Aggregate Degradation Research Articles

Tripartite motif 25 inhibits protein aggregate degradation during PRRSV infection by suppressing p62-mediated autophagy.

Viral infection causes endoplasmic reticulum stress and protein metabolism disorder, influencing protein aggregates formation or degradation that originate from misfolded proteins. The mechanism by which host proteins are involved in the above process remains largely unknown. The present study found that porcine reproductive and respiratory syndrome virus (PRRSV) infection promoted the degradation of intracellular ubiquitinated protein aggregates via activating autophagy. The host cell E3 ligase tripartite motif-containing (TRIM)25 promoted the recruitment and aggregation of polyubiquitinated proteins and impeded their degradation caused by PRRSV. TRIM25 interacted with ubiquitinated aggregates and was part of the aggregates complex. Next, the present study investigated the mechanisms by which TRIM25 inhibited the degradation of protein aggregates, and it was found that TRIM25 interacted with both Kelch-like ECH-associated protein 1 (KEAP1) and nuclear factor E2-related factor 2 (Nrf2), facilitated the nuclear translocation of Nrf2 by targeting KEAP1 for K48-linked ubiquitination and proteasome degradation, and activated Nrf2-mediated p62 expression. Further studies indicated that TRIM25 interacted with p62 and promoted its K63-linked ubiquitination via its E3 ligase activity and thus caused impairment of its oligomerization, aggregation, and recruitment for the autophagic protein LC3, leading to the suppression of autophagy activation. Besides, TRIM25 also suppressed the p62-mediated recruitment of ubiquitinated aggregates. Activation of autophagy decreased the accumulation of protein aggregates caused by TRIM25 overexpression, and inhibition of autophagy decreased the degradation of protein aggregates caused by TRIM25 knockdown. The current results also showed that TRIM25 inhibited PRRSV replication by inhibiting the KEAP1-Nrf2-p62 axis-mediated autophagy. Taken together, the present findings showed that the PRRSV replication restriction factor TRIM25 inhibited the degradation of ubiquitinated protein aggregates during viral infection by suppressing p62-mediated autophagy.IMPORTANCESequestration of protein aggregates and their subsequent degradation prevents proteostasis imbalance and cytotoxicity. The mechanisms controlling the turnover of protein aggregates during viral infection are mostly unknown. The present study found that porcine reproductive and respiratory syndrome virus (PRRSV) infection promoted the autophagic degradation of ubiquitinated protein aggregates, whereas tripartite motif-containing (TRIM)25 reversed this process. It was also found that TRIM25 promoted the expression of p62 by activating the Kelch-like ECH-associated protein 1 (KEAP1) and nuclear factor E2-related factor 2 (Nrf2) pathway and simultaneously prevented the oligomerization of p62 by promoting its K63-linked ubiquitination, thus suppressing its recruitment of the autophagic adaptor protein LC3 and ubiquitinated aggregates, leading to the inhibition of PRRSV-induced autophagy activation and the autophagic degradation of protein aggregates. The present study identified a new mechanism of protein aggregate turnover during viral infection and provided new insights for understanding the pathogenic mechanism of PRRSV.

Investigation on Effects and Properties of Concrete Structure after Exposed to Fire

Abstract: The integrity and strength of the materials used in reinforced concrete structures are highly influenced by their exposure environment. Exposing the building materials to high temperature changes their performance. The change in the performance is a result of the change in the material properties. When subjecting a building material to fire, the occurring damage depends on the severity of the fire in terms ofthe fire temperature and time of exposure. This study investigates the effects of fireexposure on the set of RC beams. Through controlled experiments, varyingtemperatures from 3000C to 7000C areapplied to RC beams, analyzing changes in compressive strength, spalling, andmicrostructure by using rebound hammer,UPV meter and applying two-point loading in UTM. Results indicate a significantreduction in compressive strength with increasing fire temperature, attributed to thermal degradation of cement paste and aggregate. Additionally, changes inmicrostructure, such as pore structure alterations and formation of cracks, are observed. Also, few of RC beams were strengthened using GFRP sheets as a U- shaped wrapping to entire beam and U- shaped wrapping at certain intervals. The strengthened specimens are again tested in UTM for two-point loading, the results of the tests showed the feasibility of rehabilitating RC beams exposed to fire using GFRP plates.U-shaped wrapping to entire beam showed the good performance

