Stepwise Aggregation Research Articles

Stepwise Spatial Global-local Aggregation Networks for Autonomous Driving

Visual-based perception is the key module for autonomous driving. Among those visual perception tasks, video object detection is a primary yet challenging one because of feature degradation caused by fast motion or multiple poses. Current models usually aggregate features from the neighboring frames to enhance the object representations for the task heads to generate more accurate predictions. Though getting better performance, these methods rely on the information from the future frames and suffer from high computational complexity. Meanwhile, the aggregation process is not reconfigurable during the inference time. These issues make most of the existing models infeasible for online applications. To solve these problems, we introduce a stepwise spatial global-local aggregation network. Our proposed models mainly contain three parts: (1). Multi-stage stepwise network gradually refines the predictions and object representations from the previous stage; (2). Spatial global-local aggregation fuses the local information from the neighboring frames and global semantics from the current frame to eliminate the feature degradation; (3). Dynamic aggregation strategy stops the aggregation process early based on the refinement results to remove redundancy and improve efficiency. Extensive experiments on the ImageNet VID benchmark validate the effectiveness and efficiency of our proposed models.

"Prion-like" seeding and propagation of oligomeric protein assemblies in neurodegenerative disorders.

Intra- or extracellular aggregates of proteins are central pathogenic features in most neurodegenerative disorders. The accumulation of such proteins in diseased brains is believed to be the end-stage of a stepwise aggregation of misfolded monomers to insoluble cross-β fibrils via a series of differently sized soluble oligomers/protofibrils. Several studies have shown how α-synuclein, amyloid-β, tau and other amyloidogenic proteins can act as nucleating particles and thereby share properties with misfolded forms, or strains, of the prion protein. Although the roles of different protein assemblies in the respective aggregation cascades remain unclear, oligomers/protofibrils are considered key pathogenic species. Numerous observations have demonstrated their neurotoxic effects and a growing number of studies have indicated that they also possess seeding properties, enabling their propagation within cellular networks in the nervous system. The seeding behavior of oligomers differs between the proteins and is also affected by various factors, such as size, shape and epitope presentation. Here, we are providing an overview of the current state of knowledge with respect to the "prion-like" behavior of soluble oligomers for several of the amyloidogenic proteins involved in neurodegenerative diseases. In addition to providing new insight into pathogenic mechanisms, research in this field is leading to novel diagnostic and therapeutic opportunities for neurodegenerative diseases.

Stepwise Aggregation Control of PEDOT:PSS Enabled High-Conductivity, High-Resolution Printing of Polymer Electrodes for Transparent Organic Phototransistors.

Electrohydrodynamic (EHD) jet printing is a widely employed technology to create high-resolution patterns and thus has enormous potential for circuit production. However, achieving both high conductivity and high resolution in printed polymer electrodes is a challenging task. Here, by modulating the aggregation state of the conducting polymer in the solution and solid phases, a stable and continuous jetting of PEDOT:PSS is realized, and high-conductivity electrode arrays are prepared. The line width reaches less than 5 μm with a record-high conductivity of 1250 S/cm. Organic field-effect transistors (OFETs) are further developed by combining printed source/drain electrodes with ultrathin organic semiconductor crystals. These OFETs show great light sensitivity, with a specific detectivity (D*) value of 2.86 × 1014 Jones. In addition, a proof-of-concept fully transparent phototransistor is demonstrated, which opens up new pathways to multidimensional optical imaging.

Stochastic Optical Reconstruction Microscopy Imaging of Multiple System Atrophy Inclusions Suggests Stepwise α-Synuclein Aggregation.

