Insoluble Deposits Research Articles

Adverse Effects of Aβ1-42 Oligomers: Impaired Contextual Memory and Altered Intrinsic Properties of CA1 Pyramidal Neurons.

Aβ1-42 (amyloid beta) oligomers, the major neurotoxic culprits in Alzheimer's disease, initiate early pathophysiological events, including neuronal hyperactivity, that underlie aberrant network activity and cognitive impairment. Although several synaptotoxic effects have been extensively studied, neuronal hyperexcitability, which may also contribute to cognitive deficits, is not fully understood. Here, we found several adverse effects of in vivo injection of Aβ1-42 oligomers on contextual memory and intrinsic properties of CA1 pyramidal neurons. Male rats underwent behavioral and electrophysiological studies 1 week after microinjections into the dorsal CA1 region, followed by histological analysis. After 1 week, Aβ1-42 oligomers impaired contextual learning without affecting basic physiological functions and triggered training-induced neuronal excitability. Furthermore, riluzole, a persistent sodium current (INaP) blocker, dose-dependently reduced Aβ1-42 oligomer-induced hyperexcitability. Congo red staining, which detects insoluble amyloid deposits, further identified labeling of CA1 pyramidal neurons while immunohistochemistry with lecanemab, which detects soluble Aβ oligomers, revealed immunoreactivity of both pyramidal and non-pyramidal cells in the target area. Therefore, our study suggests that a single injection of Aβ1-42 oligomers resulted in contextual memory deficits along with concomitant neuronal hyperexcitability and amyloid deposition in the CA1 region after 1 week.

Glial alterations in the glutamatergic and GABAergic signaling pathways in a mouse model of Lafora disease, a severe form of progressive myoclonus epilepsy.

Lafora disease (LD; OMIM#254780) is a rare form of progressive myoclonus epilepsy characterized by the accumulation of insoluble deposits of aberrant glycogen (polyglucosans), named Lafora bodies (LBs), in the brain but also in peripheral tissues. It is assumed that the accumulation of LBs is related to the appearance of the characteristic pathological features of the disease. In mouse models of LD, we and others have reported an increase in the levels of reactive astrocytes and activated microglia, which triggers the expression of the different pro-inflammatory mediators. Recently, we have demonstrated that the TNF and IL-6 inflammatory signaling pathways are the main mediators of the neuroinflammatory phenotype associated with the disease. In this work, we present evidence that the activation of these pathways produces a dysregulation in the levels of different subunits of the excitatory ionotropic glutamatergic receptors (phopho-GluN2B, phospho-GluA2, GluK2) and also an increase in the levels of the GABA transporter GAT1 in the hippocampus of the Epm2b-/- mice. In addition, we present evidence of the presence of activated forms of the Src and Lyn protein kinases in this area. These effects may increase the excitatory glutamatergic signaling and decrease the inhibitory GABAergic tone, leading to hyper-excitability. More importantly, the enhanced production of these subunits occurs in non-neuronal cells such as activated microglia and reactive astrocytes, pointing out a key role of glia in the pathophysiology of LD.

DFT-based computational analysis of 2,4-dimethyl-6-tert-butylphenol (DTBP) as an antioxidant in aviation fuels

Antioxidants are indispensable additives for ensuring the long-term stability, performance, and reliability of aviation fuels. They prevent the formation of gum and other insoluble deposits in the fuel which clog fuel systems, leading to engine problems. This is achieved by inhibiting free radical chain reactions involved in the oxidation of hydrocarbons in the fuel. The compound 2,4-Dimethyl-6-tert-butyl phenol (DTBP) is one of the widely used antioxidants in aviation fuels. In this report, the radical scavenging done by DTBP is analysed computationally by density functional theory (DFT) with the model chemistry X/6-31+G(d,p), where X represents certain Minnesota functionals such as MN15, M05-2X, M06-2X, M08-HX, and M11. Among the well-known modes of radical scavenging, namely HAT, SETPT, and SPLET, the HAT mode is preferred in the gaseous phase, while SPLET operates in non-polar solvents, as computations indicate. Fukui indices, global reactivity descriptors, electronic spectra, and natural bond orbitals (NBOs) are also generated to explain the results. Understanding the mechanism of radical scavenging is important in designing powerful and efficient antioxidants for aviation fuels such as jet fuel, aviation gasoline, Jet B, and bio-kerosene.

Achieving the Inhibition of Aluminum Corrosion by Dual-Salt Electrolytes for Sodium-Ion Batteries.