Upregulated pexophagy limits the capacity of selective autophagy

Selective autophagy is an essential process to maintain cellular homeostasis through the constant recycling of damaged or superfluous components. Over a dozen selective autophagy pathways mediate the degradation of diverse cellular substrates, but whether these pathways can influence one another remains unknown. We address this question using pexophagy, the autophagic degradation of peroxisomes, as a model. We show in cells that upregulated pexophagy impairs the selective autophagy of both mitochondria and protein aggregates by exhausting the autophagy initiation factor, ULK1. We confirm this finding in cell models of the pexophagy-mediated form of Zellweger Spectrum Disorder, a disease characterized by peroxisome dysfunction. Further, we extend the generalizability of limited selective autophagy by determining that increased protein aggregate degradation reciprocally reduces pexophagy using cell models of Parkinson’s Disease and Huntington’s Disease. Our findings suggest that the degradative capacity of selective autophagy can become limited by an increase in one substrate.

Correlation between Deformation and Volumetric Characteristics in the Aging Condition of Hot Mix Asphalt

The surface layer of pavement structures tends to experience a decrease in performance as its service life approaches. Generally, this decrease in performance is caused by aggregate degradation and aging of the asphalt binder, which can be caused by traffic loads or weather exposure. The mechanical performance of asphalt mixtures is due to the effects of aggregate degradation, which was simulated by reducing the coarse aggregate fraction and adding medium and fine aggregate fractions. The asphalt aging process simulates changes in binder characteristics by adding RAP binder to Pen 60/70 asphalt. Hot mix asphalt (HMA) with new material (SA-1) as a control for degradation simulation (SA-2, SA-3 and SA-4). Marshall test results show that aggregate degradation significantly causes a decrease in voids in the mixture (VIM) and voids in mineral aggregate (VMA), as well as an increase in voids filled with asphalt (VFA). WTM test results show that HMA degradation causes an increase in rutting depth, which increases the deformation rate and decreases dynamic stability. The correlation results between WTM and Marshall tests show a negative exponential relationship between VIM and VMA with deformation and a positive exponential relationship between VFA and asphalt mixture deformation.

Overview of the Empirical Relations between Different Aggregate Degradation Values and Rock Strength Parameters

The aggregates are essential materials in civil engineering, they are used for railway and road constructions, for hydraulic engineering but they are also the base material of concrete. The crushed stones are exposed to several effects during their lifespan. Therefore, several tests were developed to evaluate their performance. One of the most important aspects is the resistance to degradation. However, degradation tests require special types of equipment and usually take longer than common strength tests which are more likely to be available for rock materials. Therefore, the empirical connections between strength and degradation values can be extremely useful in practice. The paper aimed to collect all available relationships and datasets from the literature that presents the relations between these different parameters – such as Aggregate Impact Value (AIV), Aggregate Crushing Value (ACV), Ten Percent Fines Value (TFV), Los Angeles Abrasion Value (LAAV), and micro-Deval Coefficient (MDE) – and rock strength parameters – such as Uniaxial Compressive Strength (UCS) and Point Load Strength Index (IS(50)) – and to provide the best-fit formula for different rock types. The paper also highlights the difficulties and limitations of the compared relationships.

Decoding the Cellular Trafficking of Prion-like Proteins in Neurodegenerative Diseases.

The accumulation and spread of prion-like proteins is a key feature of neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, or Amyotrophic Lateral Sclerosis. In a process known as 'seeding', prion-like proteins such as amyloid beta, microtubule-associated protein tau, α-synuclein, silence superoxide dismutase 1, or transactive response DNA-binding protein 43 kDa, propagate their misfolded conformations by transforming their respective soluble monomers into fibrils. Cellular and molecular evidence of prion-like propagation in NDs, the clinical relevance of their 'seeding' capacities, and their levels of contribution towards disease progression have been intensively studied over recent years. This review unpacks the cyclic prion-like propagation in cells including factors of aggregate internalization, endo-lysosomal leaking, aggregate degradation, and secretion. Debates on the importance of the role of prion-like protein aggregates in NDs, whether causal or consequent, are also discussed. Applications lead to a greater understanding of ND pathogenesis and increased potential for therapeutic strategies.

