bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defective proteostasis in patient‐derived iPSC‐astrocytes and neurons carrying a MAPT IVS10+16 mutation
Authors: Mahali Sidhartha , Karch Celeste 
Published: December 2021

AbstractBackgroundImpaired proteostasis is associated with normal aging and is accelerated in neurodegeneration. This impairment may lead to the toxic protein accumulation. In a subset of frontotemporal dementia (FTD) cases, mutations in the microtubule‐associated protein tau (MAPT) that alter the relative levels of specific tau isoforms are sufficient to cause tau inclusions in neurons and astroglia and neurodegeneration without the presence of mutated protein (e.g. MAPTIVS10+16). However, the pathogenic events triggered by the expression of the alternatively spliced tau remain poorly understood.MethodTo determine whether altered tau splicing induced from MAPT IVS10+16 mutations is sufficient to alter proteostasis in neurons and glia, we used human induced pluripotent stem cell (iPSC)‐derived neurons and astrocytes from patients carrying the MAPT IVS10+16 mutation and CRISPR/Cas9, isogenic corrected controls.ResultWe found that neurons from MAPT IVS10+16 carriers exhibited significantly higher levels of 4 repeat tau, deficits in lysosomal trafficking, and reduced lysosomal acidity relative to isogenic‐control neurons. Additionally, MAPTIVS10+16 was sufficient to reduce genes associated with lysosomal biogenesis (regulated by TFEB). Interestingly, mutant astrocytes also produce elevated 4 repeat tau levels and exhibit several key hallmarks of cellular aging. Mutant astrocytes were larger in size with enlarged nuclei compared to isogenic controls. In addition to this hypertrophy phenotype, mutant astrocytes exhibited significantly elevated levels of senescence genes. Furthermore, markers of proteostasis were altered in mutant astrocytes: MAPT IVS10+16 carriers exhibited an increase in acidic lysosomes compared to isogenic‐control astrocytes, and TFEB‐regulated genes were upregulated MAPT IVS10+16 astrocytes.ConclusionOur findings suggest that altered tau splicing induced by the MAPT IVS10+16 mutation is sufficient to cause aging signatures, including hypertrophy, senescence, and altered proteostasis in a cell‐type specific manner.
Exercise‐Induced Alterations in TrkB expression in the 5XFAD Mouse Model of Alzheimer’s Disease
Authors: Moylan Christopher , Cao Thanh Vinh , Huynh Quy‐Susan , Pratap Anishchal , Holsinger R. M. Damian 
Published: December 2021

AbstractBackgroundAlzheimer’s Disease (AD) is a slow progressing neurodegenerative disease with various environmental and endogenous factors implicated in its development. Two such factors include downregulation of tropomyosin receptor kinase B (TrkB) and its ligand, brain derived neurotrophic factor (BDNF), which normally facilitate the function and survival of neurons. While the exact causes of AD are still unknown, studies have shown that interventions such as aerobic exercise may reduce the risk of its progression. Interestingly, BDNF and TrkB each have unique expression patterns in the presence Aβ plaques and tau tangles, the main pathologies of AD; these patterns further fluctuate across different exercise types, intensities, and durations.MethodIn the current study, we used the 5XFAD mouse model of AD (36 weeks of age) to investigate the nature of exercise‐induced neurotrophin alterations. We compared transgenic mice (Tg) and their wild‐type (WT) littermates following an exercise regimen consisting of a 60‐minute/day steady‐state treadmill exercise protocol for 3 weeks. We used immunofluorescent staining to examine the cortical expression of BDNF and TrkB across these groups.ResultWe found similar levels of TrkB expression in both exercised groups (WT and Tg) but significantly lower TrkB expression in the exercised 5XFAD Tg mice compared to their sedentary littermates. We failed to observe changes in BDNF expression across any of the groups.ConclusionThe ability of exercise to restore TrkB protein levels in 5XFAD Tg mice to those of exercised wildtype littermates, suggests that TrkB may be considered a potential target for therapeutic intervention. We further postulate that exercise may have a restorative function on cognition and thus may be a prospective therapeutic avenue of treatment for AD and associated cognitive disorders.
Global C3 lowering alleviates hippocampal dysfunction and cognitive impairment in aged mice
Authors: Batista Andre Felipe , Schroeder Maren K , Khan Khyrul , Li Shaomin A , Presumey Jessy , Yalcin Esra , Carroll Michael , Lemere Cynthia A 
Published: December 2021

