Loss Of Plasticity Research Articles

248-LB: Aging of Tanycytes Abolishes the Dynamic Regulation of Blood–Brain Barrier Permeability in the Hypothalamus

Aberrant metabolic regulation and blood-brain barrier (BBB) dysfunction are two well-known phenomena of aging. The hypothalamus is the main brain region that controls food intake and body weight. It contains a specialized BBB that allows for the free flow of blood through fenestrated capillaries in the median eminence (ME), which places a portion of neurons critical to feeding unprotected by the BBB. Aging's pernicious effect on the traditional BBB throughout the brain is well studied, however how the specialized BBB in the hypothalamus is altered with age is unknown. To study the effects of aging on hypothalamic injury and repair, we injected monosodium glutamate (MSG) into young and old mice to ablate neurons located outside the BBB. We found that in the hypothalamus of young animals, MSG led to tightening of the BBB imparted by a reduction in the number of fenestrated capillaries. In contrast, aged mice were unable to dynamically alter the BBB permeability or modulate fenestrated blood vessels in response to MSG injury. We show that hypothalamic tanycytes, radial glial-like cells lining the wall of the third ventricle, show a higher degree of physical contact with fenestrated blood vessels than with non-fenestrated blood vessels. Tanycytes in young mice following MSG exposure, modified their expression of pleiotrophin, a growth and angiogenic factor, and robustly proliferated. In comparison, tanycytes in aged mice lacked in these responses to injury, which indicate these cells undergo functional decline with aging. Moreover, aged mice following MSG lost a greater number of neurons outside the BBB and experienced severe weight loss weeks after treatment, whereas young mice showed no change in their body weight. These findings uncover that aging leads to loss of hypothalamic BBB plasticity and defective tanycytes, which increase hypothalamic vulnerability to injury and morbidity development in aged animals. Disclosure V. Pham: None. A. Xu: Advisory Panel; Pennington Biomedical Research Center, Research Support; Eli Lilly and Company. T. P. Bachor: None. Funding National Institutes on Aging (1R01AG063506-01)

The life and times of cellular senescence in skeletal muscle: friend or foe for homeostasis and adaptation?

A gradual decline in skeletal muscle mass and function is closely tied to increased mortality and disease risk during organismal aging. Exercise training is the most effective way to enhance muscle health, but the adaptive response to exercise as well as muscle repair potential is blunted in older individuals. Numerous mechanisms contribute to the loss of muscle mass and plasticity as aging progresses. An emerging body of recent evidence implicates an accumulation of senescent ("zombie") cells in muscle as a contributing factor to the aging phenotype. Senescent cells cannot divide but can release inflammatory factors and create an unfavorable environment for homeostasis and adaptation. On balance, some evidence indicates that cells with senescent characteristics can be beneficial for the muscle adaptive process, specifically at younger ages. Emerging evidence also suggests that multinuclear muscle fibers could become senescent. In this review, we summarize current literature on the prevalence of senescent cells in skeletal muscle and highlight the consequences of senescent cell removal on muscle mass, function, and adaptability. We examine key limitations in the field of senescence specifically in skeletal muscle and identify areas of research that require future investigation.NEW & NOTEWORTHY There is evidence to suggest that senescent "zombie" cells may or may not accrue in aging skeletal muscle. When muscle is perturbed regardless of age, senescent-like cells do appear, and the benefits of removing them could be age-dependent. More work is needed to determine the magnitude of accumulation and source of senescent cells in muscle. Regardless, pharmacological senolytic treatment of aged muscle is beneficial for adaptation.