Rock Aggregate Size Influence on Physical Degradation of Laminate Sedimentary Rocks in Flexible Pavement

Rock aggregates are the most fundamental material of highways, railroads, and other construction activities. Degradation of aggregate is the disintegration of aggregate due to the wheel load and moisture saturation causing loss of support in unbound granular layer and reduction of drainage in pavement materials. Sedimentary rocks from different quarries were evaluated to determine the influence of aggregate size on the degradation of materials. This study is to find out the effect of size on physical parameters of aggregate used in flexible and rigid pavement. The performance of river rock and crushed rock physical properties has been tested and compared. In order to determine the effect of aggregate size on their degradation properties, different sieve ranges were selected. The sieve sizes are graded into four categories according to Indian Standard sieve: R1 (20 mm-16 mm), R2 (16 mm-12.5 mm), R3 (12.5 mm-10 mm), and R4 (10 mm-4.75 mm) for degradation test such as, aggregate impact value (AIV), aggregate crushing value (ACV), water absorption (WA) and weathering test such as soundness and slake durability. It is observed that the larger size of aggregate has given better resistance against impact load, abrasion, weathering action and water absorption compare to smaller size over the same volume of rock. The rate at which aggregate degradation occurs is influenced by size. Along with the wheel load, environmental factors including moisture and temperature changes are the primary causes of the early degradation of aggregate. The river rock has a better resistance against degradation and weathering action as it has lesser lamination (a small scale sequence of fine rock layer). Adoption of larger size aggregate in the pavement base course is suggested to withstand the effect of environmental action and wheel load, especially on the friable and quickly disintegrated rock. Arating value, rating index and regression equation have been developed for aggregate degradation. Keywords: Particle Size, Properties of Rock, Weathering, Slake Durability, Degradation Index

Roflumilast escalates α-synuclein aggregate degradation in rotenone-induced Parkinson's disease in rats: Modulation of the ubiquitin-proteasome system and endoplasmic reticulum stress

Perturbation of the protein homeostasis circuit is one of the principal attributes associated with many neurodegenerative disorders, such as Parkinson's disease (PD). This study aimed to explore the neuroprotective effect of roflumilast (ROF), a phosphodiesterase-4 inhibitor, in a rotenone-induced rat model of PD and investigate the potential underlying mechanisms. Interestingly, ROF (1 mg/kg, p.o.) attenuated motor impairment, prevented brain lesions, and rescued the dopaminergic neurons in rotenone-treated rats. Furthermore, it reduced misfolded α-synuclein burden. ROF also promoted the midbrain cyclic adenosine monophosphate level, which subsequently enhanced the 26S proteasome activity and the expression of the 20S proteasome. ROF counteracted rotenone-induced endoplasmic reticulum stress, which was demonstrated by its impact on activating transcription factor 6, glucose-regulated protein 78, and C/EBP homologous protein levels. Moreover, ROF averted rotenone-induced oxidative stress, as evidenced by its effects on the levels of nuclear factor erythroid 2-related factor 2, heme oxygenase-1, reduced glutathione, and lipid peroxides with a significant anti-apoptotic activity. Collectively, this study implies repurposing of ROF as a novel neuroprotective drug owning to its ability to restore normal protein homeostasis.

Enhancement of lysosome biogenesis as a potential therapeutic approach for neurodegenerative diseases.

