Distinct Aggregation Research Articles

Tricaprylin-based drug crystalline suspension for intramuscular long-acting delivery of entecavir with alleviated local inflammation.

In order to ensure prolonged pharmacokinetic profile along with local tolerability at the injection site, tricaprylin-based drug crystalline suspension (TS) was designed and its local distribution, pharmacokinetics, and inflammatory response, were evaluated with conventional aqueous suspension (AS). As model drug particles, entecavir 3-palmitate (EV-P), an ester lipidic prodrug for entecavir (EV), was employed. The EV-P-loaded TS was prepared by ultra-sonication method. Prepared TS and conventional AS exhibited comparable morphology (rod or rectangular), median diameter (2.7 and 2.6 μm), crystallinity (melting point of 160-165°C), and in vitro dissolution profile. However, in vivo performances of drug microparticles were markedly different, depending on delivery vehicle. At AS-injected site, drug aggregates of up to 500 μm were formed upon intramuscular injection, and were surrounded with inflammatory cells and fibroblastic bands. In contrast, no distinct particle aggregation and adjacent granulation was observed at TS-injected site, with >4 weeks remaining of the oily vehicle in micro-computed tomographic observation. Surprisingly, TS exhibited markedly alleviated local inflammation compared to AS, endowing markedly lessened necrosis, fibrosis thickness, inflammatory area, and macrophage infiltration. The higher initial systemic exposure was observed with TS compared to AS, but TS provided prolonged delivery of EV for 3 weeks. Therefore, we suggest that the novel TS system can be a promising tool in designing parenteral long-acting delivery, with improved local tolerability.

Perspectives on the misconception of levitating soil aggregates

Abstract. Soil aggregation is an important process in nearly all soils across the globe. Aggregates develop over time through a series of abiotic and biotic processes and interactions, including plant growth and decay, microbial activity, plant and microbial exudation, bioturbation, and physicochemical stabilization processes, and are greatly influenced by soil management practices. Together, and through feedback with organic matter and primary soil particles, these processes form dynamic soil aggregates and pore spaces, which jointly constitute a soil's structure and contribute to overall soil functioning. Nevertheless, the concept of soil aggregates is hotly debated, leading to confusion about their function or relevancy to soil processes. We argue here that the opposition to the concept of soil aggregation likely stems from the fact that the methods for the characterization of soil aggregates have largely been developed in the context of arable soils, where tillage promotes the formation of distinct soil aggregates that are easily visible in the topsoil. We propose that the widespread use of conceptual figures showing detached and isolated aggregates can be misleading and has contributed to the skepticism towards soil aggregates. However, the fact that we do not always see discrete aggregates within soils in situ does not mean that aggregates do not exist or are not relevant to the study of soil processes. Given that, by definition, soil aggregates consist of any group of soil particles that cohere more strongly to each other than neighboring particles, aggregates may, but do not necessarily need to be, bordered by pore space. Here, we illustrate how aggregates can form and dissipate within the context of undisturbed, intact soils, highlighting the point that aggregates do not necessarily need to have a discrete physical boundary and can exist seamlessly embedded in the soil. We hope that our contribution helps the debate on soil aggregates and supports the foundation of a shared understanding on the characterization and function of soil structure.

Insights into the effect of water content on asphaltene aggregation behavior and crude oil rheology: A molecular dynamics simulation study

In the production and transportation of crude oils, the interaction between asphaltene components and water is inevitable, significantly impacting asphaltene aggregation, deposition behaviors, emulsion stability, and rheological properties of crude oils. However, the comprehension of the oil-water interaction mechanisms and corresponding viscosity responses remains unclear. Hence, we performed molecular dynamics (MD) simulations to investigate the effect of varying water content on distinct asphaltene aggregation states and the rheological behavior of crude oils. The microscopic mechanisms underlying the aggregation and rheological properties were elucidated. Our MD results show that with the continuous introduction of water, the original bulk phase aggregation of asphaltenes undergoes a transition towards interfacial adsorption behavior, culminating in the formation of water-in-crude oil emulsions. The strength and driving forces of this interfacial adsorption are influenced by different polar functional groups of asphaltene. Besides, by elucidating the contributions of external molecular friction and internal structural deformation to the viscosity, two viscosity-influencing mechanisms are revealed. Furthermore, we delineate a physical viscosity scheme. These intriguing discoveries hold promise for advancing the comprehension of rheological behavior in crude oils with distinct aggregation states, providing theoretical guidance for efficient development of crude oils.

