Fangchinoline alleviates cognitive impairments through enhancing autophagy and mitigating oxidative stress in Alzheimer’s disease models

Introduction: Alzheimer’s disease (AD) is a debilitating, progressive, neurodegenerative disorder characterized by the deposition of amyloid-β (Aβ) peptides and subsequent oxidative stress, resulting in a cascade of cytotoxic effects. Fangchinoline (Fan), a bisbenzylisoquinoline alkaloid isolated from traditional Chinese herb Stephania tetrandra S. Moorec, has been reported to possess multiple potent biological activities, including anti-inflammatory and antioxidant properties. However, the potential neuroprotective efficacy of Fan against AD remains unknown.Methods: N2AAPP cells, the mouse neuroblastoma N2A cells stably transfected with human Swedish mutant APP695, were served as an in vitro AD model. A mouse model of AD was constructed by microinjection of Aβ1–42 peptides into lateral ventricle of WT mice. The neuroprotective effects of Fan on AD were investigated through a combination of Western blot analysis, immunoprecipitation and behavioral assessments.Results and discussion: It was found that Fan effectively attenuated the amyloidogenic processing of APP by augmenting autophagy and subsequently fostering lysosomal degradation of BACE1 in N2AAPP cells, as reflected by the decrease in P62 levels, concomitant with the increase in Beclin-1 and LC3-II levels. More importantly, Fan significantly ameliorated cognitive impairment in an Aβ1–42-induced mouse model of AD via the induction of autophagy and the inhibition of oxidative stress, as evidenced by an increase in antioxidants including glutathione reductase (GR), total antioxidant capacity (T-AOC), nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and superoxide dismutase-1 (SOD-1) and a decrease in pro-oxidants including hydrogen peroxide (H2O2) and inducible nitric oxide synthase (i-NOS), coupled with a reduction in apoptosis marker, cleaved caspase-3. Taken together, our study demonstrate that Fan ameliorates cognitive dysfunction through promoting autophagy and mitigating oxidative stress, making it a potential therapeutic agent for AD

CRL4Wdr70 regulates H2B monoubiquitination and facilitates Exo1-dependent resection

Double strand breaks repaired by homologous recombination (HR) are first resected to form single stranded DNA which binds replication protein A (RPA). RPA attracts mediators which load the Rad51 filament to promote strand invasion, the defining feature of HR. How the resection machinery navigates nucleosome-packaged DNA is poorly understood. Using Schizosaccharomyces pombe we report that a conserved DDB1-CUL4-associated factor (DCAF), Wdr70, is recruited to DSBs as part of the Cullin4-DDB1 ubiquitin ligase (CRL4Wdr70) and stimulates distal H2B lysine 119 monoubiquitination(uH2B). Wdr70 deletion, or uH2B loss, results in increased loading of the checkpoint adaptor and resection inhibitor Crb253BP1, decreased Exo1 association and delayed resection. Wdr70 is dispensable for resection upon Crb253BP1 loss, or when the Set9 methyltransferase that creates docking sites for Crb2 is deleted. Finally we establish that this histone regulatory cascade similarly controls DSB resection in human cells

Wireless communication integrated hybrid ANC system with impulsive noise cancellation capability for infant incubator

Advisors: Lichuan Liu.Committee members: Veysel Demir; Donald S. Zinger.Includes bibliographical references.Includes illustrations.Preterm infants are often admitted into neonatal intensive care unit (NICU) to increase their survival rate. However, fragile infants are exposed to ambient noise from medical equipment and human activities. High intensities of noise have been involved with numerous advanced health effects in infants. There is a growing concern that a mechanism can be used to cancel noise both inside and outside the incubator. More and more researches show that communication between parents and infants from an early stage accelerates the maturation of infants and has good influence on infants' self-esteem and socialization. This causes the need for a medium that transfers the information between parents and neonates while infants are still protected in a safe environment. Since impulsive noise is a main portion in real-time NICU noise, an effective and stable method should be conducted to solve the problem. However, the traditional algorithm in active noise control (ANC) system has high chance to diverge when impulsive noise occurs. In this thesis, based on three major problems in the existing ANC system, a wireless communication integrated hybrid ANC (WCHANC) system with impulsive noise cancellation for infant incubator is proposed. My main contributions are: 1) The hybrid active noise control (HANC) system implemented in this thesis can cancel both inside and outside noise. 2) The wireless communication function is integrated to the main HANC system in order to transfer speech signals between parents and infants. 3) An alternative Kalman filter is proposed to reduce the impulsive noise. Real-time experiment results for WCHANC show that the proposed system can dramatically reduce the noise level inside infant incubators while providing two-way communication between parents and infants. Simulations for the proposed Kalman filter algorithm show that it can effectively track and cancel the impulsive noise.M.S. (Master of Science