Millions of people are suffering from Alzheimer's disease globally, but there is still no effective treatment for this neurodegenerative disease. Thus, novel therapeutic approaches for Alzheimer's disease are needed, which requires further evaluation of the regulatory mechanisms of protein aggregate degradation. Lysosomes are crucial degradative organelles that maintain cellular homeostasis. Transcription factor EB-mediated lysosome biogenesis enhances autolysosome-dependent degradation, which subsequently alleviates neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. In this review, we start by describing the key features of lysosomes, including their roles in nutrient sensing and degradation, and their functional impairments in different neurodegenerative diseases. We also explain the mechanisms - especially the post-translational modifications - which impact transcription factor EB and regulate lysosome biogenesis. Next, we discuss strategies for promoting the degradation of toxic protein aggregates. We describe Proteolysis-Targeting Chimera and related technologies for the targeted degradation of specific proteins. We also introduce a group of LYsosome-Enhancing Compounds, which promote transcription factor EB-mediated lysosome biogenesis and improve learning, memory, and cognitive function in APP-PSEN1 mice. In summary, this review highlights the key aspects of lysosome biology, the mechanisms of transcription factor EB activation and lysosome biogenesis, and the promising strategies which are emerging to alleviate the pathogenesis of neurodegenerative diseases.

Petrographic and Physiomechanical Investigation of Late Cretaceous Kawagarh Formation Kahi Section, Nizampur Basin

The late Cretaceous Kawagarh Formation has been investigated in terms of field observation, and petrographic analysis, to understand the petrography and its impact on the geotechnical properties. The Kawagarh Formation is well exposed among the upper Indus Basin, and has been studied by various workers in different aspects. Kawagarh Formation exposed in Kahi section of Nizampur Basin has been selected in this study to know the behavior of carbonate rocks for engineering purposes. Lithologically, this formation is composed of thick to medium bedded, highly fractured limestone, marls, and dolomitic limestone which has undertaken diagenetic alteration including dolomite, calcite veins, and stylolites. Followed by petrographic analysis which reveals that the Kawagarh limestone is mostly fossiliferous comprised of a large number of planktonic foraminifera fossils like Globotruncana Hilli and Globotruncana Linneana fossils. Furthermore, to know the impact of petrographic minerals on engineering behavior, mechanical properties in terms of uniaxial compressive strength (UCS) and uniaxial tensile strength (UTS) were also computed by using a universal testing machine (UTM). The resultant mechanical values lie in the strong compressive strength and suggest their usage for various construction purposes. Aggregate degradation tests including water absorption, specific gravity, aggregate impact value, Los angles abrasion, and soundness was also computed according to the International standard organization, ASTM (American Society for testing materials) and British standard. The aggregate values of the Cretaceous Kawagarh Formation are within the defined standard limits and can be used as an aggregate source for different construction engineering projects.

Genetic Interaction of tRNA-Dependent Mistranslation with Fused in Sarcoma Protein Aggregates

High-fidelity protein synthesis requires properly aminoacylated transfer RNAs (tRNAs), yet diverse cell types, from bacteria to humans, show a surprising ability to tolerate errors in translation resulting from mutations in tRNAs, aminoacyl-tRNA synthetases, and other components of protein synthesis. Recently, we characterized a tRNASerAGA G35A mutant (tRNASerAAA) that occurs in 2% of the human population. The mutant tRNA decodes phenylalanine codons with serine, inhibits protein synthesis, and is defective in protein and aggregate degradation. Here, we used cell culture models to test our hypothesis that tRNA-dependent mistranslation will exacerbate toxicity caused by amyotrophic lateral sclerosis (ALS)-associated protein aggregation. Relative to wild-type tRNA, we found cells expressing tRNASerAAA showed slower but effective aggregation of the fused in sarcoma (FUS) protein. Despite reduced levels in mistranslating cells, wild-type FUS aggregates showed similar toxicity in mistranslating cells and normal cells. The aggregation kinetics of the ALS-causative FUS R521C variant were distinct and more toxic in mistranslating cells, where rapid FUS aggregation caused cells to rupture. We observed synthetic toxicity in neuroblastoma cells co-expressing the mistranslating tRNA mutant and the ALS-causative FUS R521C variant. Our data demonstrate that a naturally occurring human tRNA variant enhances cellular toxicity associated with a known causative allele for neurodegenerative disease.