Characterization of the daucosterol-lecithin complex and its impact on lipid metabolism in hyperlipidemic mice.

This investigation delves into the daucosterol-lecithin complex (DS-LC) and its effects on lipid homeostasis in hyperlipidemic mice. DS-LC was assessed for complexation efficiency, physicochemical properties (UV, XRD, FTIR, SEM, DSC), and its impact on organ health and serum lipid levels. The results revealed that daucosterol formed an effective complex with lecithin at a 2 : 1 ratio, producing a translucent beige DS-LC with distinctive aggregation. UV-vis spectra confirmed that daucosterol's chromophore structure remained intact in DS-LC, indicating no new compound formation. FTIR analysis identified hydrogen bonding and increased molecular association without changing lecithin peaks, highlighting specific intermolecular interactions. SEM and XRD showed that complexation transformed daucosterol into an irregular form within the lecithin matrix, forming a new phase and demonstrating a strong lecithin-daucosterol interaction. Thermal analysis suggested homogeneous daucosterol distribution due to intermolecular interactions. DS-LC treatment effectively alleviated hyperlipidemia, enhancing liver function and reducing lipid accumulation in epididymal fat. It also significantly decreased total cholesterol, triglycerides, LDL-C, and arteriosclerosis index in hyperlipidemic mice, indicating DS-LC's potential as a therapeutic agent for lipid metabolism and related metabolic disorders.

Identification of Urban Ecological Security Pattern Based on Ecosystem Services Supply–Demand

The construction of ecological security pattern (ESP) is an effective way to ensure regional ecological security. Although the method of constructing the regional ESP based on ecosystem services (ESs) has been widely recognized and applied, the spatial characteristics of ESs supply–demand mismatch has not been well included into ESP construction. We constructed a regional ESP framework connecting demand sources and ecological sources from the perspective of ESs supply–demand mismatch. Taking the Wuhan urban agglomeration (WUA), findings indicated distinct spatial aggregations of ecological sources and demand sources due to the supply–demand mismatch of ESs. Ecological sources (12,406.29 km 2 or 21.42%) were primarily located in the south and north of WUA, while demand sources (1,191.26 km 2 or 2.07%) were concentrated mainly in the central. Two types of corridors jointly ensured regional ecological security. A total of 86 supply–supply corridors in the north ensured the supply ability of ESs by connecting ecological sources, while 35 supply–demand corridors in the south alleviated the supply–demand mismatch of ESs. The targeted implementation of ecological governance based on the corridor types provides a new approach to coordinate the mismatch of ESs supply–demand and enhance ecological security. However, 63.38 km 2 of pinch points, recognized as high-flow areas within the corridors, primarily comprised fragmented landscapes, and barriers covering 99.67 km 2 obstructed corridor flow, notably surrounding the demand sources. These regions should be prioritized for ecological conservation. Overall, this research framework provides a reliable scientific basis for configuring spatial landscape patterns and developing ecological strategies in urban agglomerations.

Fluoranthene imide dimers with strong isomeric effects on the charge transport properties.