Sodium bis(fluorosulfonyl)imide (NaFSI) electrolytes are renowned for their superior physicochemical and electrochemical properties, making them ideal for high-performance sodium-ion batteries (SIBs). However, severe oxidative dissolution of aluminum current collectors (commonly known as Al corrosion) in NaFSI-based electrolytes occurs at high potentials. To address this challenge, aiming to understand the Al corrosion mechanism and develop strategies to inhibit corrosion, we propose dual-salt electrolytes using 0.8 mol L-1 (M) NaFSI and 0.2 M of a second fluorine-containing sodium salt dissolved in EC/PC solutions (1:1, v/v) to construct an insoluble deposits layer on the Al. Dual-salt electrolytes adopting a second sodium salt capable of passivating the Al collector have been extensively investigated through various techniques, such as cyclic voltammetry, scanning electron microscopy, chronoamperometry, X-ray photoelectron spectroscopy, and charge-discharge tests. Our findings demonstrate that introducing sodium difluoro(oxalato)borate (NaDFOB) into the NaFSI electrolytes inhibits Al corrosion, which is attributed to the formation of insoluble deposits of Al-F (AlF3) and B-F containing polymers. Moreover, the capacity retention of Na||Na3V2(PO4)3 (NVP) cells using the NaFSI-NaDFOB dual-salt electrolyte reaches 99.2% along with a Coulombic efficiency over 99.3% at a 1 C rate after 200 cycles. This research provides a practical solution for passivating Al collectors in SIBs with NaFSI electrolytes and promotes the development of sodium batteries with long calendar lifetimes.

Serum Amyloid P Secreted by Bone Marrow Adipocytes Drives Skeletal Amyloidosis.

The accumulation of amyloid fibrils has been identified in tissues outside the brain, yet little is understood about the formation of extracerebral amyloidosis and its impact on the aging process of these organs. Here, we demonstrate that both transgenic mice modeling Alzheimer's disease (AD) and naturally aging mice exhibit accumulated senescent bone marrow adipocytes (BMAds), accompanied by amyloid deposits surrounding the BMAds. Senescent BMAds acquire a secretory phenotype, resulting in a marked increase in the secretion of serum amyloid P component (SAP), also known as pentraxin 2 (PTX2). SAP/PTX2 colocalizes with amyloid deposits around senescent BMAds in vivo and is sufficient to promote the formation of insoluble amyloid deposits from soluble Aβ peptides in in vitro and ex vivo 3D BMAd-based culture experiments. Additionally, Combined treatment with SAP/PTX2 and Aβ peptides promotes osteoclastogenesis but inhibits osteoblastogenesis of the precursor cells. Transplantation of senescent BMAds into the bone marrow cavity of healthy young mice is sufficient to induce bone loss. Finally, pharmacological depletion of SAP/PTX2 from aged mice abolishes bone marrow amyloid deposition and effectively rescues the low bone mass phenotype. Thus, senescent BMAds, through the secretion of SAP/PTX2, contribute to the age-associated development of skeletal amyloidosis and resultant bone deficits.

Acute lead (Pb2+) exposure increases calcium oxalate crystallization in the inner medullary collecting duct, and is ameliorated by Ca2+/Mg2+-ATPase inhibition, as well as Capa receptor and SPoCk C knockdown in a Drosophila melanogaster model of nephrolithiasis

Calcium oxalate (CaOx) kidney stones accumulate within the renal tubule due to high concentrations of insoluble deposits in the urine. Pb2+-induced Ca2+ mobilization along with Pb2+-induced nephrotoxic effects within the proximal tubule have been well established; however, Pb2+ mediated effects within the collecting duct remains insufficiently studied. Thus in vitro and ex vivo model systems were treated with increasing concentrations of lead (II) acetate (PbAc) ± sodium oxalate (Na2C2O4) for 1 h, both individually and in combination. Pb2+-mediated solution turbidity increased 2 to 5 times greater post-exposure to 75, 100 and 200 μM Pb2+ with the additional co-treatment of 10 mM oxalate in mouse inner medullary collecting duct (mIMCD-3) cells. Additionally, 100 μM and 200 μM Pb2+ alone induced significant levels of intracellular Ca2+ release. To validate Pb2+-mediated effects on the formation of CaOx crystals, alizarin red staining confirmed the presence of CaOx crystallization. Pb2+-induced intracellular Ca2+ was also observed ex vivo in fly Malpighian tubules with significant increases in CaOx crystal formation via Pb2+-induced intracellular Ca2+ release significantly increasing the average crystal number, size, and total area of crystal formation, which was ameliorated by tissue-specific SPoCk C transporter and Capa receptor knockdown. These studies demonstrate Pb2+-induced Ca2+ release likely increases the formation of CaOx crystals, which is modulated by a Gq-linked mechanism with concurrent Ca2+ extracellular mobilization.