An assessment of the relationship between the petrographic, physical, and morphological properties of aggregates used for railway ballast

• Qualitative petrographic variables affect aggregate degradation resistance. • Mineralogy defines the physical and morphological behavior of aggregates. • Rocks with a higher concentration of felsic have undergone greater degradation. • Rocks with higher concentrations of mafic and biotite showed angularity gain. The performance of the ballasted permanent track is linked to the quality of the aggregates that make up the ballast layer. This layer is the only one that allows the regularization and leveling of the rail pavement. Evaluating the relationships between the properties of rocks and aggregates helps in predicting the behavior of rail ballast and in reducing wear and premature failures in the permanent way. The objective of this study is to evaluate the relationship between the petrographic, physical and morphological properties of the aggregates. The materials were selected from the literature with application of rocks for different areas. The petrographic properties of the rocks were filtered or identified through photomicrographs. The physical and/or morphological tests of the rocks were verified. Based on the database of 21 rocks, the results show the strong influence of grain shape, granulation, texture, contact between minerals and, mainly, mineralogy on the physical and morphological behavior of the aggregates. Rocks with higher mafic content provide greater resistance to aggregate degradation. Rocks with higher mafic and biotite contents contribute to increase the angularity value of aggregates after Micro-Deval (MD) wear tests. Medium/coarse grained rocks induce a higher value of unfilled intergrain microcracks between minerals and, consequently, higher porosity and water absorption and higher compression degradation. Furthermore, the results show that it is possible to predict the morphological behavior of aggregates after degradation from the morphological variables before their degradation.

Functional responses of aggregate‐colonizing copepods

AbstractZooplankton consumption of aggregates, such as marine snow, is an important factor in determining the efficiency of the biological carbon pump. However, the feeding rates of aggregate‐associated small harpacticoid and poecilostomatoid copepods are largely unknown, as are the factors that influence these rates. We measured the functional responses of pellet production (PP) of aggregate‐feeding copepods on appendicularian houses, algal and detrital aggregates, and on Trichodesmium spp. tufts. The PP rates of all copepods increased with increasing aggregate concentrations, but the response varied depending on the aggregate type. The pelagic harpacticoid copepod Microsetella norvegica had the highest PP rates on algal aggregates, while the poecilostomatoid copepod Oncaea spp. and the benthic harpacticoid copepod Amonardia normanni PP rates were highest on appendicularian houses. The ingestion rates of M. norvegica and Oncaea spp. were typically 0.04–0.13 μg C ind.−1 d−1, with the exception of ca. three times higher rates of Oncaea spp. on appendicularian houses and ca. 10 times higher rates of M. norvegica on algal aggregates. The ingestion rates of the larger species, A. normanni, were generally higher, 0.3–1.3 μg C ind.−1 d−1 on algal aggregates, and even ca. 10‐fold higher on appendicularian houses. Our results suggest that the aggregate degradation rates by copepods can vary many‐fold depending on the quality (origin) of the aggregate and the copepod species. This can have large consequences for the attenuation of vertical carbon flux.

(Digital Presentation) Bioelectrochemistry of Neuronal Tau Protein

Tau is a neuronal protein and one of the biomarkers of neurodegenerative diseases, such as Alzheimer’s disease. Tau protein undergoes post-translational modifications, aggregation, and is a viable drug target. In addition, this protein is a vital biomarker in biological fluids towards early detection of neurodegenerative diseases. We reported on using electrochemical impedance spectroscopy and cyclic voltammetry for detection of protein-protein interactions (1), protein-ligand interactions (2), enzymatic catalysis and enzyme inhibition (3) while focusing on tau protein and its biochemistry. For example, tau-tau, tau-ferritin, tau-transferrin protein interactions were monitored, and protein kinase-catalyzed phosphorylation of tau protein was detected. The phosphorylation inhibitors, such as antibodies, were screened for their efficacy. Bioelectrochemical methodologies were used to gain insight into various facets of protein biochemistry, and represent promising tools in neuroscience research. References A) Carlin, N., Martic-Milne, S. (2018). Anti-tau antibodies based electrochemical sensor for detection of tau protein. J. Electrochem. Soc.165: G3018-G3025. B) Jahshan, A., Esteves, J.O.V., Martic-Milne, S. (2016). Evaluation of ferritin and transferrin binding to tau protein. J. Inorg. Biochem. 162: 127-134. C) Esteves, J.O.V., Trzeciakiewicz, H., Loeffler, D.A., Martic, S. (2015). Effects of tau domain-specific antibodies and intravenous immunoglobulin on tau aggregation and aggregate degradation. Biochemistry. 54: 15-18.Trzeciakiewicz, H., Esteves, J.O.V., Carlin, N., Martic, S. (2015). Electrochemistry of heparin binding to tau protein on Au surfaces. Electrochim. Acta. 162: 24-30,Esteves, J.O.V., Martic-Milne, S. (2016). Electrochemical detection of anti-tau antibodies binding to tau protein and inhibition of GSK-3-β-catalyzed phosphorylation. Anal. Biochem. 496: 55-62