To date, the development of high-performance n-type organic semiconductors has remained challenging due to the scarcity of highly electron-deficient π-conjugated structural units and the difficulty of controlling intermolecular packing in the thin-film state. In addition, there have been few reports on the use of dimer design to tune the optoelectronic properties of materials. Herein, we report new cyano-substituted fluoranthene imide-based dimers (F16 and F17) for small-molecule n-type organic semiconductors. It is noteworthy that substituents at different positions lead to different film morphologies and very distinct thermal aggregation behaviors due to different dihedral angles. The self-assembly behavior of F17 improves thermal stability. Therefore, F17, which has a closer cyano groups structure, exhibits better field-effect transistor performance, with a maximum mobility of 6.6 × 10-4 cm2 V-1 s-1, while F16 does not exhibit any transistor performance.

Exploring the self-assembly dynamics of novel steroid-coumarin conjugates: a comprehensive spectroscopic and solid-state investigation.

The design, synthesis, and characterization of seven novel steroid-coumarin conjugates with diverse steroidal nuclei as lipophilic fluorescent materials for bioimaging applications are presented. The conjugates were synthesized through amidation, characterized using spectroscopic and spectrometric methods, and their main photophysical properties were determined. Dioxane : water titration experiments revealed their ability to self-assemble, forming J-aggregates as evidenced by new spectral bands at higher wavelengths. Monocrystal X-ray diffraction analysis disclosed distinctive aggregation patterns exhibiting J- or H-aggregates for selected compounds. Bioimaging studies demonstrated cell membrane localization for most conjugates, with some of them displaying an interesting selectivity for lipid droplets. Notably, the presence of the steroid fragments significantly influenced both the self-assembly patterns and the cellular localization of the fluorescent probes.

Synthesis and characterisation of copper(I) complexes with relevance to intramolecular Ullmann O,S-arylation.

Copper-catalysed intramolecular Ullman arylation has been frequently used to synthesise benzoxazoles and benzothiazoles. Despite widespread use, investigations into the mechanism and speciation of copper-containing complexes relevant to the catalytic pathway have remained relatively limited. Accordingly, this study aims to elucidate the structural details of potential copper(I) intermediates through the analysis of their solid-state structures using X-ray crystallography, while also investigating the reactivities of these complexes. Five novel copper complexes are reported which are formed prior to the aryl halide activation step and feature distinct aggregation modes based on either Cu4N4O4C4 or Cu4N4S4C4 clusters.

Functionalized cyanostilbene-based nano-AIEgens: multipoint binding interactions for improved sensing of gallic acid in real-life food samples.

Cyano-substituted stilbene (CSS) derivatives have been synthesized that can form luminescent nanoscopic assemblies in an aqueous medium. The optical properties of such materials, as governed by the relative ratios of their monomer and aggregated forms, are found to be susceptible to pH and temperature of the medium. The compound with boronic acid attached at the terminal positions shows a turn-on fluorescence response (LOD: 15.4 ppb) with gallic acid (GA). The mechanistic studies indicate that the 1,2-diol unit of GA is involved in ester formation with the boronic acid residue, while the carboxylic end engages in hydrogen bonding interaction with the nitrile unit. Such multi-point binding interaction provides better selectivity over other structurally similar analytes. Moreover, the distinct aggregation properties of such boronate ester derivatives are responsible for the GA-specific optical response. The sensory system has been utilized for the determination of the levels of GA derivatives in tea (green tea and black tea) and various fruit (mango, orange, guava, pomegranate) extracts. In all cases, the estimated values of GAE were found to be in the same range reported by others. Finally, low-cost, chemically-modified paper strips have been designed for rapid, on-location detection of GA.

