acid, and production of free radicals, with evidence that IL-1 potentiates the actions of Bk in ischemia.7. Serotonin (5HT) has been reported to increase blood–brain barrier permeability in some but not all studies. Where barrier opening was seen, there was evidence for activation of 5-HT₂ receptors and a calcium-dependent permeability increase.8. Histamine is one of the few central nervous system neurotransmitters found to cause consistent blood–brain barrier opening. The earlier literature was unclear, but studies of pial vessels and cultured endothelium reveal increased permeability mediated by H₂ receptors and elevation of [Ca²⁺]_i and an H₁ receptor-mediated reduction in permeability coupled to an elevation of cAMP.9. Brain endothelial cells express nucleotide receptors for ATP, UTP, and ADP, with activation causing increased blood–brain barrier permeability. The effects are mediated predominantly via a P_2U (P2Y₂) G-protein-coupled receptor causing an elevation of [Ca²⁺]_i; a P2Y₁ receptor acting via inhibition of adenyl cyclase has been reported in some in vitro preparations.10. Arachidonic acid is elevated in some neural pathologies and causes gross opening of the blood–brain barrier to large molecules including proteins. There is evidence that arachidonic acid acts via generation of free radicals in the course of its metabolism by cyclooxygenase and lipoxygenase pathways.11. The mechanisms described reveal a range of interrelated pathways by which influences from the brain side or the blood side can modulate blood–brain barrier permeability. Knowledge of the mechanisms is already being exploited for deliberate opening of the blood–brain barrier for drug delivery to the brain, and the pathways capable of reducing permeability hold promise for therapeutic treatment of inflammation and cerebral edema.     

Microring Plasmonic Circuit Characteristics Using Space–Time Modulation Control

Plasmonics - The biased plasmonic circuit is proposed using a Panda-ring infinitesimal space–time function control. The circuit has two small rings alongside the main microring. The small...     

Modulation of α-Synuclein Aggregation by Dopamine: A Review

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is characterized by (1) the selective loss of dopaminergic neurons in the substantia nigra and (2) the deposition of misfolded α-synuclein (α-syn) as amyloid fibrils in the intracellular Lewy bodies in various region of the brain. Current thinking suggests that an interaction between α-syn and dopamine (DA) leads to the selective death of neuronal cells and the accumulation of misfolded α-syn. However, the exact mechanism by which this occurs is not fully defined. DA oxidation could play a key role is the pathogenesis of PD by causing oxidative stress, mitochondria dysfunction and impairment of protein metabolism. Here, we review the literature on the role of DA and its oxidative intermediates in modulating the aggregation pathways of α-syn.     

Modulation–Frequency Analysis of an Electrically Pumped Plasmonic Amplifier

Frequency of variations of surface plasmon intensity at the input of a plasmonic amplifier is called modulation–frequency. High modulation–frequency behavior of a Schottky junction-based plasmonic amplifier has been in the focus of this paper. Both small signal and large signal conditions have been considered. In small signal condition, an analytical solution of the rate equations of the electrons and photons has been presented which its results are in accordance with the simulation results of a harmonic balance method. For an amplifier of 100 μm length, the small signal gain has been 14.62 dB from both methods. Large signal behavior has been described by IIP2 and IIP3 in a two tone test which has been implemented by the harmonic balance method. IIP2 and IIP3 of the plasmonic amplifier of this work at 1 GHz are –21.2 and –19.95 dBm, respectively, and their values increase with frequency.     

Modulation of endogenous prostaglandins by thymosin-α1 in lymphocytes

The effects of thymosin-α₁ on the stimulation of specific release of prostaglandin E₂ (PGE₂) from splenic lymphocytes and thymocytes were studied. Experiments were also performed to study in parallel the absolute levels of thymosin-α₁ in the blood and the induction of serum FTS activity and of azathioprine sensitivity of spleen cells from adult thymectomized (ATx) mice. A significant difference in the release of PGE₂ between normal splenocytes and splenocytes from ATx mice was observed. Thymosin-α₁ at certain concentrations was able to stimulate PGE₂ release from lymphocytes of ATx mice while inhibiting release in lymphocytes of normal mice. Also, thymocytes were stimulated to release PGE₂ after incubation with α₁ in a manner similar to that seen in spleen cells of ATx mice. Approximately the same concentration of α₁ was found to also correct the low azathioprine sensitivity of splenocytes from ATx mice. Determinations of FTS-like activity in the blood and the pharmacokinetics of α₁ after administration of this synthetic molecule show a clear dissociation. A maximum peak of α₁ activity was obtained after 1 hr, while maximal FTS-like activity was observed after 24 hr. The inhibition of the induction by α₁ of FTS-like activity and of Thy 1.2 antigen by indomethacin suggests that the action of α₁ requires prostaglandin biosynthesis.     