Improving the Corrosion Resistance of Anodized Al 1050 Alloy by Sealing in Cerium-Containing and Mixed Sodium Phosphate Mono Basic and Calcium Nitrate Solutions

This investigation presents results on the improvement of the corrosion-protective effect of consecutive sealing treatments of anodized Al 1050 (AlAnod). The treatments were performed in cerium-containing and mixed NaH2PO4 + Ca(NO3)2 solutions. The changes of the surface morphology, structure and chemical composition, chemical state of the elements, and basic corrosion parameters of the studied systems were investigated by SEM, EDXS, XRD, XPS, and a complex of electrochemical techniques (PDP, EOCP vs. timeplot, chronoamperometric transients, Rp and CR at EOCP, etc.). The results obtained show that the basic components of the obtained sealing conversion layers (before and after exposure to model Cl−-containing corrosion media) are characterized by Ca10(PO4)6(OH)2, AlO(OH), CePO4, and CeAlO3 (after the corrosion tests, they are converted to insoluble Me-PO3 and Me-P4O10). We conclude that the observed decrease in the corrosion rate of Al and the corresponding increase in the polarization resistance are accomplished by the two-step sealing treatment, which fills up the AlAnod pores with insoluble deposits.

Identification of key eRNAs for intervertebral disc degeneration by integrated multinomial bioinformatics analysis

BackgroundIntervertebral disc degeneration (IVDD) is a common degenerative condition leading to abnormal stress distribution under load, causing intervertebral stenosis, facet joint degeneration, and foraminal stenosis. Very little is known about the molecular mechanism of eRNAs in IVDD.MethodsGene expression profiles of 38 annulus disc samples composed of 27 less degenerated discs (LDs) and 11 more degenerated discs (MDs) were retrieved from the GEO database. Then, differentially expressed enhancer RNAs (DEeRNAs), differentially expressed target genes (DETGs), and differentially expressed transcription factors (DETFs), hallmark of cancer signalling pathways according to GSVA; the types and quantity of immune cells according to CIBERSORT; and immune gene sets according to ssGSEA were analysed to construct an IVDD-related eRNA network. Then, multidimensional validation was performed to explore the interactions among DEeRNAs, DETFs and DEGs in space.ResultsA total of 53 components, 14 DETGs, 15 DEeRNAs, 3 DETFs, 5 immune cells, 9 hallmarks, and 7 immune gene sets, were selected to construct the regulatory network. After validation by online multidimensional databases, 21 interactive DEeRNA-DEG-DETF axes related to IVDD exacerbation were identified, among which the C1S-CTNNB1-CHD4 axis was the most significant.ConclusionBased upon the results of our study, we theorize that the C1S-CTNNB1-CHD4 axis plays a vital role in IVDD exacerbation. Specifically, C1S recruits CTNNB1 and upregulates the expression of CHD4 in IVDD, and subsequently, CHD4 suppresses glycolysis and activates oxidative phosphorylation, thus generating insoluble collagen fibre deposits and leading to the progression of IVDD. Overall, these DEeRNAs could comprise promising therapeutic targets for IVDD due to their high tissue specificity.

Pollution Characteristics and Sources of Ambient Air Dustfall in Urban Area of Beijing

Since 2016, the Ministry of Ecology and Environment and the Beijing Municipal Government have adjusted the minimum concentration limit for ambient air dustfall several times, indicating that they attach great importance to dustfall. To grasp the pollution characteristics and sources of dustfall, in this work, the filtration method was used to determine the insoluble dustfall and water-soluble dustfall in the urban area of Beijing. From our analysis, the influence of the meteorological parameters on dustfall was found, and the chemical components of dustfall were determined. The positive matrix factorization (PMF) model was also utilized to analyze the sources of dustfall. The results indicated that the average amount of dustfall in 2021–2022 was 4.4 t·(km2·30 d)−1, and the proportion of insoluble dustfall deposition was 82.4%. Dustfall was positively correlated with the average wind speed and temperature and negatively correlated with the relative humidity and rain precipitation. The impact of the meteorological parameters on insoluble dustfall and water-soluble dustfall was the opposite. The average proportions of crustal material, ions, organic matter, element carbon, trace elements, and unknown components were 48%, 16%, 14%, 1.4%, 0.20%, and 20%, respectively. The proportions of the crustal material and ions were the highest in spring (57%) and summer (37%). The contribution rates of fugitive dust source, secondary inorganic source, mobile source, coal combustion source, snow melting agent source, and other sources were 42.4%, 19.3%, 8.3%, 3.0%, 2.7%, and 24.3%, respectively. This study supported dustfall pollution control by analysing the pollutant characteristics and sources of dustfall from the standpoint of total chemical components. In order to better control dustfall pollution, control measures and evaluation standards for fugitive dust pollution should be formulated.