Incubator-based Sound Attenuation: Active Noise Control In A Simulated Clinical Environment.

ObjectiveNoise in the neonatal intensive care unit can be detrimental to the health of the hospitalized infant. Means of reducing that noise include staff training, warning lights, and ear coverings, all of which have had limited success. Single family rooms, while an improvement, also expose the hospitalized infant to the same device alarms and mechanical noises found in open bay units.MethodsWe evaluated a non-contact incubator-based active noise control device (Neoasis™, Invictus Medical, San Antonio, Texas) in a simulated neonatal intensive care unit (NICU) setting to determine whether it could effectively reduce the noise exposure of infants within an incubator. In the NICU simulation center, we generated a series of clinically appropriate sound sequences with bedside medical devices such as a patient monitor and fluid infusion devices, hospital air handling systems, and device mechanical sounds. A microphone-equipped infant mannequin was oriented within an incubator. Measurements were made with the microphones with the Neoasis™ deactivated and activated.ResultsThe active noise control device decreased sound pressure levels for certain alarm sounds by as much as 14.4 dB (a 5.2-fold reduction in sound pressure) at the alarm tone's primary frequency. Frequencies below the 2 kHz octave band were more effectively attenuated than frequencies at or above the 2 kHz octave band. Background noise levels below 40 dBA were essentially not impacted by the active noise control device.ConclusionsThe active noise control device further reduces noise inside infant incubators. Device safety and potential health benefits of the quieter environment should be verified in a clinical setting

On the Paleo-Mesoproterozoic boundary from the breakup event of the Columbia supercontinent

In the International Precambrian Stratigraphic Chart, the Paleo-/Mesoproterozoic boundary is always set at 1.6Ga while in Chinese literatures, this boundary is always placed at 1.8Ga. The fundamental reason for this difference is the understanding of the nature of the geological events in this period. This paper focuses on discussing the boundary between Paleoproterozoic and Mesoproterozoic from the nature of the geological events during 1.8 similar to 1.6Ga. A large amount of geological data shows that the Columbia/Nuna supercontinent began to stretch and breakup from 1.8Ga to 1.75Ga and formed a series of intracontinental rifting-sag basins, such as Thelon basin in North America (Laurentia), Leichhardt superbasin in northern Australia, Sao Francisco basin in South America, Xiong'er rifting basin in the southern margin of the North China Craton, Dongchuan basin in the southwestern margin of the Yangtze Block, and others. During the early stage of basin formation, the clastic rocks of alluvial fan facies and fluvial facies were deposited, followed by extensive volcanic eruptions. During the middle and late stage, the ealier fluvial facies and lacustrine facies rocks were overlied by carbonate platform sediments deposited in shallow sea, which reflects a process of stretching and breakup. Anorogenic magmatic rocks of 1.78 similar to 1.72Ga distributed widely in continents/blocks that formed the Columbia supercontinent, including bimodal igneous rocks, AMCG assemblages (anorthosite, mangerite, charnockite and granite), rapakivi granite, A-type granite, etc., as well as widely distributed mafic dyke swarms. All these igneous rocks reflect the stretching and breaking process. During 1.8 similar to 1.6Ga, both sedimentary events and magmatic events were related to the stretching and breaking of the supercontinent, but did not show the characteristics of orogeny, continental solidation and cratonization. Therefore, it is not appropriate to use the Statherian to summarize the nature of the geological events in this stage. In Columbia supercongtinent, many intracontinental basins experienced a wide uplift at around 1.6Ga, resulting in a short interval of sedimentation. After that, the original basins continued to develop and accepted a wider range of sedimentation, which sustained until about 1.4 similar to 1.3Ga. Magmatic events related to supercontinental stretching and breaking can also be intermittent from 1.78Ga to 1.4 similar to 1.32Ga. From 1.8Ga (or 1.78Ga) to 1.4 similar to 1.3Ga, both sedimentary events in the basins and magmatic events related to stretching and breaking are basically continuous. Therefore, the set of Paleo-Mesoproterozoic boundary at 1.6Ga artificially destroys the continuity of global sedimentary events and magmatic events, which were obviously contrary to the principle that the major sequences of sedimentation, igneous emplacement, or orogeny should be cut off as little as possible in the Precambrian stratigraphic division. Since the time of the successive depositional events in rifting-basins and of the anorogenic magmatic events in continents can be traced back to 1.8Ga (or 1.78Ga), we propose to place the Paleo-Mesoproterozoic boundary at 1.8Ga or 1.78Ga, rather then 1.6Ga. Considering that the rifting process leads to the development of the overlying strata on the preexisting supercontinent or craton, we suggest classifying the sediments of ca. 1.8 similar to 1.4Ga into the Calymmian