AbstractBackgroundComplement component C3, an innate immune molecule, is important for removing pathogens and eliminating synapses during brain development, aging, and Alzheimer’s disease (AD). Previously, our group demonstrated that C3 deficiency protected against synapse loss during normal aging in wild‐type and APPswe/PS1dE9 mice. Induction of C3 deficiency after normal brain development will help inform whether its inhibition in aging or early stages of AD may serve as a future therapeutic strategy.MethodWe crossed C3fl/fl mice with an inducible, global Cre line (Rosa26‐Cre‐ERT2+/‐) for 2 generations to generate novel inducible C3 conditional knockout C3fl/fl; Rosa26‐Cre‐ERT2+/‐ mice (C3iKO). In one cohort, four‐to‐five‐month‐old mice were injected with tamoxifen (TAM) or corn oil (CO) daily for 5 days. Behavioral tasks were performed when these mice reached 16‐17 months of age. In another study, three‐to‐four‐month‐old female mice were injected with either CO/TAM and electrophysiological recording of long‐term potentiation (LTP) was conducted in hippocampal slices of TAM‐treated and CO‐treated mice at 7‐8 months of age following incubation of the slices with neurotoxic Aβ S26 dimers.ResultC3iKO mice had a significant 85‐95% reduction in serum C3 levels compared to controls, which was consistent at all timepoints analyzed (from Day 7 to Day 365). In this cohort, behavioral testing for hippocampal‐dependent spatial memory, object memory, and object location was performed when TAM‐treated and CO‐treated mice reached 16‐17 months of age. C3iKO+TAM mice performed significantly better than C3iKO+CO‐treated mice in these behavioral tasks, indicating that C3 lowering after brain development protected mice from age‐related cognitive decline. In the second study, we found that C3 lowering in adult mice protected hippocampal synapses from Aβ S26 dimer‐mediated LTP impairment.ConclusionGlobal C3 depletion in C3iKO young adult mice protected against hippocampal dysfunction as they aged, suggesting that C3 lowering may be an effective therapeutic strategy for aging and possibly, AD. Future studies are underway to investigate the C3‐mediated mechanisms of synaptic dysfunction in the hippocampus.
Impact of PLCG2 expression on Microglial Biology and Disease Pathogenesis in Alzheimer’s Disease
Authors: Tsai Andy Po‐Yi , Lin Peter Bor‐Chian , Dong Chuanpeng , Moutinho Miguel , Liu Yunlong , Bissel Stephanie J , Oblak Adrian L , Nho Kwangsik , Lamb Bruce T. , Landreth Gary E 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) and other neurodegenerative diseases are typified by a robust microglial‐mediated immune response. Genetic studies have demonstrated that variants in microglial genes are linked to risk for AD. Phospholipase C gamma 2 (PLCG2), whose variants confer altered risk for AD, is a critical signaling element for various immune receptors and is a key regulatory hub gene for immune signaling. To date, it is known that PLCG2 might be important in AD due to the pervious findings that a hypermorphic variant in PLCG2, rs72824905, is protective against AD risk. However, the role of PLCG2 has not yet been comprehensively explored. We believe that genetic mouse models are needed to further clarify the role of PLCG2 in plaque‐associated microglia and to determine whether decreased PLCG2 expression in plaque‐associated microglia favors disease exacerbation or attenuation.MethodTo investigate the impact of reduced PLCG2 gene expression on microglia biology and disease pathology, we have generated PLCG2 inactivation mice, all crossed onto the 5XFAD amyloidogenic murine model of AD.ResultWe provide data demonstrating that in individuals with AD, there is increased expression of PLCG2 in the brain, a finding that is recapitulated in 5XFAD mice. We show that reduced PLCG2 gene expression program microglial phenotypes in 5XFAD mice, affect plaque pathology, and drive distinct transcriptional phenotypes of microglia in the presence of amyloid pathology. Analysis of plaque pathology revealed that 5XFAD PLCG2 inactivation mice have elevated plaque burden. Compared to 5XFAD mice, behavioral analysis of 5XFAD with PLCG2 inactivation mice demonstrated an impaired performance in the Y maze assay, reflecting impaired cognitive decline. Our data suggest that the inactivation of PLCG2 had accelerated and exacerbated disease‐related pathology.ConclusionTogether, our findings provide evidence that PLCG2 plays an important role in AD pathophysiology, indicating PLCG2 as a potential new therapeutic target for AD.
AI‐based selection of superior proteomic biomarkers for classifying Alzheimer’s disease
Authors: Tandon Raghav , Seyfried Nicholas T. , Mitchell Cassie S 
Published: December 2021