The architecture and composition of glial (GCI) and neuronal (NCI) α-synuclein inclusions observed in multiple system atrophy (MSA) remain to be precisely defined to better understand the disease. Here, we used stochastic optical reconstruction microscopy (STORM) to characterize the nanoscale organization of glial (GCI) and neuronal (NCI) α-synuclein inclusions in cryopreserved brain sections from MSA patients. STORM revealed a dense cross-linked internal structure of α-synuclein in all GCI and NCI. The internal architecture of hyperphosphorylated α-synuclein (p-αSyn) inclusions was similar in glial and neuronal cells, suggesting a common aggregation mechanism. A similar sequence of p-αSyn stepwise intracellular aggregation was defined in oligodendrocytes and neurons, starting from the perinuclear area and growing inside the cells. Consistent with this hypothesis, we found a higher mitochondrial density in GCI and NCI compared to oligodendrocytes and neurons from unaffected donors (P < 0.01), suggesting an active recruitment of the organelles during the aggregation process. These first STORM images of GCI and NCI suggest stepwise α-synuclein aggregation in MSA. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Aggregation behaviors of alkyl α-keto acids in water

Single-tailed α-keto acids are a kind of fatty acid derivatives and weakly acidic amphiphiles. Only the aggregation behavior of α-ketooctanoic acid (KC8) in water was investigated so far, and thus the current understanding of their aggregation behavior, such as the effect of alkyl chain length, is still limited. It is essential to investigate the aggregation behavior of alkyl α-keto acids such as α-ketodecanoic acid (KC10) and α-ketododecanoic acid (KC12), to fully understand the features of α-keto acids. The aggregation behavior of KC10 and KC12 in water was investigated by changing their concentrations (C), using equilibrium surface tension, cryogenic transmission electron microscopy, dynamic light scattering, small-angle X-ray scattering, and deuterium nuclear magnetic resonance, and compared with that of KC8. A C-dependent stepwise aggregation was observed for the KC10 and KC12 systems. With increasing C, vesicles, precipitates, micelles, and lamellar phase (or α-gel phase) form successively in the systems, where precipitates and micelles both coexist with vesicles, similar to the case of KC8. With an increase in chain length, the pKa of α-keto acids increases while their critical concentrations of stepwise aggregations decrease, arising from the enhancement of the interactions between alkyl chains. The aggregation behavior observed can be explained by the existence of multispecies (including the “acid-soap” dimers) and the interaction between alkyl chains.

GLSNet: A Global Guided Local Feature Stepwise Aggregation Network for polyp segmentation

Accurate polyp segmentation is of great significance for the prevention and diagnosis of early colon cancer. Transformer-based image segmentation models have been proposed for polyp segmentation with good results, however, these methods do not sufficiently consider the negative impact of background noise in different levels of features, resulting in the loss of local details. To alleviate this problem, we propose a GLSNet (A Global Guided Local Feature Stepwise Aggregation Network for polyp segmentation) network, including a spatial feature enhancement (SFE) module, a globally guided local feature enhancement (GLFE) module, and a feature stepwise aggregation (FSA) module. SFE can enhance the spatial feature representation of polyps to better capture the polyp information in the features. GLFE uses high-level features to filter noise in low-level features to capture polyp information hidden in shallow features; FSA fuses the semantic and positional information of polyps across scales to obtain the final segmentation results. Qualitative and quantitative experiments were conducted on 7 benchmark datasets, and the experimental results demonstrated that GLSNet outperforms other existing methods and has stronger generalization performance. In particular, we achieved a mean Dice of 92.9% on the large-scale Kvasir dataset, and mean Dice of 81.3% and 81.6% on CVC-ColonDB and ETIS, respectively, which are significantly higher than those of the competing methods.

Adaptations to a cold climate promoted social evolution in Asian colobine primates.

The biological mechanisms that underpin primate social evolution remain poorly understood. Asian colobines display a range of social organizations, which makes them good models for investigating social evolution. By integrating ecological, geological, fossil, behavioral, and genomic analyses, we found that colobine primates that inhabit colder environments tend to live in larger, more complex groups. Specifically, glacial periods during the past 6 million years promoted the selection of genes involved in cold-related energy metabolism and neurohormonal regulation. More-efficient dopamine and oxytocin pathways developed in odd-nosed monkeys, which may have favored the prolongation of maternal care and lactation, increasing infant survival in cold environments. These adaptive changes appear to have strengthened interindividual affiliation, increased male-male tolerance, and facilitated the stepwise aggregation from independent one-male groups to large multilevel societies.