Cationicity-Enhanced Analogues of the Antimicrobial Peptides, AcrAP1 and AcrAP2, from the Venom of the Scorpion, Androctonus crassicauda, Display Potent Growth Modulation Effects on Human Cancer Cell Lines

The non disulphide-bridged peptides (NDBPs) of scorpion venoms are attracting increased interest due to their structural heterogeneity and broad spectrum of biological activities. Here, two novel peptides, named AcrAP1 and AcrAP2, have been identified in the lyophilised venom of the Arabian scorpion, Androctonus crassicauda, through “shotgun” molecular cloning of their biosynthetic precursor-encoding cDNAs. The respective mature peptides, predicted from these cloned cDNAs, were subsequently isolated from the same venom sample using reverse phase HPLC and their identities were confirmed by use of mass spectrometric techniques. Both were found to belong to a family of highly-conserved scorpion venom antimicrobial peptides - a finding confirmed through the biological investigation of synthetic replicates. Analogues of both peptides designed for enhanced cationicity, displayed enhanced potency and spectra of antimicrobial activity but, unlike the native peptides, these also displayed potent growth modulation effects on a range of human cancer cell lines. Thus natural peptide templates from venom peptidomes can provide the basis for rational analogue design to improve both biological potency and spectrum of action. The diversity of such templates from such natural sources undoubtedly provides the pharmaceutical industry with unique lead compounds for drug discovery

Presentation1_Fangchinoline alleviates cognitive impairments through enhancing autophagy and mitigating oxidative stress in Alzheimer’s disease models.pdf

Introduction: Alzheimer’s disease (AD) is a debilitating, progressive, neurodegenerative disorder characterized by the deposition of amyloid-β (Aβ) peptides and subsequent oxidative stress, resulting in a cascade of cytotoxic effects. Fangchinoline (Fan), a bisbenzylisoquinoline alkaloid isolated from traditional Chinese herb Stephania tetrandra S. Moorec, has been reported to possess multiple potent biological activities, including anti-inflammatory and antioxidant properties. However, the potential neuroprotective efficacy of Fan against AD remains unknown.Methods: N2AAPP cells, the mouse neuroblastoma N2A cells stably transfected with human Swedish mutant APP695, were served as an in vitro AD model. A mouse model of AD was constructed by microinjection of Aβ1–42 peptides into lateral ventricle of WT mice. The neuroprotective effects of Fan on AD were investigated through a combination of Western blot analysis, immunoprecipitation and behavioral assessments.Results and discussion: It was found that Fan effectively attenuated the amyloidogenic processing of APP by augmenting autophagy and subsequently fostering lysosomal degradation of BACE1 in N2AAPP cells, as reflected by the decrease in P62 levels, concomitant with the increase in Beclin-1 and LC3-II levels. More importantly, Fan significantly ameliorated cognitive impairment in an Aβ1–42-induced mouse model of AD via the induction of autophagy and the inhibition of oxidative stress, as evidenced by an increase in antioxidants including glutathione reductase (GR), total antioxidant capacity (T-AOC), nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and superoxide dismutase-1 (SOD-1) and a decrease in pro-oxidants including hydrogen peroxide (H2O2) and inducible nitric oxide synthase (i-NOS), coupled with a reduction in apoptosis marker, cleaved caspase-3. Taken together, our study demonstrate that Fan ameliorates cognitive dysfunction through promoting autophagy and mitigating oxidative stress, making it a potential therapeutic agent for AD.</p