Widespread nuclear lamina injuries defeat proteostatic purposes of α-synuclein amyloid inclusions.

Biogenesis of inclusion bodies (IBs) facilitates protein quality control (PQC). Canonical aggresomes execute degradation of misfolded proteins while non-degradable amyloids sequester into insoluble protein deposits. Lewy bodies (LBs) are filamentous amyloid inclusions of α-synuclein, but PQC benefits and drawbacks associated with LB-like IBs remain underexplored. Here, we report that crosstalk between filamentous LB-like IBs and aggresome-like IBs of α-synuclein (Syn-aggresomes) buffer the load, aggregation state, and turnover of the amyloidogenic protein in mouse primary neurons and HEK293T cells. Filamentous LB-like IBs possess unorthodox PQC capacities of self-quarantining α-synuclein amyloids and being degradable upon receding fresh amyloidogenesis. Syn-aggresomes equilibrate biogenesis of filamentous LB-like IBs by facilitating spontaneous degradation of α-synuclein and conditional turnover of disintegrated α-synuclein amyloids. Thus, both types of IB primarily contribute to PQC. Incidentally, the overgrown perinuclear LB-like IBs become degenerative once these are misidentified by BICD2, a cargo-adapter for the cytosolic motor-protein dynein. Microscopy indicates that microtubules surrounding the perinuclear filamentous inclusions are also distorted, misbalancing the cytoskeleton-nucleoskeleton tension leading to widespread lamina injuries. Together, nucleocytoplasmic mixing, DNA damage, and deregulated transcription of stress chaperones defeat the proteostatic purposes of the filamentous amyloids of α-synuclein.

Геохимическая оценка системы «поверхностная вода – донные отложения» в зоне горнопромышленного техногенеза

Introduction. Tailings dumps are the most common by-product of the process of extracting valuable minerals and metals from mined ore. Their placement is accompanied by a violation of the natural properties of natural landscapes, changes in the geochemistry of soils and the hydrochemistry of the aquatic environment, the accumulation of heavy metals and toxicants in depositing media. The issues of geochemistry and stability of landscapes, the safety of natural and technical systems, the identification, study, assessment and forecast of their development in the conditions of increasing techno genesis is an urgent global problem. One of the most important directions in the geochemistry of mountain landscapes and mining and industrial ecology is the purposeful study of the relationship and interdependence of the processes of technogenic geochemical migration of the main and associated ore-forming elements into the environment with the technological processes of ore extraction and processing. The development of scientifically-based principles for the organization of control and monitoring of disturbed geo-systems in the conditions of techno genesis is not only an important fundamental research task, but has practical significance in order to preserve natural landscapes and mountain geo-systems. Purpose of research. Geochemical assessment of the “surface water-bottom sediments” system in the area of a copper-molybdenum deposit. Materials and methods. The research methodology is based on the theoretical foundations of landscape geochemistry. The object of the study is the system “surface water-bottom sediments” in the zone of technogenic influence of the tailings dump of a copper-molybdenum deposit. Field and standard physical-chemical methods, Excel graphics, geo-information analysis, 3D modeling Statistica were used. Discussion. Geochemical testing of the surface river in the tailings storage area revealed a significant enrichment of the aquatic environment with salt ions, which enter the surface water in the form of dam filtrate. The violation of the ratio of alkali metal ions, as well as the ratio of alkali-earth metal ions to alkali metal ions, which is a geochemical anomaly for fresh surface natural waters, is shown. As a result of constant filtration through the body of the tailings dam, heavy metals also enter the river water, primarily Cu, Mo, Fe, which, under conditions of an alkaline water environment, accumulate mainly at the bottom of the watercourse in the form of insoluble deposits. The coefficients of accumulation of metals in bottom sediments relative to clerks are obtained. The spatial dynamics of their distribution and variability along the riverbed are revealed, which makes it possible to predict the development of the situation in the zone of mining and industrial techno genesis. 3D models of the distribution of the analyzed metals from the properties of the pH medium, the main regulating factor of the formation of various forms of heavy metals, are obtained. Conclusion. It is shown that the hydro-geochemical features in the “surface water – bottom sediments” system of the river in the area of the tailings dam inherit chemical ore occurrence during Cu, Mo, Fe extraction. This indicates a technogenic transformation of the hydrosphere in a zone with a predominance of mining and industrial specialization of the deposit. The results obtained are of scientific interest as an empirical model for studying the process of formation of sedimentary ores, which, in turn, represents a fundamental aspect for the development of the theory of subsoil development design and studying the processes of formation of technogenic deposits.