Spelling-sound consistency influences second-language age of acquisition effect: evidence for the arbitrary mapping hypothesis

ABSTRACT The age at which people acquire a word influences word recognition, known as the age of acquisition (AoA) effect. In the first language (L1), AoA effects are widely found in various languages and experimental tasks. Arbitrary Mapping Hypothesis proposes that AoA effects reflect the loss of network plasticity during the learning of mappings between input and output representations. It predicts that the AoA effect appears (or is larger) when the input-output mapping is arbitrary/inconsistent, relative to consistent input-output mapping. The present study examined how these predictions generalised to the second language (L2). We explored whether the L2 AoA effect was modulated by spelling-sound consistency in Chinese-English bilinguals, adopting a delayed word naming task. The results showed that the mapping consistency modulated the L2 AoA effect on the N170, P200 and N400 components. L2 AoA effect was insignificant in the consistent condition but was significant in the inconsistent condition: late-acquired words elicited larger N170, smaller P200, and larger N400 compared to early-acquired words. These findings suggest that L2 AoA effects occur in the spelling-sound connections, providing direct evidence for the Arbitrary Mapping Hypothesis.

Analysis of Phenomenon of Plasticity Loss of Steel Core Made by Selective Laser Melting Method in Zone of Pressure Mould Conformal Cooling Channel.

This paper presents the results of testing the mechanical properties of maraging steel 1.2709 that were obtained by the SLM method under uniaxial and triaxial states of stress. The triaxial state of stress was realised by making circumferential notches in the samples with different radii of rounding. The specimens were subjected to two types of heat treatment, which consisted of ageing at 490 °C and 540 °C for 8 h. The results of the tests that were conducted on the samples were considered as references and compared with the results of the strength tests that were conducted directly on the SLM-made core model. Differences were found between the results of these tests. Based on the experimental results, the relationship between the equivalent strain of the specimen in the bottom of notch εeq and triaxiality factor η was determined. Function εeq = f(η) was proposed as a criterion for the decrease in the plasticity of the material in the area of the pressure mould cooling channel. Using the FEM method, equivalent strain field εeq and triaxiality factor η were determined in the conformal channel cooled core model. Based on the proposed criterion of plasticity loss and the results of numerical calculations, it was shown that the values of equivalent strain εeq and triaxiality factor η in the core that was aged at 490 °C did not meet this criterion. On the other hand, the values of strain εeq and triaxiality factor η did not exceed the safety limit when ageing was carried out at 540 °C. The plasticity loss method presented in this paper assumes that the value of the triaxiality factor in the vicinity of the channel is influenced by the shape, cross-sectional dimensions and trajectory of the channel axis. Using the methodology proposed in this paper, it is possible to determine the value of allowable deformations in the cooling channel zone and to determine whether the heat treatment applied to the SLM steel does not cause an excessive reduction in the plastic properties.

An Ancestral Balanced Inversion Polymorphism Confers Global Adaptation.

Since the pioneering work of Dobzhansky in the 1930s and 1940s, many chromosomal inversions have been identified, but how they contribute to adaptation remains poorly understood. In Drosophila melanogaster, the widespread inversion polymorphism In(3R)Payne underpins latitudinal clines in fitness traits on multiple continents. Here, we use single-individual whole-genome sequencing, transcriptomics, and published sequencing data to study the population genomics of this inversion on four continents: in its ancestral African range and in derived populations in Europe, North America, and Australia. Our results confirm that this inversion originated in sub-Saharan Africa and subsequently became cosmopolitan; we observe marked monophyletic divergence of inverted and noninverted karyotypes, with some substructure among inverted chromosomes between continents. Despite divergent evolution of this inversion since its out-of-Africa migration, derived non-African populations exhibit similar patterns of long-range linkage disequilibrium between the inversion breakpoints and major peaks of divergence in its center, consistent with balancing selection and suggesting that the inversion harbors alleles that are maintained by selection on several continents. Using RNA-sequencing, we identify overlap between inversion-linked single-nucleotide polymorphisms and loci that are differentially expressed between inverted and noninverted chromosomes. Expression levels are higher for inverted chromosomes at low temperature, suggesting loss of buffering or compensatory plasticity and consistent with higher inversion frequency in warm climates. Our results suggest that this ancestrally tropical balanced polymorphism spread around the world and became latitudinally assorted along similar but independent climatic gradients, always being frequent in subtropical/tropical areas but rare or absent in temperate climates.