Mitochondrial DNA Mutation Screening in an Ethnically Diverse Nonsyndromic Deafness Cohort

Deafness is a heterogeneous trait with many known genetic and environmental causes. Hereditary hearing loss is an extremely common disorder in the general population. Mutations in mitochondrial DNA (mtDNA) are known to be associated with nonsyndromic deafness (NSD) and syndromic deafness. The objective of this article is to investigate the frequency of common mitochondrial mutations (A1555G, G7444A, and A3243G) in an ethnically diverse cohort of probands with NSD from South Florida. These patients were ascertained at the University of Miami. Polymerase chain reaction–restriction fragment length polymorphism analysis and direct sequencing methods were used for mutation screening in a cohort of 217 patients with NSD. The frequency of common mitochondrial mutations is 1.84% (4/217) in this cohort. A1555G and G7444A accounted for four patients with NSD. Our mutation frequencies are comparable with those previously reported in other populations, indicating that mutations in mtDNA are an important cause of NSD in our patient cohort

Geochemistry of ∼2.7Ga basalts from Taishan area: Constraints on the evolution of early Neoarchean granite-greenstone belt in western Shandong Province, China

Western Shandong Province (WSP) is one of the typical Neoarchean granite-greenstone belts in the North China Craton (NCC). The Taishan association, consisting of a ∼2.7 Ga komatiite–tholeiite sequence and a ∼2.5 Ga felsic volcanic-sedimentary sequence, is the major supracrustal assemblage in the WSP. The ∼2.7 Ga komatiite–tholeiite sequence can be subdivided into the Yanlingguan and Liuhang units. The 150–800 m thick basaltic lava sequence of the Liuhang unit is exposed in the Qixingtai area, with the bottom unit composed of massive and layered basalts. Pillow basalts and tuff dominate the upper parts of the sequence. We report a weighted mean SHRIMP 207Pb/206Pb zircon age of 2706 ± 9 Ma (MSWD = 0.61) for a trondhjemitic dike that intrudes the base of the pillow basalts, constraining the timing of this sequence to be older than this age. The basaltic lava sequence in the Liuhang unit is characterized by voluminous tholeiites and a minor component of enriched basalts. The tholeiites show relatively high MgO (5.5–9.0 wt.%), but low TiO2 (0.8–1.3 wt.%) and Nb (2.1–3.3 ppm) contents. They display co-variations between Zr and other immobile trace elements and flat REE and trace elements patterns on chondrite- and primary mantle-normalized diagrams, respectively. In contrast, the enriched basalts have low MgO (3.6–5.4 wt.%), but high TiO2 (1.6–2.2 wt.%) and Nb (8.4–11.6 ppm) contents. They display moderately enriched LREE and fractionated HREE patterns on chondrite-normalized diagrams. The basaltic sequence of the Liuhang unit displays a moderate range of initial ɛNd (−0.1 to +3.0) values. The element concentration and Nd isotopes of tholeiitic rocks in the Liuhang unit are comparable with the contemporaneous tholeiites in greenstone belts globally. In particular, the geochemical systematics of the tholeiite and enriched basalts show close similarity with those of the Wawa greenstone belt in the Superior Province. The Nb/Th, La/Smcn and Nb/La ratios of these basalts indicate that the basaltic lava sequence of the Liuhang unit has not been significantly affected by crustal contamination compared to the Yanlingguan komatiite–tholeiite sequence. The variation in lithology and geochemistry of basalts between the Liuhang and Yanlingguan units reflects a lateral change in composition of the ∼2.7 Ga basaltic eruption. We propose that the komatiite–tholeiite sequence in the Taishan association was derived from an upwelling mantle plume with eruption close to the continental margin within an ocean basin. Our study does not provide any evidence to support that the WSP granite-greenstone belt was subjected to significant arc–plume interaction during the early Neoarchean. Our results contribute to the understanding of early Neoarchean crustal growth globally identified from different regions