Role of core-shell structure in binary mixture of amino sulfonate amphoteric surfactant with nonionic surfactant in solubilization behavior of pyrene

In order to understand the role of core-shell structure of mixed surfactant micelle and the effect of hydrophilicity of amphiphile in the enhanced remediation of contaminated soils and water, a novel amphoteric sodium 3-(N-dodecylethylenediamino)− 2-hydroxypropyl sulfonate (C12AS), three nonionic octylphenol polyoxyethylated ethers with unit number n of oxyethylene glycol ether (OP-n, n = 4, 7 and 10) and these binary mixtures of C12AS/OP-n were adopted to probe the solubilization behavior of pyrene by both the UV–vis spectrometric and the 1H NMR techniques. Some parameters including the molar solubilization ratio (MSR), the partition coefficient (Pm), the standard free energy change (∆Gp) of partition, the interaction parameter (B) based on regular solution theory and the ratio (K1/n) of first stepwise association coefficient (K1) and aggregation number (n) in mixed micelle were estimated using different models. In these single surfactants, the values of MSR and Pm depend mainly on the hydrophilic-lipophilic balance (HLB) of amphiphiles for the homologues of OP surfactants. The solubilization behavior in these mixtures, however, does not again follow the HLB effect, but is subjected to the mixing ratio of component in mixed micelle and the micellar structure. The data from these B and K1/n values can gain some understanding in tune with these parameters, e.g., MSR, Pm, R, etc. Based on the chemical shift of hydroxyl group, the core-shell structure of mixed micelle assumed in this investigation is proposed to demonstrate the solubilization locus and rationally describe the spontaneous process of solubilization and the related behaviors. These findings will help with understanding the solubilization behavior of hydrophobic organic compounds in these surfactants with a core-shell structure of micelle and designing the surfactant formulations in the surfactant enhanced remediation of contaminated soils and water.

Hydrogel-Coated Gate Field-Effect Transistor for Real-Time and Label-Free Monitoring of β-Amyloid Aggregation and Its Inhibition.

In this paper, we propose a hydrogel-coated gate field-effect transistor (FET) for the real-time and label-free monitoring of β-amyloid (Aβ) aggregation and its inhibition. The hydrogel used in this study is composed of poly tetramethoxysilane (TMOS), in which Aβ monomers are entrapped and then aggregate, and coated on the gate insulator; that is, Aβ aggregation is induced in the vicinity of the sensing surface. With the Aβ hydrogel-coated gate FET, the steplike decrease in the surface potential of the Aβ hydrogel-coated gate electrode is electrically monitored in real time, according to the stepwise aggregation of Aβ monomers to form into fibrils through oligomers and so forth in stages. This is because the capacitance of the Aβ-hydrogel membrane decreases depending on the stage of aggregation; that is, the hydrophobicity of the Aβ-hydrogel membrane increases stepwise depending on the amount of Aβ aggregates. The formation of Aβ fibrils is also confirmed in the measurement solution using a fluorescent dye, thioflavin T, which selectively binds to the Aβ fibrils. Moreover, the addition of daunomycin, an inhibitor of Aβ aggregation, to the measurement solution suppresses the stepwise electrical response of the Aβ hydrogel-coated gate FET. Thus, a platform based on the Aβ hydrogel-coated gate FET is suitable for a simple screening system for inhibitors of Aβ aggregation, which may lead the identification of potential therapeutic agents for Alzheimer's disease.

Stepwise aggregation method for the WQI-CCME to generate a water quality profile for a long river: case study-São Francisco River, Brazil.