GRADIENTE URBANO

As in many other countries, official measures of urbanization in Brazil have been unable to properly distinguish spatial patterns of rural and urban organization. The literature discusses various classification systems and recognizes the existence of a “rural-urban continuum”, as well as theoretical frameworks and alternative categorizations that aim to look beyond the urban-rural dichotomy. However, there are no practical solutions to properly formalize or operationalize them, especially at the micro-level such as census tracts. We propose a methodology that assumes a measurable rural-urban continuum. The “Urban Gradient Index” uses simple and comprehensive variables to quantify the degree to which a certain area is urban based on demographic and spatial features. We build it at the level of census tracts for both Brazil and the Belo Horizonte Metropolitan Region to verify consistency at distinct aggregation levels. Results indicate that the index provides a much more nuanced picture of settlement patterns, unveiling a spatial gradient between rural and urban in distinct spatial extents. It offers an advantage over the traditional measure “degree of urbanization” by revealing “hidden ruralities” in predominantly urban areas that require specific territorial planning and public policy interventions. Keywords: Urban Gradient, Rural-Urban Continuum, Territorial Planning, Belo Horizonte Metropolitan Region, Brazil.

Highly selective fluorometric detection of streptokinase via fibrinolytic release of photoluminescent carbon dots integrated into fibrin clot network

This work pioneers a selective fluorometric assay for the fibrinolytic agent streptokinase by strategically coupling its thrombolytic action to fluorescence signaling using carbon dots integrated into fibrin clot network. Streptokinase triggers clot lysis and caused release of photoluminescent carbon dots integrated within the fibrin network in a concentration-dependent manner. Transmission electron microscope (TEM) imaging verifies distinct aggregation of the carbon dots upon addition to fibrin. The carbon dots are derived via an eco-friendly hydrothermal approach using cucumber peel as the source of carbon. Structural and optical characterization of the carbon dots were performed using different techniques including X-ray diffraction, TEM, Fourier-transform infrared spectroscopy, and ultraviolet–visible absorption and fluorescence spectroscopies. All experimental parameters influencing the formation of the fibrin clot and factors governing the release of carbon dots upon the addition of streptokinase have been fully optimized. This fluorescence assay offers high selectivity for streptokinase over potential interferences in addition to excellent sensitivity with a 0.017 μg/mL limit of detection and a wide linear range (0.05–500 μg/mL). Successful application to pharmaceutical formulations is demonstrated with excellent recovery and precision. By ingeniously linking streptokinase activity to carbon dot fluorescence, this novel assay provides a rapid, simple and eco-friendly method for selective streptokinase detection.

Phenotype-Genotype Correlations in Three Different Cases of Adult-Onset Genetic Focal Segmental Glomerulosclerosis.

This study highlights the importance of a combined diagnostic approach in the diagnosis of rare diseases, such as adult-onset genetic FSGS. We present three adult patient cases evaluated with kidney biopsy for proteinuria, chronic kidney disease, and hypertension, which were suggestive of adult-onset genetic FSGS. Renal biopsy samples and formalin-fixed, paraffin-embedded fetal kidneys were evaluated using standard light microscopical stainings, direct immunofluorescence on cryostat sections, and electron microscopy. Clinical exome sequencing was performed for each case, and 45 FSGS-related genes were analyzed. Identifying mutations in the PAX2, ACTN4, and COL4A5 genes have prompted a re-evaluation of the previous histopathological examinations. The PAX2 mutation led to a thinner nephrogenic zone and decreased number of glomeruli, resulting in oligohydramnios during fetal development and oligomeganephronia and adaptive focal-segmental glomerulosclerosis in adulthood. The ACTN4 mutation caused distinct electron-dense aggregates in podocyte cell bodies, while the COL4A5 mutation led to segmental sclerosis of glomeruli with marked interstitial fibrosis and tubular atrophy. The identification of specific mutations and their histopathological consequences can lead to a better understanding of the disease and its progression, as well as potential treatment options.

Subtle Molecular Changes Largely Modulate Chiral Helical Assemblies of Achiral Conjugated Polymers by Tuning Solution-State Aggregation.