Sequestrase chaperones protect against oxidative stress-induced protein aggregation and [PSI+] prion formation.

Misfolded proteins are usually refolded to their functional conformations or degraded by quality control mechanisms. When misfolded proteins evade quality control, they can be sequestered to specific sites within cells to prevent the potential dysfunction and toxicity that arises from protein aggregation. Btn2 and Hsp42 are compartment-specific sequestrases that play key roles in the assembly of these deposition sites. Their exact intracellular functions and substrates are not well defined, particularly since heat stress sensitivity is not observed in deletion mutants. We show here that Btn2 and Hsp42 are required for tolerance to oxidative stress conditions induced by exposure to hydrogen peroxide. Btn2 and Hsp42 act to sequester oxidized proteins into defined PQC sites following ROS exposure and their absence leads to an accumulation of protein aggregates. The toxicity of protein aggregate accumulation causes oxidant sensitivity in btn2 hsp42 sequestrase mutants since overexpression of the Hsp104 disaggregase rescues oxidant tolerance. We have identified the Sup35 translation termination factor as an in vivo sequestrase substrate and show that Btn2 and Hsp42 act to suppress oxidant-induced formation of the yeast [PSI+] prion, which is the amyloid form of Sup35. [PSI+] prion formation in sequestrase mutants does not require IPOD (insoluble protein deposit) localization which is the site where amyloids are thought to undergo fragmentation and seeding to propagate their heritable prion form. Instead, both amorphous and amyloid Sup35 aggregates are increased in btn2 hsp42 mutants consistent with the idea that prion formation occurs at multiple intracellular sites during oxidative stress conditions in the absence of sequestrase activity. Taken together, our data identify protein sequestration as a key antioxidant defence mechanism that functions to mitigate the damaging consequences of protein oxidation-induced aggregation.

Neuromuscular manifestations of wild type transthyretin amyloidosis: a review and single center's experience.

Transthyretin amyloidosis (ATTR) is a condition defined by accumulation of insoluble transthyretin amyloid deposits in multiple organs, especially in the peripheral nerve and heart muscle. ATTR may result from transthyretin mutations (variant ATTR or ATTRv) or may occur with normal transthyretin genotype (wild type ATTR or ATTRwt). ATTRwt was previously known as "senile amyloidosis" and causes cardiomyopathy which may lead to heart failure with a preserved ejection fraction, affecting predominantly elderly men. The exact prevalence of ATTRwt in the general population remains unclear, but its occurrence may be underestimated in women. It was observed that a proportion of ATTRwt cardiomyopathy patients may develop slowly progressing neuropathy that is milder and indolent in comparison with typical progressive neuropathy associated with ATTRv. Furthermore, the causality of neuropathy is often uncertain in patients with ATTRwt. Neuropathy symptoms, including distal sensory loss, unsteadiness and (neuropathic) pain are common in elderly patients with multiple potential causes, and as ATTRwt patients are typically older, relatively high prevalence of peripheral neuropathy is expected with frequent comorbidities. Relatively high prevalence of ATTRwt in elderly population contrasts few documented cases of neuropathy caused by ATTRwt, and there is uncertainty whether ATTRwt neuropathy is an infrequent occurrence or a significant manifestation of multisystemic ATTRwt. We review neurologic and musculoskeletal manifestations of ATTRwt and present clinical features of a single center cohort of ATTRwt patients with suspected peripheral neuropathy.