Mechanism of μ-Opioid Receptor-Magnesium Interaction and Positive Allosteric Modulation

In the era of opioid abuse epidemics, there is an increased demand for understanding how opioid receptors can be allosterically modulated to guide the development of more effective and safer opioid therapies. Among the modulators of the μ-opioid (MOP) receptor, which is the pharmacological target for the majority of clinically used opioid drugs, are monovalent and divalent cations. Specifically, the monovalent sodium cation (Na⁺) has been known for decades to affect MOP receptor signaling by reducing agonist binding, whereas the divalent magnesium cation (Mg²⁺) has been shown to have the opposite effect, notwithstanding the presence of sodium chloride. Although ultra-high-resolution opioid receptor crystal structures have revealed a specific Na⁺ binding site and molecular dynamics (MD) simulation studies have supported the idea that this monovalent ion reduces agonist binding by stabilizing the receptor inactive state, the putative binding site of Mg²⁺ on the MOP receptor, as well as the molecular determinants responsible for its positive allosteric modulation of the receptor, are unknown. In this work, we carried out tens of microseconds of all-atom MD simulations to investigate the simultaneous binding of Mg²⁺ and Na⁺ cations to inactive and active crystal structures of the MOP receptor embedded in an explicit lipid-water environment and confirmed adequate sampling of Mg²⁺ ion binding with a grand canonical Monte Carlo MD method. Analyses of these simulations shed light on 1) the preferred binding sites of Mg²⁺ on the MOP receptor, 2) details of the competition between Mg²⁺ and Na⁺ cations for specific sites, 3) estimates of binding affinities, and 4) testable hypotheses of the molecular mechanism underlying the positive allosteric modulation of the MOP receptor by the Mg²⁺ cation.     

Modulation of mammalian circadian rhythms by tumor necrosis factor-α

Systemic low doses of the endotoxin lipopolysaccharide (LPS, 100?µg/kg) administered during the early night induce phase-delays of locomotor activity rhythms in mice. Our aim was to evaluate the role of tumor necrosis factor (Tnf)-alpha and its receptor 1/p55 (Tnfr1) in the modulation of LPS-induced circadian effects on the suprachiasmatic nucleus (SCN). We observed that Tnfr1-defective mice (Tnfr1 KO), although exhibiting similar circadian behavior and light response to that of control mice, did not show LPS-induced phase-delays of locomotor activity rhythms, nor LPS-induced cFos and Per2 expression in the SCN and Per1 expression in the paraventricular hypothalamic nucleus (PVN) as compared to wild-type (WT) mice. We also analyzed Tnfr1 expression in the SCN of WT mice, peaking during the early night, when LPS has a circadian effect. Peripheral inoculation of LPS induced an increase in cytokine/chemokine levels (Tnf, Il-6 and Ccl2) in the SCN and in the PVN. In conclusion, in this study, we show that LPS-induced circadian responses are mediated by Tnf. Our results also suggest that this cytokine stimulates the SCN after LPS peripheral inoculation; and the time-related effect of LPS (i.e. phase shifts elicited only at early night) might depend on the increased levels of Tnfr1 expression. We also confirmed that LPS modulates clock gene expression in the SCN and PVN in WT but not in Tnfr1 KO mice.

Highlights: We demonstrate a fundamental role for Tnf and its receptor in circadian modulation by immune stimuli at the level of the SCN biological clock.     

Modulation of Voltage-dependent Properties of a Swelling-activated Cl? Current

We used the patch-clamp technique to study the voltage-dependent properties of the swelling-activated Cl⁻ current (I _Cl,swell) in BC₃H1 myoblasts. This Cl⁻ current is outwardly rectifying and exhibits time-dependent inactivation at positive potentials (potential for half-maximal inactivation of +75 mV). Single-channel Cl⁻ currents with similar voltage-dependent characteristics could be measured in outside-out patches pulled from swollen cells. The estimated single-channel slope conductance in the region between +60 and +140 mV was 47 pS. The time course of inactivation was well described by a double exponential function, with a voltage-independent fast time constant (∼60 ms) and a voltage-dependent slow time constant (>200 ms). Recovery from inactivation, which occurred over the physiological voltage range, was also well described by a double exponential function, with a voltage-dependent fast time constant (10–80 ms) and a voltage-dependent slow time constant (>100 ms). The inactivation process was significantly accelerated by reducing the pH, increasing the Mg²⁺ concentration or reducing the Cl⁻ concentration of the extracellular solution. Replacing extracellular Cl⁻ by other permeant anions shifted the inactivation curve in parallel with their relative permeabilities (SCN⁻ > I⁻ > NO₃ ⁻ > Cl⁻ >> gluconate). A leftward shift of the inactivation curve could also be induced by channel blockers. Additionally, the permeant anion and the channel blockers, but not external pH or Mg²⁺, modulated the recovery from inactivation. In conclusion, our results show that the voltage-dependent properties of I _Cl,swell are strongly influenced by external pH , external divalent cations, and by the nature of the permeant anion.     

The Modulation and Control of the Gecko＇s Foot Movement

The modulation and control of gecko＇s foot movements were studied electrophysiologically in order to design the motor control system of a gecko-mimic robot. In this study （1） the anatomy of the peripheral nerves controlling the gecko＇s foot movements was determined; （2） the relationship between the limb nerves of the gecko and its foot motor patterns was studied; （3） the afferent impulses of the nerves evoked by rubbing the gecko＇s toes and palm were recorded; （4） copying the natural patterns of movement of the gecko＇s foot （abduction, adduction, flexion, and revolution） and its limb nerve modulation and control mechanism, the nerves were stimulated under computer control, and the results recorded by CCD. Results suggest that gecko＇s foot movements can be successfully controlled by artificial electrical signals.