Stiffness and damping properties of railway ballast aggregate considering influence of degradation of aggregate and incorporation of crumb rubber

Impact loads over ballasted railway tracks can accelerate ballast aggregate degradation and deformation. The incorporation of energy-absorbing materials is a practical method to improve the stiffness and damping characteristics of granular layer and diminish aggregate degradation. This study investigated the dynamic responses of ballast aggregates subjected to the drop-weight impact loading test to further illuminate the effect of loading conditions and crumb rubber (CR) incorporation on the stiffness and damping coefficients of ballast material. Experimental measurements were combined with the analytical approach to link the aggregate degradation level to energy evolution and characterize the relationship between the induced impact load and the dynamic properties of granular material. The results demonstrated that the damping properties of ballast material decreased as the number of loading steps increased, which is mainly attributed to further aggregate degradation. The experimental-analytical analysis corroborated lower stiffness and higher damping coefficient for CR-reinforced mixtures. Smaller CR particles led to greater energy dissipation. A linear relationship was also found between the breakage level of aggregates and the energy induced due to friction development between particles and individual aggregate breakage.

Triaxial testing of new and degraded ballast under dry and wet conditions

While many studies focused on both new and fouled ballast behavior due to contamination by external fouling agents, far fewer studies have focused on the mechanical breakdown of crushed ballast stones and the behavior of used ballast due to gradual aggregate degradation. This paper presents triaxial test results conducted on both new and degraded limestone ballast samples to investigate deformation trends and evaluate effects of varying moisture contents. Based on the limited experimental results, degraded ballast samples in dry conditions and typically at a denser state compared to the new and clean ballast did not result in significant strength loss. In most cases, the degraded ballast yielded even higher strengths, which is different than reported in previous studies focused on testing contaminated ballast. However, when subjected to repeated load cycles, degraded ballast specimens exhibited much higher permanent deformation accumulations. When moisture was introduced, the degraded ballast showed significantly larger permanent deformations and strength losses compared to the results observed from dry testing conditions. Negative impacts of moisture on degraded ballast were generally similar as on the contaminated ballast, but the mechanical property changes were more abrupt mainly due to size reductions in coarse aggregate particles and the aggregate skeleton itself.

Petrographic and Physiomechanical Investigation of Late Cretaceous Kawagarh Formation Kahi Section, Nizampur Basin

The late Cretaceous Kawagarh Formation has been investigated in terms of field observation, and petrographic analysis, to understand the petrography and its impact on the geotechnical properties. The Kawagarh Formation is well exposed among the upper Indus Basin, and has been studied by various workers in different aspects. Kawagarh Formationexposed in Kahi section of Nizampur Basin has been selected in this study to know the behavior of carbonate rocks for engineering purposes. Lithologically, this formation is composed of thick to medium bedded, highly fractured limestone, marls, and dolomitic limestone which has undertaken diagenetic alteration including dolomite, calcite veins, and stylolites. Followed by petrographic analysis which reveals that the Kawagarh limestone is mostly fossiliferouscomprised of a large number of planktonic foraminifera fossils like Globotruncana Hilli and Globotruncana Linneana fossils. Furthermore, to know the impact of petrographic minerals on engineering behavior, mechanical properties in terms of uniaxial compressive strength (UCS) and uniaxial tensile strength (UTS) were also computed by using a universal testing machine (UTM). The resultant mechanical values lie in the strong compressive strength and suggest their usage for various construction purposes. Aggregate degradation tests including water absorption, specific gravity, aggregate impact value, Los angles abrasion, and soundness was also computed according to the International standard organization, ASTM (American Society for testing materials) and British standard. The aggregate values of the Cretaceous Kawagarh Formation are within the defined standard limits and can be used as an aggregate source for different construction engineering projects.