Effect of Glycine on a Fe-Based Electrolyte for Redox Flow Batteries

Among the rising stationary energy storage technologies, Redox Flow Batteries (RFBs) emerge as a promising electrochemical device capable of high flexibility in terms of power and energy combined with potential low cost and low environmental impact. Alternative chemistries can employ cheap and earth-abundant materials, possibly alleviating the demand for critical raw materials, which are extensively employed in the field of energy production and storage. Iron-based chemistries are among the best candidates for aqueous pH-neutral catholytes, offering fast reaction kinetics and a well-placed standard reduction potential of 0.771 V, that, coupled with a Zinc-based anolyte, would give a nominal cell voltage of 1.53 V [1]. Unfortunately, the dissolution of Iron salts in a neutral aqueous solution triggers hydrolysis, resulting in the formation of Iron hydroxides in the form of insoluble deposits. This causes the loss of electroactive species from the electrolyte, and consequently decreases the battery capacity. Thus far, the conventional solution is the electrolyte acidification, which, however, significantly increases the costs of materials for stacks and electrolyte handling components and aggravates the already critical problem of Hydrogen evolution at the Zinc side. As an alternative, several complexing agents have been proposed in the literature, with preliminary studies on their complexation mechanisms [2]. Glycine is often considered as one of the most promising candidates, even though its suppressing effect on the Fe(II)/Fe(III) kinetics at high concentrations is widely reported [3].This research investigates an optimized pH-neutral catholyte for Zinc-Iron RFBs, focusing on the use of Glycine to avoid Iron-induced hydrolysis. The study is carried out on highly concentrated solutions of Iron chlorides, with the addition of Glycine as ligand at various concentrations. The aim is to preserve the performances of Fe(II)/Fe(III) kinetics and to avoid insoluble hydroxides formation by an accurate choice of the Gly-Fe ratio. The produced electrolytes have been characterized by measuring the solutions conductivity, kinematic viscosity and density. Then, an electrochemical characterization is performed evaluating the diffusion coefficients (𝐷) of the dissolved species, the equilibrium potential (𝐸0) and the exchange current density (𝑗0) as well as the rate constant of the reactions (𝑘0) by means of cyclic voltammetries with a glassy carbon rotating disc electrode. The diffusion coefficients are obtained from Randles-Sevcik equation while the equilibrium potential, the exchange current density and the reaction rate constants are evaluated with a Koutecky-Levich analysis. An optimization of the electrolyte preparation method was also performed, evaluating the effects of pH and temperature and monitoring the complexation time, with the aim of accelerating the Gly-Fe complexation reaction. The effects of KCl and CaCl2 on the electrolyte conductivity are also investigated, to identify suitable supporting electrolytes.The research results show how the addition of Glycine successfully prevents the formation of precipitates in equimolar solutions even at low Gly-Fe ratios. However, Glycine suppresses Fe(II)/Fe(III) kinetics and lowers the electrolyte equilibrium potential, consequently reducing both energy density and the maximum current for its use in RFBs. It is thus possible to identify an optimum for the Gly-Fe ratio by setting a compromise between chemical stability and electrochemical performances. We propose the range 0.5:1 to 1:1 as a convenient Gly-Fe ratio for the 1M FeCl2 and 1M FeCl3 system, reaching a potential higher than 0.721 V vs. SHE, making it a very attractive catholyte with excellent suppression of Iron hydrolysis as no precipitation is observed after more than three months.This work is funded by the Italian Ministry of Enterprises and Made in Italy in the framework of the Important Project of Common European Interest (IPCEI) European Battery Innovation (project IPCEI Batterie 2 - CUP: B62C22000010001). The IPCEI European Battery Innovation is also funded by public authorities from Austria, Belgium, Croatia, Finland, France, Germany, Greece, Poland, Slovakia, Spain and Sweden.[1] Zhang, Huan, Chuanyu Sun, and Mingming Ge. "Review of the research status of cost-effective zinc–iron redox flow batteries." Batteries 8.11 (2022): 202.[2] Hawthorne, Krista L., Jesse S. Wainright, and Robert F. Savinell. "Studies of iron-ligand complexes for an all-iron flow battery application." Journal of The Electrochemical Society 161.10 (2014): A1662.[3] Xie, Congxin, et al. "A Low‐Cost Neutral Zinc–Iron Flow Battery with High Energy Density for Stationary Energy Storage." Angewandte Chemie International Edition 56.47 (2017): 14953-14957. Figure 1

Resorufin retainment by extracellular DNA ensures efficient extracellular electron transfer of Geobacter biofilm

Electrochemically active bacteria (EAB) have promising applications in renewable energy recovery, biofuel production, environmental remediation, and wastewater treatment. Resazurin (RZ) is an effective exogenous electron mediator to facilitate extracellular electron transfer (EET) in EAB, but it is not fully understood that how it catalyzes EET within thick electroactive biofilm. Using Geobacter sulfurreducens as a model EAB, this study investigated the effect and mechanisms of RZ-mediated electron transfer in anode biofilm in a bioelectrochemical system. It was found that the amendment of RZ substantially enhanced current generation of anode biofilm, and the facilitating effect of RZ remained even after fresh electrolyte replacement without RZ replenishment. As an intermediate product of RZ, resorufin (RR) was the actual electron shuttle retained within the entire anode biofilm, responsible for the observed stable electron shuttling efficiency. The retention of RR in anode biofilm might be the consequences of insoluble RR deposition and RR binding with extracellular DNA (eDNA) through intercalative interactions. This study provided in vivo and in vitro evidences for the first time that eDNA provided binding sites for RR in Geobacter biofilm, and proposed a novel electron shuttling mechanism of phenoxazine catalyzing efficient EET of electroactive biofilm.