AbstractBackgroundProteomic changes are a hallmark of Alzheimer’s Disease (AD) and related disorders. Thousands of different proteins can be measured in clinical patients. A succinct, universally available clinical AD protein diagnostic panel is needed. The objective of the present study was to utilize artificial intelligence (AI) to determine a subset of proteins best for differentiating healthy controls, asymptomatic AD (ASymAD) cases, and AD cases.MethodAn AI‐based protein selection approach is constructed using published clinical proteomic datasets, which had over 3300+ measured proteins from brain tissues in the dorsolateral prefrontal cortex. Four published data sets (n = 419 patients) were used to construct and train the model while two published data sets (n = 201 patients) were used to independently validate the model results. Machine learning classification with support vector machine and logistical regression was combined with recursive feature elimination to identify the most discriminative proteins, which distinguish between AD, Control, and AsymAD cases. The final protein subset was a small fraction of all the proteins measured in the data.ResultThe algorithm identified a primary subset of 29 important proteins out of the 3300+, which can differentiate AD cases from control cases with high accuracy (AUC = 0.93). However, 88 proteins of 3300+ are necessary to differentiate AD from asymptomatic AD with high accuracy (AUC = 0.96 for AD; AUC = 0.89 for Control; AUC = 0.85 for ASymAD). Selected proteins were significantly enriched for metabolic function, namely glucose metabolism. Notably, amyloid precursor protein (APP), VGF, and RABEP1 are strong differentiators of AD compared to Control or ASymAD. However, to differentiate ASymAD and AD, examples of superior predictive proteins include ALDH1A1, BDH2, C4A, FABP7, GABBR2, GNAI3, PBXIP1, and PRKAR1B.ConclusionClinical cases can be successfully differentiated based on their measured biomarker levels. AI platforms can be leveraged to identify a subset of the most discriminative proteins useful for future AD clinical diagnostics and disease staging.
In silico identification of phytocompounds as potential inhibitors of Glycogen synthase kinase 3 beta (GSK‐3β)
Authors: Chowdhury Suman 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) pathogenesis involves multiple pathological pathways, among different drug targets of AD,Glycogen synthase kinase 3 beta (GSK‐3β) is a well‐known therapeutic drug target. Identification of GSK‐3β inhibitors will also help in the treatment of other neurological disorders such as Parkinson’s disease, bipolar disorders, and traumatic brain injury. The therapeutic activity of phytocompounds in neurological disorders is already established, in this study phytocompounds from well‐known spices were screened for molecular interaction GSK‐3β enzyme.MethodSelected phytocompounds such as cuminaldehyde, alpha terpinyl acetate, eugenol, piperine, and cinnamaldehyde mainly found in spices such as Cuminum cyminum L, Elettaria cardamomum L, Eugenia caryophyllus Thumb, Piper nigrum L and Cinnamomum zeylanicum Blume, respectively, were analyzed for interaction with GSK‐3β enzyme. In silicomolecular docking was performed using Schrodinger software, where the X‐ray crystallographic structure of GSK‐3β (PDB ID‐1Q3D) from Protein Data Bank server and 3D structure of phytocompounds from PubChem, were prepared using protein preparation wizard (PPW) and ligprep module. Extra precision (XP) docking was performed using a glide module. Phytocompounds poses were ranked based on docking scores and glide energy.ResultThe phytocompounds showed docking score and glide energy within the range of ‐6.3 to ‐4.6, and ‐22.6 to ‐19.5 kcal/mol, respectively. Among the five selected phytocompounds, cuminaldehyde showed the highest docking score of ‐6.3 and binding affinity of ‐22.6 kcal/mol, whereas the lowest docking score was observed for cinnamaldehyde of ‐4.6. Cuminaldehyde also showed hydrogen bonding with important amino acid residue Val135 of the binding pocket, contact with this is key to enhance affinity.ConclusionGSK‐3β is an important drug target due to its role in AD, among other disorders. Though many inhibitors have been reported, the challenge is discovering an inhibitor that can translate potent inhibition into cellular settings with low toxicity, here, phytocompounds play an important role due to low toxicity. Cuminaldehyde showed strong affinity towards GSK‐3β enzyme, which could be potential inhibitor and provides a lead towards finding anti‐AD drug.
Free Space Realization of the Symmetrical Tunable Auto‐Focusing Lommel Gaussian Vortex Beam
Authors: Tu Jialong , Wang Xinyue , Yu Xing , Wang Haonan , Deng Dongmei 
Published: December 2021