Tarooneh extract relieves anxiety-like behaviors and cognitive deficitsby inhibiting synaptic loss in the hippocampus and frontal cortex in rats subjected to chronic restraint stress.

In traditional medicine, Tarooneh (a hardcover of the datepalm; Phoenix dactylifera) has known as a sedative and relaxant medicine. In this study, we evaluated the protective effects of Tarooneh in the anxiety-like behavior, cognitive deficit, and neuronal damages in the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus and frontal cortex neurons employing a rat model of chronic restraint stress. The animal received Tarooneh extract for 14 consecutive days in water, and chronic restraint stress was performed daily during this period. The results of the Barnes maze test showed that treatment with Tarooneh significantly improves spatial memory parameters such as latency time to find the target hole, number of errors, and distance traveling compared to the stress group. The EPM results showed that Tarooneh significantly increased the time spent in open arms and the percentage of entries into open arms and significantly decreased the frequency of head dipping behavior compared to animals in the stress group. Golgi-Cox staining indicates that loss of neural spine density in DG, CA1, CA3, and frontal cortex due to chronic restraint stress, was prevented with daily administration of Tarooneh. The results of cresyl-violet staining indicate that Tarooneh significantly increased the number of CV-positive neurons in the frontal cortex and CA1 region of the hippocampus compared to the stress group. Our results suggest that Tarooneh potentially prevented and improved effects in anxiety-like behavior, memory impairment, and synaptic plasticity loss in frontal and hippocampal neurons induced by chronic restraint stress. In conclusion, our results suggest that Tarooneh prevented and improved anxiety-like behavior, cognitive deficit, and neuronal damages in the CA1, CA3, and DG regions of the hippocampus and frontal cortex neurons induced by chronic restraint stress.

An Update on Autophagy as a Target in the Treatment of Alzheimer's Disease.

Proteostasis is crucial for the maintenance and proper operation of cells. Under typical circumstances, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway are used to clean out undesired, damaged, misfolded, or aggregated proteins. Any dysregulation in the above-mentioned pathways leads to neurodegeneration. One of the most renowned neurodegenerative disorders is AD. This condition is more prevalent in senior people and is frequently linked to dementia, progressive memory loss, and cognitive function decline, which further contributes to cholinergic neuron degradation and synaptic plasticity loss. Extracellular accumulation of amyloid beta plaques and the intraneuronal deposition of misfolded neurofibrillary tangles are two prime pathological reasons for AD. At present, there is no treatment for AD. All that remains available is the symptomatic treatment of this disease. Autophagy is the major mechanism by which the cells degrade the protein aggregates. Deposited immature autophagic vacuoles (AVs) in AD brains suggest interruption of a person's normal autophagy process. This review has briefly covered various forms and mechanisms of autophagy. Furthermore, the discussion in the article is supported by different ways and mechanisms via which autophagy can be stimulated in a beneficial way and can emerge as a novel target in the treatment of various metabolic CNS related disorders. In the current review article, the mTOR-dependent ones are PI3K/Akt/TSC/mTOR, AMPK/TSC/mTOR, and Rag/mTOR pathways and mTOR-independent ones which include Ca2+/calpain, inositol-dependent, cAMP/EPAC/PLC, and JNK1/Beclin-1/PI3K pathways have been discussed in details. The article sheds light on drugs which are validated with details in tabular form from recent updates in clinical trials.

Age-related changes in mice behavior and the contribution of lipocalin-2.