An ultra performance liquid chromatography method for transthyretin variants screening and heart failure assisting diagnosis

BackgroundTransthyretin (TTR) gene mutations are associated with hereditary amyloidosis (ATTR) caused by mutant TTR protein dissociation, misfolding, aggregation, and insoluble fibrils deposition. Herein, we reported a chromatographic approach for quantification and identification of TTR tetramer in human blood serum by ultra performance liquid chromatography (UPLC). MethodsTTR proteins and serum were incubated with a fluorescent TTR tetramer sensor (A2). The A2 sensor specifically reacted with tetrameric TTR and released stoichiometric fluorescence that was detected by fluorescence detector coupled to UPLC. The external standard was used for quantification, the chromatographic peak parameters were used to identification certain mutation types. ResultsUPLC correctly distinguished 18 types of mutant TTR proteins from wild type. The results were consistent with follow-up analysis of two ATTR patients’ blood serum samples. In addition, the tetrameric TTR of 30 heart failure (HF) patients showed strongly correlation (r = −0.63, p < 0.00) with NT-proBNP, a HF clinical biomarker. ConclusionsUPLC method has sufficient accuracy to eliminate the necessity of sequencing for certain types of TTR mutations and allows for facile initial screening of ATTR amyloidosis patients, carriers, and healthy individuals for time-saving and economical purposes. TTR tetramer may serve as a diagnostic biomarker to evaluate the risk of HF diseases.

Pooled Analysis of Safety from Birtamimab Phase 1-3 Studies in Patients with Light Chain (AL) Amyloidosis

Introduction: SystemicAL amyloidosis is a progressive and often fatal disease caused by misfolded light chains that aggregate into amyloid fibrils and deposit in vital organs, leading to organ dysfunction. Current standard of care (SoC) therapies for AL amyloidosis target the plasma cell clone to reduce or eliminate light chain production, but do not remove soluble toxic light chain aggregates or insoluble amyloid deposits. Early mortality remains high for patients with advanced disease (e.g., Mayo 2012 Stage IV disease, median overall survival &amp;lt;6 months). Birtamimab - a humanized monoclonal antibody that neutralizes soluble, toxic light chain aggregates and depletes insoluble amyloid deposits by inducing phagocytosis - is under investigation for the treatment of AL amyloidosis. Here, we present a pooled safety analysis from previous Phase 1-3 clinical trials, with a focus on the 2 double-blind randomized controlled trials (RCTs): PRONTO (NCT02632786) and VITAL (NCT02312206). Methods: Patients with AL amyloidosis were treated with intravenous birtamimab up to 24 mg/kg every 28 daysin the non-placebo-controlled Phase 1/2 open-label trial (NCT01707264) with open-label extension (OLE; NCT02613182) and 2 RCTs (Phase 2 PRONTO with OLE [NCT03154047] and Phase 3 VITAL). In PRONTO, patients had received ≥1 previous systemic therapy with at least a partial hematologic response and persistent cardiac dysfunction, and received birtamimab or placebo. In VITAL, newly diagnosed treatment-naïve patients with cardiac involvement received birtamimab + SoC or placebo + SoC (where SoC was a bortezomib-containing chemotherapy regimen). The analysis included all patients who received ≥1 dose of birtamimab. Pooled median exposure times were calculated, and baseline characteristics and demographics were summarized. For VITAL and PRONTO, pooled rates and severity of treatment-emergent adverse events (TEAEs) with birtamimab were compared with rates in the placebo arms. In addition, safety data from the non-placebo-controlled studies were summarized. Results: The median (range) exposure to birtamimab among 302 patients pooled from the Phase 1-3 trials was 12.24 (0.03-57.72) months. Of the 302 patients exposed to birtamimab, 295 received at least one 24-mg/kg infusion, up to 2500 mg. Analysis of the 2 randomized, placebo-controlled trials included data from 196 patients treated with birtamimab from the PRONTO (n=66) and VITAL (n=130) trials and 193 patients who received placebo (PRONTO, n=63; VITAL, n=130). Both trials had comparable treatment durations overall. The rates of TEAEs, serious and grade ≥3 TEAEs were similar between birtamimab and placebo arms within each trial and between treatment arms in the placebo-controlled pooled analysis set (PRONTO and VITAL; Table 1). Higher rates of treatment-related, serious, and grade ≥3 TEAEs were reported in VITAL compared with PRONTO, presumably due to the treatment-naïve population and receipt of concomitant SoC therapy in VITAL. In the pooled analysis set, the most common TEAEs that occurred with greater frequency in the birtamimab vs placebo arms in either trial were, respectively, fatigue (36.2%, 34.2%), diarrhea (33.2%, 33.7%), nausea (31.6%, 30.1%), constipation (31.1%, 31.6%), and dyspnea (25.0%, 24.9%). The most commonly reported (≥5%) serious and grade ≥3 TEAEs were primarily cardiac disorders (cardiac failure, syncope, cardiac arrest), consistent with the underlying disease. Infusion-associated TEAE rates were low in the pooled birtamimab and placebo arms (5.1% vs 3.6%, respectively) and were generally mild to moderate. The safety profile observed in the non-placebo-controlled Phase 1/2 trial plus OLE and PRONTO OLE (n=106) was consistent with the safety data reported in the placebo-controlled studies. Conclusions: Birtamimab was well tolerated in patients with AL amyloidosis when administered as monotherapy and did not demonstrate additive toxicity when given with SoC chemotherapy. Rates of TEAEs in the birtamimab arm were similar to rates in the placebo arm in the PRONTO and VITAL trials. The safety and efficacy of birtamimab is being further investigated in an ongoing confirmatory Phase 3 double-blind RCT in patients with Mayo Stage IV AL amyloidosis (AFFIRM-AL; NCT04973137), which is currently enrolling.