Understanding the solution-state aggregate structure and the consequent hierarchical assembly of conjugated polymers is crucial for controlling multiscale morphologies during solid thin-film deposition and the resultant electronic properties. However, it remains challenging to comprehend detailed solution aggregate structures of conjugated polymers, let alone their chiral assembly due to the complex aggregation behavior. Herein, we present solution-state aggregate structures and their impact on hierarchical chiral helical assembly using an achiral diketopyrrolopyrrole-quaterthiophene (DPP-T4) copolymer and its two close structural analogues wherein the bithiophene is functionalized with methyl groups (DPP-T2M2) or fluorine atoms (DPP-T2F2). Combining in-depth small-angle X-ray scattering analysis with various microscopic solution imaging techniques, we find distinct aggregate in each DPP solution: (i) semicrystalline 1D fiber aggregates of DPP-T2F2 with a strongly bound internal structure, (ii) semicrystalline 1D fiber aggregates of DPP-T2M2 with a weakly bound internal structure, and (iii) highly crystalline 2D sheet aggregates of DPP-T4. These nanoscopic aggregates develop into lyotropic chiral helical liquid crystal (LC) mesophases at high solution concentrations. Intriguingly, the dimensionality of solution aggregates largely modulates hierarchical chiral helical pitches across nanoscopic to micrometer scales, with the more rigid 2D sheet aggregate of DPP-T4 creating much larger pitch length than the more flexible 1D fiber aggregates. Combining relatively small helical pitch with long-range order, the striped twist-bent mesophase of DPP-T2F2 composed of highly ordered, more rigid 1D fiber aggregate exhibits an anisotropic dissymmetry factor (g-factor) as high as 0.09. This study can be a prominent addition to our knowledge on a solution-state hierarchical assembly of conjugated polymers and, in particular, chiral helical assembly of achiral organic semiconductors that can catalyze an emerging field of chiral (opto)electronics.

Underappreciated microplastic galaxy biases the filter-based quantification

Long-term environmental loading of microplastics (MPs) causes alarming exposure risks for a variety of species worldwide, considered a planetary threat to the well-being of ecosystems. Robust quantitative estimates of MP extents and featured diversity are the basis for comprehending their environmental implications precisely, and of these methods, membrane-based characterizations predominate with respect to MP inspections. However, though crucial to filter-based MP quantification, aggregation statuses of retained MPs on these substrates remain poorly understood, leaving us a “blind box” that exaggerates uncertainty in quantitive strategies of preselected areas without knowing overview loading structure. To clarify this uncertainty and estimate their impacts on MP counting, using MP imaging data assembled from peer-reviewed studies through a systematic review, here we analyze the particle-specific profiles of MPs retained on various substrates according to their centre of mass with a fast-random forests algorithm. We visualize the formation of distinct galaxy-like MP aggregation—similar to the solar system and Milky Way System comprised of countless stars—across the pristine and environmental samples by leveraging two spatial parameters developed in this study. This unique pattern greatly challenges the homogeneously or randomly distributed MP presumption adopted extensively for simplified membrane-based quantification purposes and selective ROI (region of interest) estimates for smaller-sized plastics down to the nano-range, as well as the compatibility theory using pristine MPs as the standard to quantify the presence of environmental MPs. Furthermore, our evaluation with exemplified numeration cases confirms these location-specific and area-dependent biases in many imaging analyses of a selective filter area, ascribed to the minimum possibility of reaching an ideal turnover point for the selective quantitive strategies. Consequently, disproportionate MP schemes on loading substrates yield great uncertainty in their quantification processing, highlighting the prompt need to include pattern-resolved calibration prior to quantification. Our findings substantially advance our understanding of the structure, behavior, and formation of these MP aggregating statuses on filtering substrates, addressing a fundamental question puzzling scientists as to why reproducible MP quantification is barely achievable even for subsamples. This study inspires the following studies to reconsider the impacts of aggregating patterns on the effective counting protocols and target-specific removal of retained MP aggregates through membrane separation techniques.