AbstractAn auto‐focusing beam with adjustable symmetry is proposed numerically and experimentally. The initial field of the auto‐focusing Lommel Gaussian vortex beam (ALoGVB) consists of the Lommel function and the Gaussian term. When the asymmetry factor ε of the beam approaches zero, the ALoGVB will degenerate into a circular Bessel Gaussian vortex beam (CBGVB). Compared with the CBGVB, the ALoGVB is more diverse. The shape, symmetry, normalized focusing intensity, and focus distance of the ALoGVB can be controlled by flexibly adjusting the asymmetry factor ε and the topological charge n. In addition, the effect of off‐axis vortices on the propagating characteristics of the beam is also discussed. The experiment is in good agreement with the numerical simulation. The results could be beneficial for potential applications in optical trapping or micromachining.
Porous Liquid‐Crystalline Networks with Hydrogel‐Like Actuation and Reconfigurable Function
Authors: Jiang Jie , Han Li , Ge Feijie , Xiao Yaoyu , Cheng Ruidong , Tong Xia , Zhao Yue 
Published: December 2021

AbstractA porous liquid‐crystalline network (LCN), prepared by using a template method, was found to exhibit peculiar actuation functions. The creation of porosity makes the initially hydrophobic LCN behave like a hydrogel, capable of absorbing a large volume of water (up to ten times the sample size of LCN). When the amount of absorbed water is relatively small (about 100 % swelling ratio), the porous LCN displays anisotropic swelling in water and, in the same time, the retained uniaxial alignment of mesogens ensures a thermally induced shape change associated with a LC‐isotropic phase transition. Combining the characteristic actuation mechanisms of LCN (order–disorder transition of mesogens) and hydrogel (water absorption), such porous LCNs can be explored for versatile stimuli‐triggered shape transformations. Moreover, the porosity enables loading/removal/reloading of functional fillers such as ionic liquids, photothermal dyes and fluorophores, which imparts the porous LCN actuator with reconfigurable functions such as ionic conductivity, light‐driven locomotion, and emissive color.
Multinuclear silver N‐heterocyclic carbene complexes provoke potent anticancer activity via mitochondrial dysfunction and cell necrosis induction
Authors: Zheng Weihong , Zheng Qing , Chen Chao , Wang Hangxiang 
Published: December 2021

AbstractThree silver N‐heterocyclic carbene (NHC) complexes (Ag1–Ag3) were designed and synthesized using quinoline‐functionalized benzoimidazole salts (L1–L3). Both NHC precursors and resultant silver‐NHC complexes were characterized by NMR, FT‐IR spectroscopy, and elemental analysis. X‐ray diffraction analysis was additionally performed to investigate the crystal structures of these silver‐NHC complexes. The results showed that Ag1 is a dinuclear silver complex with a deviated linear geometry. Ag2 has a disilver core in which two silver atoms are coordinated by two quinoline‐functionalized carbene ligands and one acetonitrile molecule. The silver‐NHC complex Ag3 is composed of a silver‐triangle formed by three silver atoms and three carbene ligands. The in vitro cytotoxic studies revealed that silver‐NHC complexes had stronger antitumor activity than their corresponding NHC precursors. Notably, after a 24‐h exposure to cancer cells, Ag2 presented the highest cytotoxicity with a half maximal inhibitory concentration (IC50) at 1.74 ± 0.08 μM in A2780 cells, which was approximately 14‐fold lower than that of the clinically approved metallodrug cisplatin (IC50 = 24.74 ± 1.35 μM). Detailed mechanistic studies suggested that the complex Ag2 provoked intracellular reactive oxygen species (ROS) overproduction and mitochondrial membrane depolarization, which eventually resulted in mitochondrial dysfunction and cell potent necrosis. Overall, our studies show that NHC‐coordinated silver complexes can be readily constructed and used as an attractive class of anticancer agents, which is conductive for further investigation of their therapeutic potential for treating cisplatin‐resistant cancers.
Influence of dispersing aids on nano alumina/micro aluminum tri hydrate filled silicone rubber composites for outdoor high voltage insulators
Authors: Ashitha Parambalath Narendran , Akhil Sreedharan , Varughese Konnanilkummathil Thomas 
Published: December 2021