Aging causes considerable changes in the nervous system, inducing progressive and long-lasting loss of physiological integrity and synaptic plasticity, leading to impaired brain functioning. These age-related changes quite often culminate in behavioral dysfunctions, such as impaired cognition, which can ultimately result in various forms of neurodegenerative disorders. Still, little is known regarding the effects of aging on behavior. Moreover, the identification of factors involved in regenerative plasticity, in both the young and aged brain, is scarce but crucial from a regenerative point of view and for our understanding on the mechanisms that control the process of normal aging. Recently, we have identified the iron-trafficking protein lipocalin-2 (LCN2) as novel regulator of animal behavior and neuronal plasticity in the young adult brain. On the other hand, others have proposed LCN2 as a biological marker for disease progression in neurodegenerative disorders such as Alzheimer's disease and multiple sclerosis. Still, and even though LCN2 is well accepted as a regulator of neural processes in the healthy and diseased brain, its contribution in the process of normal aging is not known. Here, we performed a broad analysis on the effects of aging in mice behavior, from young adulthood to middle and late ages (2-, 12-, and 18-months of age), and in the absence of LCN2. Significant behavioral differences between aging groups were observed in all the dimensions analyzed and, in mice deficient in LCN2, aging mainly reduced anxiety, while sustained depressive-like behavior observed at younger ages. These behavioral changes imposed by age were further accompanied by a significant decrease in cell survival and neuronal differentiation at the hippocampus. Our results provide insights into the role of LCN2 in the neurobiological processes underlying brain function and behavior attributed to age-related changes.

Cascading Polymer Macro-Debris Upcycling and Microparticle Removal as an Effective Life Cycle Plastic Pollution Mitigation Strategy.

Plastic pollution caused by material losses and their subsequent chemical emissions is pervasive in the natural environment and varies with age. Cascading the life cycles of plastic losses with solid waste reclamation via re-manufacturing virgin polymers or producing fuels and energy may extend resource availability while minimizing waste generation and environmental exposure. Here, we systematically investigate this cascaded plastic waste processing over other waste end-of-life management pathways by analyzing the environmental consequences of plastic losses across the entire life cycle. Plastic losses can form volatile organic chemicals via photo-degradation and pose non-negligible global warming, ecotoxicity, and air pollution effects that worsen by at least 189% in the long run. These environmental burdens increase by above 9.96% under high ultraviolet radiation levels and participation rates, which facilitate plastic particulate compartment transport and degradation. Cascaded plastic waste processing aided by fast pyrolysis upcycling technologies can effectively cut environmental losses and outperform landfills and incineration in reducing 23.35% ozone formation and 19.91% air pollution by offsetting the external monomer manufacturing and fuels and energy production while saving at least 25.75% fossil fuels.

Abstract 3083: Targeting androgen receptor coregulators to enhance enzalutamide sensitivity in prostate cancer