Failure criteria and microstructure evolution mechanism of the alkali–silica reaction of concrete

Abstract In this study, the influence of two distinct reactive aggregate dosages on the alkali–silica reaction (ASR) of concrete was investigated. The expansion ratio, axial compressive strength, splitting tensile strength, and relative dynamic elastic modulus (RDEM) of concrete were considered as the main parameters to study the failure criteria of concrete induced by ASR at 40°C. Microscopic experiments, such as scanning electron microscopy and X-ray computed microtomography, were applied to analyze the damage induced by ASR on the concrete prisms and the propagation of internal cracks of the reactive aggregates in nanospace. The results showed that the two ranges can be used as the failure criteria produced by the ASR of concrete containing 3 and 6% dosages of reactive aggregates at 40°C, respectively, when the RDEM of concrete was reduced to 70‒75% and 85‒90%. Additionally, the results of CT indicated that microcracks tended to extend from the initial defects of aggregate to the cement slurry. Meanwhile, ASR gel packed with the pores, which reduced the porosity. It was noteworthy that the adhesive force between the ASR gel and the cement matrix after filling pores could not make up for the loss of the mechanical properties of concrete.

Synthesis and structures of bimetallic (Mg/K) acetylide complexes from terminal alkynes and an Mg–Mg-bonded compound

The reactions of α-diimine-ligated dimagnesium(I) compound [K(THF)3]2[LMg−MgL] (1, L = [(2,6-iPr2C6H3)NC(Me)]22−) and terminal alkynes afford bimetallic (Mg/K) acetylide complexes (2–10). The reactions proceed via reductive dehydrogenation of the alkynes with release of H2, while the original Mg(I) center is oxidized to Mg(II). In the complexes, Mg atom is σ-coordinated either by one (2 and 3), two (4–9) or four (10) RCC− moieties. The (solvated) K atoms, on the other hand, are π-coordinated by the CC triple bonds and form extensive interactions with the NCCN backbone and aryl rings of the ligand and alkyl substituents of the alkyne. Interestingly, the versatile bonding modes of potassium ions result in three distinct aggregates of the complexes in the solid state, the monomer (2–7), dimer (8, 9), and polymer (10), where the latter two cases benefit from the “intermolecular” interactions of K+ ions with the ligands or acetylides.

Bacterial Colonization in the Airways and Intestines of Twin and Singleton Preterm Neonates: A Single-Center Study.

Limited studies have investigated the microbial colonization of the airways and intestines in preterm neonates. We studied the composition of intestinal and airway bacterial colonies in several preterm twin pairs and singletons to explore the dominant bacteria, assess their variability, and predict their phenotypic and metabolic functions. In this descriptive study, we collected sputum and fetal stool specimens from 10 twin pairs (20 cases) and 20 singleton preterm neonates. These specimens were analyzed using 16S rRNA deep sequencing to study the alpha and beta diversities and community structures of airway and intestinal bacteria and predict their metabolic functions. Specimens from twins and singleton neonates had distinct aggregations of intestinal and airway bacteria but showed similarities and high microbial diversities during initial colonization. The top five phyla were Proteobacteria, Firmicutes, Actinobacteriota, Bacteroidota, and Cyanobacteria. The top ten genera were Streptococcus, Acinetobacter, Ralstonia, Staphylococcus, Comamonas, Enterococcus, Stenotrophomonas, Dechlorosoma, Sphingopyxis, and Rothia. Potentially pathogenic and highly stress-tolerant Gram-negative bacteria were predominant in the intestinal flora. A considerable proportion of colonies recovered from the airway and intestines of preterm neonates were functional bacteria. The richness of the intestinal and airway flora was not significantly different between twins and singletons, and the flora clustered together. Both intestinal and airway bacteria of twins and singletons were similar. The species involved in initial colonization were similar but different in proportions; therefore, changes in microbial structure and richness may not be attributed to these species.