AbstractNano alumina and micro aluminum tri hydrate filled high‐temperature vulcanizing silicone rubber composites were prepared with dispersing aids of surfactant Triton™‐X‐100 (TX‐100) and silane coupling agent 3‐methacryloxypropyltrimethoxysilane (KH‐570), through an in situ modification technique. Fourier transform infrared spectroscopy (FTIR) and X‐ray diffraction (XRD) analysis were carried out to understand the effects of dispersing aids on the structural and crystallographic properties of composites. Scanning electron microscopy images of TX‐100 dispersed composites revealed the presence of several localized regions of agglomeration, whereas KH‐570 dispersed composites showed moderate dispersion. Measurements of volume resistivity demonstrated an increment of four decades for KH‐570 dispersed nanocomposite over TX‐100. Better compatibility between fillers and base matrix through KH‐570 was evident from the low loss factor values. Inclined plane tracking and erosion results were discussed in detail with leakage current analysis. The binary composite prepared with KH‐570 was observed to resist the detrimental dry band arcing and subsequent erosion by 2 h and 20 min over TX‐100 dispersed composite. Dry arc resistance and the formation of thermal pathways connecting micro and nanofillers were discussed in detail. FTIR analysis of ash generated after inclined plane tracking and erosion test confirmed the surfacing of added fillers. KH‐570 dispersed composites showed superior properties as compared to composites prepared with TX‐100.
Role of blend phase ratio in controlling morphology, compressive, and recovery behavior of low‐density polyethylene/ethylene‐vinyl acetate foams
Authors: Katbab Pouya , Jafari Seyed Hassan , Katbab Ali Asghar , Kontopoulou Marianna 
Published: December 2021

AbstractThis work presents a detailed study on the influence of blend phase ratio upon the morphology, crystallinity, mechanical and viscoelastic properties of cross‐linked foams based on blends of low‐density polyethylene (LDPE) and ethylene‐vinyl acetate copolymer (EVA). Non‐isothermal foaming is carried out via melt compression molding using dicumyl peroxide and azodicarbonamide as crosslinking and foaming agents, respectively. Rheo‐mechanical spectrometer characterization reveals faster crosslinking for EVA, leading to higher rate of melt viscosity increase for EVA‐rich blends during heating. This results in the formation of foams with higher cell density and gel content than LDPE‐rich foams. Compressive stress–strain behavior and viscoelastic hysteresis of the LDPE‐rich foams are governed by the degree of crystallinity and cell density, whereas for the EVA‐rich foams cell density and gel content are dominant. Increasing the crosslink density results in enhanced compressive behavior with excellent recovery of stress to 60% strain during four compression cycles.
Sweepstakes or contests: The effect of uncertainty type on consumption behavior
Authors: Shen Zhengyu , Ming Yaxin 
Published: December 2021

AbstractGiven their widespread application and the benefits provided to marketers, the inconclusive effects of uncertain promotions need to be further explored. This research demonstrates that the effectiveness of uncertain promotions varies with the type of uncertainty involved in the promotions (i.e., sweepstakes and contests). Based on real‐world data from one of the largest commercial banks in China and three controlled experiments, we found consistent evidence supporting the advantages of sweepstakes promotions over contest promotions, even when both uncertain promotions had the same cost for consumers. We suggest that this effect occurs because of the consumers have a higher perception of confidence and thus, perceive the probability of winning the reward is higher in sweepstakes than in contest, thereby indicating the underlying mechanism of the effect of the uncertain promotion type on consumer preference.
Grain micronutrient composition and yield components in field‐grown wheat are negatively impacted by high night‐time temperature
Authors: Hein Nathan T. , Impa Somayanda M. , Wagner Dan , Bheemanahalli Raju , Kumar Ritesh , Tiwari Manish , Prasad P. V. Vara , Tilley Michael , Wu Xiaorong , Neilsen Mitchell , Jagadish S. V. Krishna 
Published: December 2021

AbstractBackground and objectivesWheat (Triticum aestivum L.) is highly vulnerable to heat stress during sensitive growth and developmental stages, including grain‐filling. The impact of high daytime heat stress on wheat yield and quality losses has been extensively investigated, while information related to high night‐time temperature (HNT) is limited. The major objective was to ascertain the changes in wheat grain macro‐ and micro‐nutrient composition and yield‐related parameters on exposure to HNT during grain‐filling. Twelve diverse genotypes were grown in field‐based custom‐built heat tents that allowed natural light and temperature conditions during the day and imposed stress overnight.FindingsThe field‐tents imposed a 3.2°C higher night‐time temperature compared to ambient conditions throughout the grain‐filling period. HNT stress reduced 200 grain weight by 1.9%, grain yield by 3.1%, seed starch content by 2.5%, and seed protein content by 3.6% per °C increase in HNT.ConclusionsHNT had significant negative effect on grain macro‐ and micro‐nutrient content. However, starch and protein concentrations were differentially correlated with grain nutrients, with starch negatively correlated with many of the micronutrients under control and HNT.Significance and noveltyThis negative correlation highlights the imperative balance of seed micronutrient composition that needs to be maintained as efforts are intensified to enhance grain yield under favorable and warming environments.