Abstract Steroid hormone signaling axes drive proliferation and survival in prostate cancer (PCa), breast and other cancers. In late stage PCa, the androgen receptor (AR) is therapeutically antagonized with success, for example with Enzalutamide (Enza). Although initially successful, resistance emerges associated with tissue plasticity and patient mortality. Enza-resistance mechanisms include altered AR coregulator interactions. Identifying which coregulators change Enza sensitivity is attractive as they may represent new drug targets but challenging given the multitude of coregulators expressed in PCa and the diverse roles they play in transcription and translation.To meet this challenge, we designed a bioinformatic workflow to identify under-investigated yet clinically-impactful coregulators. We tested coactivators (CoA, n~750), corepressors (CoR, n ~600), and mixed function coregulators (Mixed, n~600) associations with patient outcome in TCGA PCa cohorts; applied partial correlation analyses to reveal coregulators that impacted AR target genes; utilized DepMap essentiality scores to rank importance; and examined interactions in publicly available AR RIME data. The impact of the top ranked coregulators (n=18) on Enza sensitivity was examined using shRNA or siRNA approaches, and with inhibitor drugs in Enza-resistant PCa cell lines (LNCaP C42B, 22Rv1). Finally, coregulator expression was examined in single cell RNA-Seq from PCa 3D organoids derived from the PBCre4:Ptenf/f:Rb1f/f (DKO) and the PBCre4:Ptenf/f:Rb1f/f:Trp53f/f (TKO) PCa mouse model, which recapitulate the loss of Enza sensitivity and lineage plasticity. ShRNA targeting coregulators was undertaken in organoids. The bioinformatics workflow identified 18 coregulators, including CoA (e.g., WDR5, KAT7, BLM, SMARCC1), CoR (e.g., SETDB1, PSPC1), and Mixed (e.g., KDM5A, BPTF, TCEGR1) to screen for impact on Enza. KAT7 shRNA modulated Enza sensitivity, regulated expression of AR target genes, and synergized with a KAT7 inhibitor (WM3835) to enhance Enza sensitivity. Similarly, a BLM inhibitor (ML216) synergized with Enza. Interestingly, although WDR5 siRNA alone did not alter Enza responses, the combination of KAT7 shRNA and WDR5 siRNA significantly potentiated Enza responses. Similarly, SMARCC1 shRNA cooperated with siRNA to several targets (TBX3, BPTF, or SETDB1) to enhance Enza responses. Smarcc1 and Tbx3 were upregulated in Enza-resistant neuroendocrine PCa, and the recently identified Pou2f3 Enza-resistant phenotypes, and Bptf was upregulated in the Tff3 Enza-resistant phenotype. We have shRNA targeted Blm, Smarcc1, Tbx3, and Bptf in the DKO and TKO organoids and are measuring the impact of Enza responses. Overall, we have identified potentially novel AR coregulators that associate with the development of therapy resistance and shown that targeting these coregulators may augment Enza sensitivity in PCa. Citation Format: Rayzel C. Fernandes, Debasis Nayak, Damien A. Leach, Meenalakshmi Chinnam, Wilbert Zwart, David W. Goodrich, Moray J. Campbell, Charlotte L. Bevan. Targeting androgen receptor coregulators to enhance enzalutamide sensitivity in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3083.

Plastic loss of motile cilia in the gills of Polypterus in response to high CO2 or terrestrial environments.

The evolutionary transition of vertebrates from water to land during the Devonian period was accompanied by major changes in animal respiratory systems in terms of physiology and morphology. Indeed, the fossil record of the early tetrapods has revealed the existence of internal gills, which are vestigial fish-like traits used underwater. However, the fossil record provides only limited data on the process of the evolutionary transition of gills from fish to early tetrapods. This study investigated the gills of Polypterus senegalus, a basal ray-finned/amphibious fish which shows many ancestral features of stem Osteichthyes. Based on scanning electron microscopy observations and transcriptome analysis, the existence of motile cilia in the gills was revealed which may create a flow on the gill surface leading to efficient ventilation or remove particles from the surface. Interestingly, these cilia were observed to disappear after rearing in terrestrial or high CO2 environments, which mimics the environmental changes in the Devonian period. The cilia re-appeared after being returned to the original aquatic environment. The ability of plastic changes of gills in Polypterus revealed in this study may allow them to survive in fluctuating environments, such as shallow swamps. The ancestor of Osteichthyes is expected to have possessed such plasticity in the gills, which may be one of the driving forces behind the transition of vertebrates from water to land.

Dynamic Energy Dissipation Performance of Nonlinear Large-Deformation Viscoelastic Joint Damper under Strong Dynamic Load