Israeli Oncocyclus irises: Phylogenetic relationships and evolutionary history

Abstract Oncocyclus is a large group of bearded irises with poorly known phylogeny and evolutionary history. In Israel, Iris sect. Oncocyclus comprises eight species belonging to three aggregates. We used a combination of approaches to resolve the phylogenetic relationships of these species and indicate the evolutionary forces responsible for their origin. We sequenced the whole chloroplast genomes of species and integrated a phylogenetic tree with results of genetic (AFLP) divergence, degree of reproductive isolation, and species distribution modeling. Our findings suggest that quantitative and even qualitative morphological characters, such as flower color, are unreliable diagnostic traits for Oncocyclus taxonomy; that some recognized species comprise more than one species; and that group evolution did not involve the origin of distinct flower aggregates. A lack of pre-zygotic reproductive isolation agrees with the very low variability of the Oncocyclus plastome, suggesting that Israeli Oncocyclus species are very young. Homoploid hybridization followed or preceded by long periods of geographic isolation, and local selection likely contributed to speciation in Oncocyclus. In the group evolutionary history, importance of homoploid hybridization and local selection differed among species, but limited gene flow played a crucial role for all species.

Thermoresponsive hydrogels with sulfated polysaccharide-derived copolymers: the effect of carbohydrate backbones on the responsive and mechanical properties

Thermoresponsive hydrogels based on ionic cellulose/chitosan are widely used various fields, such as smart windows and tissue engineering, while the effect of carbohydrate backbones of cellulose/chitosan on the thermal response and mechanical properties of hydrogels has received less attention so far. Herein, poly(2(dimethylamino)ethyl methacrylate) (PDMAEMA)-grafted cellulose sulfate (P-CS) and PDMAEMA-grafted chitosan sulfate (P-CHS) as research models are successfully synthesized through multi-step reactions. The P-CS and P-CHS polymers are further applied in crosslinked polyacrylamide networks, resulting in the P-CS and P-CHS hydrogels. Compared to P-CS hydrogels, P-CHS hydrogels could obviously block the transmission of visible light when the temperature is changed from 25 to 42 °C. In contrast to P-CHS hydrogels, the P-CS hydrogels change easily from soft and weak state to stiff and strong state according to their mechanical behaviors. These results indicate that different carbohydrate backbones of cellulose and chitosan should have caused distinct aggregation behaviors of corresponding P-CS and P-CHS hydrogels, which are accompanied by different light transmittance and mechanical properties.Graphical abstract Thermoresponsive hydrogels using PDMAEMA-grafted ionic cellulose sulfate (P-CS) and chitosan sulfate (P-CHS) are successfully prepared. Distinct carbohydrate backbone displayed different effects on the thermoresponsive and mechanical properties of hydrogels.

Loss of TDP‐43 oligomerization or RNA binding elicits distinct aggregation patterns

Aggregation of the RNA‐binding protein TAR DNA‐binding protein 43 (TDP‐43) is the key neuropathological feature of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). In physiological conditions, TDP‐43 is predominantly nuclear, forms oligomers, and is contained in biomolecular condensates assembled by liquid–liquid phase separation (LLPS). In disease, TDP‐43 forms cytoplasmic or intranuclear inclusions. How TDP‐43 transitions from physiological to pathological states remains poorly understood. Using a variety of cellular systems to express structure‐based TDP‐43 variants, including human neurons and cell lines with near‐physiological expression levels, we show that oligomerization and RNA binding govern TDP‐43 stability, splicing functionality, LLPS, and subcellular localization. Importantly, our data reveal that TDP‐43 oligomerization is modulated by RNA binding. By mimicking the impaired proteasomal activity observed in ALS/FTLD patients, we found that monomeric TDP‐43 forms inclusions in the cytoplasm, whereas its RNA binding‐deficient counterpart aggregated in the nucleus. These differentially localized aggregates emerged via distinct pathways: LLPS‐driven aggregation in the nucleus and aggresome‐dependent inclusion formation in the cytoplasm. Therefore, our work unravels the origins of heterogeneous pathological species reminiscent of those occurring in TDP‐43 proteinopathy patients.