Lysophosphatidylcholine acyltransferase 1 promotes pathology and toxicity in two distinct cell-based alpha-synuclein models

Alpha-synuclein (αSyn) pathology is a hallmark of Parkinson’s disease. Here we show that lysophosphatidylcholine acyltransferase 1 (LPCAT1) is a regulator of αSyn pathology and cytotoxicity. LPCAT1 is upregulated by αSyn E35K E46K E61K (3K) in human M17 neuroblastoma cells and primary rat cortical neurons, and in postmortem brain tissue from PD patients with confirmed αSyn aggregate pathology. Suppression of LPCAT1 reduces αSyn accumulations and toxicity in our neuroblastoma αSyn 3K overexpression model. Further overexpression of LPCAT1 promotes pS129 αSyn positive aggregation in primary neurons in the αSyn pre-formed fibril (PFF) model. A phospholipid product of LPCAT1 enzymatic activity, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, similarly promotes neuronal PFF seeded aggregation. Using a pH sensitive PFF model we provide evidence that αSyn fibrils have altered endo-lysosomal processing under LPCAT1 enhancement, suggesting less aggregate degradation. Our data demonstrates that LPCAT1 and associated phospholipids can regulate αSyn pathology.

E3 ligase Smurf1 protects against misfolded SOD1 in neuronal cells by promoting its K63 ubiquitylation and aggresome formation.

K63-linked polyubiquitination of the neurodegenerative disease-associated misfolded protein copper-zinc superoxide dismutase 1 (SOD1) is associated with the formation of inclusion bodies. Highly expressed E3 ligase Smad ubiquitylation regulatory factor 1 (Smurf1) promotes cellular homeostasis through the enhanced capability of aggregate degradation. However, it is not well explored the role of Smurf1 in the dynamics of SOD1 aggresomes. In this study, we report that Smurf1 promotes the recruitment of SOD1 to form aggresomes. Mechanistically, Smurf1 interacts with mutant SOD1 to promote aggresome formation by modification of its K63-linked polyubiquitination. Moreover, overexpressed Smurf1 enhances mutant SOD1 aggresome formation and autophagic degradation to prevent cell death. Thus, our data suggest that Smurf1 plays an important role in attenuating protein misfolding-induced cell toxicity by both driving the sequestration of misfolded SOD1 into aggresomes and autophagic degradation.

Investigation of the changes in aggregate morphology during different aggregate abrasion/degradation tests using image analysis

There are different tests for measuring aggregate abrasion/degradation resistance, which simulated the destruction conditions in various applications of aggregate. Although these tests have been used for a long time, the process of changing the aggregate shape after the test is still not well known. These changes could be an essential factor in the quality of aggregate materials during their life cycle and play a vital role in the simulated model of aggregate degradation. In this study, the aggregate shape properties in terms of form, angularity, and surface texture are investigated and compared before and after the AAD tests by image analysis techniques. Two common types of coarse aggregates were selected, i.e., limestone and andesite. The AAD tests include different standard test methods, i.e., Micro-Deval (MD), Los Angeles abrasion losses (LAAL), aggregate crushing value (ACV), and aggregate impact value (AIV) were conducted. The results indicated that the change of aggregate shape is based on AAD tests and rock type. The heterogeneity in the mechanism of AAD tests led to the different changes in aggregate morphology and also to opposite behavior due to rock type in texture. The changes in surface texture and angularity are very different, although changes in form have the same trend after LAAL, ACV, and AIV tests. The results showed that the shape changes of the aggregates are affected by both the test type and rock type. The behavior of ACV, AIV, and LAAL in shape changes is similar and is different from MD. The knowledge obtained from this research presents a primary step concerning the numerical modeling and quantitative evaluation of the AAD tests.