Large-displacement corner deformation often occurs at the joints of towering structures and long-span space structures subjected to strong earthquake. In order to improve the energy dissipation capacity of structural joints, the Nitrile Butadiene Rubber/High Abrasion Furnace Black (NBR/HAF) high damping composite was fabricated by formulation optimization in this paper, where a nonlinear large-deformation viscoelastic joint damper was proposed. The damper consists of five layers of restrained steel plates and four layers of shear energy dissipating material, which can reach 60[Formula: see text]mm shear displacement. In this paper, dynamic mechanical performance tests and static mechanical tests were firstly conducted on the core energy dissipating media of the damper. The loss factor of NBR/HAF composite reached a peak of 1.51 at about 8.2°C, while its wide damping temperature range was 27°C. Second, the accuracy of the simulation method was verified by comparing the simulated and experimental hysteresis curves. Then, the refined numerical simulation of this damper was carried out using ABAQUS finite element software with the high damping material as its core energy dissipating media. Finally, the magnitude and type of energy dissipation of each part of the viscoelastic joint damper under different loads were investigated. It was found that the large-deformation viscoelastic joint damper based on the composite had good damping capacity. Its dynamic characteristics were affected by the displacement amplitude and excitation frequency, which exhibited hardening nonlinear characteristics. As the frequency and load amplitude increased, the peak displacement in the loading direction gradually decreased, whereas the total energy input to the damper and the energy dissipated by the viscoelastic material increased monotonically. The input energy was only dissipated by the viscoelastic material, and no plastic loss occurred in the steel plate during the entire loading stage. Under high frequency and large loads, the damper can also have good energy dissipation characteristics. Because of the negative strain energy caused by plastic dilatancy, the energy dissipated by the material was gradually greater than the input energy with the load increasing.

Physical Modeling of Steel Resistance to Hydrogen Embrittlement

Hydrogen can be used in the same energy processes as natural gas and become a tool for implementing the transition to a sustainable low-carbon economy. The level of contamination resulting from controlled combustion of hydrogen or methane-hydrogen mixture is relatively low, which will significantly reduce CO2 emissions. However, the use of hydrogen can involve considerable difficulties associated with the hydrogen compatibility of materials. With the increase in the production, storage and transportation of hydrogen gas, including through gas pipelines, hydrogen-resistant materials are needed. The main problem with hydrogen is its embrittling effect. Under the influence of hydrogen, pipelines materials can probably have the following: hydrogen charging of the surface layer under pressure, loss of plasticity at tensile loads, formation of cracks and blisters (by decogesia mechanism), diffusion to the stress concentrator according to adsorption theory, accumulation of hydrogen at the top of the crack (which can lead to cracking) and so on. To assess the possibility of using a pipeline system for transportation of hydrogen gas in large volumes, it is necessary to know hydrogen compatibility of pipe steel. Physical modeling of steel resistance to hydrogen embrittlement can be carried out using electrochemical and gas charging methods.

Esters of Cinnamic Acid as Green Plasticizers for Polylactide Formulations with Improved Ductility

AbstractThis study demonstrates the potential of different cinnamate esters, namely methyl trans‐cinnamate (MC), isobutyl cinnamate (IBC), allyl cinnamate (AC), and ethyl cinnamate (EC), as environmentally friendly plasticizers for polylactide (PLA). Plasticized PLA formulations with a constant nominal wt% of 20 of each plasticizer are compounded in a twin‐screw co‐rotating extruder and subsequently processed by injection molding. The results show exceptional plasticization efficiency of AC with an increase in elongation at break from 3.9% (neat PLA), up to 339.4% and a remarkable increase in impact strength, thus showing great potential to overcome the main drawback related to PLA intrinsic brittleness. The incorporation of cinnamates in a PLA matrix leads to a decrease in Tg from 61.7 °C down to 36.1 °C for the plasticized PLA formulation containing 20 wt% AC. Thermogravimetry analysis reveals that a slight plasticizer loss occurs during processing, as it happens with other monomeric plasticizers, but this phenomenon does not limit their plasticization efficiency. Therefore, the results obtained in this study confirm the suitability of a new family of organic compounds derived from the esterification of cinnamic acid as green plasticizers for PLA with improved toughness, with comparable, or even superior, ductile properties of typical plasticizers for PLA.