A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models.

Brains are highly metabolically active organs, consuming 20% of a person's energy at resting state. A decline in glucose metabolism is a common feature across a number of neurodegenerative diseases. Another common feature is the progressive accumulation of insoluble protein deposits, it's unclear if the two are linked. Glucose metabolism in the brain is highly coupled between neurons and glia, with glucose taken up by glia and metabolised to lactate, which is then shuttled via transporters to neurons, where it is converted back to pyruvate and fed into the TCA cycle for ATP production. Monocarboxylates are also involved in signalling, and play broad ranging roles in brain homeostasis and metabolic reprogramming. However, the role of monocarboxylates in dementia has not been tested. Here, we find that increasing pyruvate import in Drosophila neurons by over-expression of the transporter bumpel, leads to a rescue of lifespan and behavioural phenotypes in fly models of both frontotemporal dementia and Alzheimer's disease. The rescue is linked to a clearance of late stage autolysosomes, leading to degradation of toxic peptides associated with disease. We propose upregulation of pyruvate import into neurons as potentially a broad-scope therapeutic approach to increase neuronal autophagy, which could be beneficial for multiple dementias.

The yeast guanine nucleotide exchange factor Sec7 is a bottleneck in spatial protein quality control and detoxifies neurological disease proteins

ER-to-Golgi trafficking partakes in the sorting of misfolded cytoplasmic proteins to reduce their cytological toxicity. We show here that yeast Sec7, a protein involved in proliferation of the Golgi, is part of this pathway and participates in an Hsp70-dependent formation of insoluble protein deposits (IPOD). Sec7 associates with the disaggregase Hsp104 during a mild heat shock and increases the rate of Hsp104 diffusion in an Hsp70-dependent manner when overproduced. Sec7 overproduction increased formation of IPODs from smaller aggregates and mitigated the toxicity of Huntingtin exon-1 upon heat stress while Sec7 depletion increased sensitivity to aẞ42 of the Alzheimer’s disease and α-synuclein of the Parkinson’s disease, suggesting a role of Sec7 in mitigating proteotoxicity.

Fusion of Hsp70 to GFP Impairs Its Function and Causes Formation of Misfolded Protein Deposits under Mild Stress in Yeast.

Protein misfolding is a common feature of aging, various diseases and stresses. Recent work has revealed that misfolded proteins can be gathered into specific compartments, which can limit their deleterious effects. Chaperones play a central role in the formation of these misfolded protein deposits and can also be used to mark them. While studying chimeric yeast Hsp70 (Ssa1-GFP), we discovered that this protein was prone to the formation of large insoluble deposits during growth on non-fermentable carbon sources under mild heat stress. This was mitigated by the addition of antioxidants, suggesting that either Ssa1 itself or some other proteins were affected by oxidative damage. The protein deposits colocalized with a number of other chaperones, as well as model misfolded proteins, and could be disassembled by the Hsp104 chaperone. Notably, the wild-type protein, as well as a fusion protein of Ssa1 to the fluorescent protein Dendra2, were much less prone to forming similar foci, indicating that this phenomenon was related to the perturbation of Ssa1 function by fusion to GFP. This was also confirmed by monitoring Hsp104-GFP aggregates in the presence of known Ssa1 point mutants. Our data indicate that impaired Ssa1 function can favor the formation of large misfolded protein deposits under various conditions.