Degradation of thermoplastic cellulose acetate-based bioplastics by full-scale experimentation of industrial anaerobic digestion and composting

The ability of full-scale industrial plants to degrade bioplastics waste must be verified to exclude any negative effects on the quality of the process outputs. This study aims to assess the degradation of two thermoplastic cellulose acetate-based bioplastics, in pure and composite forms in both Anaerobic Digestion (AD) and Composting (C) industrial conditions. The main degradation occurred during AD, where a disintegration of about 36% and 50% was achieved from pure and composite thermoplastic cellulose acetate, respectively. The disintegration during C did not exceed 20% for both samples. The combined process resulted in a slightly higher degradation (58–40%) than that obtained in AD, revealing how the main alteration of samples occurred in an anaerobic environment. Despite this macroscopic degradation, the samples showed only minor superficial degradation as highlighted from SEM analysis. FT-IR spectroscopy, TGA andDSC analyses showed that the biodegradation mechanism involved mainly the plasticizer loss and deacetylation of the cellulose matrix, with only partial degradation of cellulose backbone However, both deacetylation and degradation were favored in AD and AD + C processes and from the presence of filler in anaerobic conditions. These results demonstrated how the degradation obtained on an industrial scale can differ significantly from those obtained in the laboratory scale, especially for pure thermoplastic cellulose acetate. Furthermore, current industrial AD and C process resulted not optimized for the treatment of thermoplastic cellulose acetate-based bioplastics. Hence, this works could help waste facilities managers to process emerging materials such as bioplastics in a more sustainable way.

PSA-NCAM Regulatory Gene Expression Changes in the Alzheimer's Disease Entorhinal Cortex Revealed with Multiplexed in situ Hybridization.

Alzheimer's disease (AD) is the most common form of dementia and is characterized by a substantial reduction of neuroplasticity. Our previous work demonstrated that neurons involved in memory function may lose plasticity because of decreased protein levels of polysialylated neural cell adhesion molecule (PSA-NCAM) in the entorhinal cortex (EC) of the human AD brain, but the cause of this decrease is unclear. To investigate genes involved in PSA-NCAM regulation which may underlie its decrease in the AD EC. We subjected neurologically normal and AD human EC sections to multiplexed fluorescent in situ hybridization and immunohistochemistry to investigate genes involved in PSA-NCAM regulation. Gene expression changes were sought to be validated in both human tissue and a mouse model of AD. In the AD EC, a cell population expressing a high level of CALB2 mRNA and a cell population expressing a high level of PST mRNA were both decreased. CALB2 mRNA and protein were not decreased globally, indicating that the decrease in CALB2 was specific to a sub-population of cells. A significant decrease in PST mRNA expression was observed with single-plex in situ hybridization in middle temporal gyrus tissue microarray cores from AD patients, which negatively correlated with tau pathology, hinting at global loss in PST expression across the AD brain. No significant differences in PSA-NCAM or PST protein expression were observed in the MAPT P301S mouse brain at 9 months of age. We conclude that PSA-NCAM dysregulation may cause subsequent loss of structural plasticity in AD, and this may result from a loss of PST mRNA expression. Due PSTs involvement in structural plasticity, intervention for AD may be possible by targeting this disrupted plasticity pathway.

Glutamatergic neurotransmission: A potential pharmacotherapeutic target for the treatment of cognitive disorders.

In the mammalian brain, glutamate is regarded to be the primary excitatory neurotransmitter due to its widespread distribution and wide range of metabolic functions. Glutamate plays key roles in regulating neurogenesis, synaptogenesis, neurite outgrowth, and neuron survival in the brain. Ionotropic and metabotropic glutamate receptors, neurotransmitters, neurotensin, neurosteroids, and others co-ordinately formulate a complex glutamatergic network in the brain that maintains optimal excitatory neurotransmission. Cognitive activities are potentially synchronized by the glutamatergic activities in the brain via restoring synaptic plasticity. Dysfunctional glutamate receptors and other glutamatergic components are responsible for the aberrant glutamatergic activity in the brain that cause cognitive impairments, loss of synaptic plasticity, and neuronal damage. Thus, controlling the brain's glutamatergic transmission and modifying glutamate receptor function could be a potential therapeutic strategy for cognitive disorders. Certain drugs that regulate glutamate receptor activities have shown therapeutic promise in improving cognitive functions in preclinical and clinical studies. However, several issues regarding precise functional information of glutamatergic activity are yet to be comprehensively understood. The present article discusses the scope of developing glutamatergic systems as prospective pharmacotherapeutic targets to treat cognitive disorders. Special attention has been given to recent developments, challenges, and future prospects.

Transformation of Physical Characteristics in Fired Clay Bricks by Adopting Waste-based Fluxing Agent

The current practices in the recent development of fired clay brick (FCB) by adopting waste materials have tremendously reduced the usage of the primary source of FCB, which is clay soil (CS). In this study, the main objective is to reduce the utilisation of CS as the main component in the FCB-making process. Other waste materials such as soda lime silica (SLS) glass bottles, and sea shells (SS) were also added into the precursor admixtures. The admixtures containing CS, SLS and SS were mixed according to the empirical formula of (1-x)[40SLS - 60CS]: x[SS] = 0, 10, 20, 30, 40 wt.%. A batch of 40 g mixture was prepared, and 21% water was added. The admixtures were mixed, moulded into a rectangular brick shape, and dried before the sintering process at 850 °C. The physical properties of the FCB were investigated as a function of the SS content in the form of apparent density, linear shrinkage, loss of ignition and plasticity. As a result, the apparent density and loss of ignition of the FCB increased from 1.91 gcm-3 to 2.31 gcm-3 and 10.60 % to 20.81%, respectively. The linear shrinkage and plasticity percentage decreased from 2.50% to 2.27% and 11.01% to 8.70% with an increase of SS content. This study has uncovered the above findings, and has demonstrated a promising discovery of the SS as a possible substitute in FCB.

Evolution of the free volume during water desorption in thermoplastic starch/citric acid films: In situ positron annihilation studies

The effect of citric acid (CA) concentration and water content on the free hole volume of thermoplastic cassava starch films (TPS) was studied. To this aim, continuous in situ positron annihilation lifetime spectroscopy measurements were performed at fixed moisture content and during water desorption. The results show that the increase in CA concentration leads to wider free hole volume distributions with lower mean values. During water desorption, the mean values and width of such distributions systematically decrease with the exposure time, and the evolution of the hole volumes was well-described using the Kohlrausch-Williams-Watts function. The water vapour permeability was significantly higher in films incorporating 5 % (w/w) of CA, in line with the more open network of this material that was revealed in the hole volumes distribution. The Young's modulus of all the developed films increased significantly after partial water desorption, which was attributed to the plasticizer loss reflected in a decrease in the mean hole volume value (between 4 % and 13 %). This work evidences that the control and report of the relative humidity are essential when testing TPS-based films, as their nanostructures are strongly dependent on external conditions.

Epidermal growth factor receptor promotes high-fructose nonalcoholic fatty liver disease by inducing mitochondrial fission in zebrafish

Mitochondrial function has a pivotal role in the pathogenesis of NAFLD. Mitochondrial dynamics is a foundational activity underlying the maintenance of mitochondrial function in bioenergetics, the maintenance of MtDNA, calcium homeostasis, reactive oxygen species metabolism, and quality control. Loss of mitochondrial plasticity in terms of functions, morphology and dynamics may also be the critical switch from NAFLD/NASH to HCC. However, the cause of mitochondrial fission in NAFLD remains unclear. Recent studies have reported that EGFR can bind to Mfn1 and interfere with its polymerization. In this study, we investigated whether EGFR binds to Mfn1 in NAFLD, and whether reducing their binding can improve NAFLD in zebrafish model. Our results demonstrated that EGFR was activated in hepatocytes from high fructose (HF)-induced NAFLD zebrafish and interfered with Mfn1 polymerization, leading to reduction of MtDNA. Suppression of EGFR activation or mitochondrial translocation significantly improved mitochondrial morphology and increased mitochondrial DNA, ultimately preventing hepatic steatosis. In conclusion, these results suggest that EGFR binding to Mfn1 plays an important role in NAFLD zebrafish model and that inhibition of their binding could be a potential therapeutic target.