This paper presents a new aggregation method to calculate the WQI-CCME, named stepwise aggregation method, to communicate the water quality of the São Francisco River, Brazil, a river of national expression, with more than 2700km long. Differently from the original proposal for the WQI-CCME, the new aggregation method uses data from a single monitoring campaign, to avoid the loss of data, as many variables are not systematically measured in all monitoring campaigns. The stepwise aggregation method also requires to combine data from a minimum of four monitoring locations per section of the river, to attend the statistical requirement, a proposal already presented in the literature. After using the first four points, the next calculation requires to abandon the first point (upstream) and to include the next point (downstream), and the sequential calculation will generate the results to build the river water quality profile. In the present work, with 31 monitoring points, the stepwise aggregation method allowed to calculate the WQI-CCME for 25 sections. The stepwise method has the advantage of multiplying the number of index calculations, allowing to construct a more uniform water quality profile for a long river. The choice of using the WQI-CCME in this work, is because this index has many successful applications all over the world, favored by its flexibility of parameter selection, ease of calculation, adaptability to legal requirements of different locations and different water uses. The WQI-CCME profiles were compared with those for the WQI-CETESB, an index derived from the WQI-NSF and extensively used by the Brazilian Monitoring Programs. The comparison demonstrated similarity, only if the same number of parameters were used, but WQI-CETESB gives better water quality, similarly reported for the WQI-NSF, which systematically classify the water quality in the superior range. In this paper, the calculation of the WQI-CCME, with 38 and 20 parameters, confirmed the dependence of the WQI-CCME factors (F1, F2) on the number of variables considered. The calculation with more variables (38) gave better results for the water quality than the calculation with less variable (20). Thus, while the application of the WQI-CCME has a variety of advantages, it requires careful evaluation about the variables to use, and the objectives for the index calculation, as considered by many authors.

APPLICATION OF FUZZY ELECTRE METHOD WITH TRAPEZOIDAL FUZZY NUMBERS

The article is devoted to the problem of multi-criteria decision-making. Methods for solving this problem can be divided into two large groups:methods using the aggregation of all alternatives according to all criteria and the solution of the resulting single-criterion problem. The second group isassociated with the procedure of pairwise comparisons and stepwise aggregation. The first group includes methods: weighted average sum,product and their various modifications, the second group includes - AHP, ELECTRE, TOPSIS, PROMETHEE, ELECTRE. For many problemsassessment of the criteria implemented by experts and presented in linguistic form. The effective approach for dealing with linguistic information is fuzzyset theory proposed by L. Zadeh. In this paper is proposed fuzzy ELECTRE method. This method is presented in details. As application problem is usedthe equipment selection problem The issues of practical implementation of this method are discussed in details. The results of the solution test problem at all stages are presented.

Vibrational Spectroscopy of Benzonitrile-(Water)1-2 Clusters in Helium Droplets.

Polycyclic aromatic hydrocarbons are considered as primary carriers of the unidentified interstellar bands. The recent discovery of the first interstellar aromatic molecule, benzonitrile (C6H5CN), suggests a repository of aromatic hydrocarbons in the outer earth environment. Herein, we report an infrared (IR) study of benzonitrile-(D2O)n clusters using mass-selective detection in helium nanodroplets. In this work, we use isotopically substituted water, D2O, instead of H2O because of our restricted IR frequency range (2565-3100 cm-1). A comparison of the experimental and predicted spectra computed at the MP2/6-311++G(d,p) level of benzonitrile-(water)1-2 clusters reveals the formation of a unique local minimum structure, which was not detected in previous gas-phase molecular beam experiments. Here, the solvent water forms a nearly linear hydrogen bond (H-bond) with the nitrile nitrogen of benzonitrile, while the previously reported most stable cyclic H-bonded isomer is not observed. This can be rationalized by the stepwise aggregation process of precooled monomers. The addition of a second water molecule results in the formation of two different isomers. In one of the observed isomers, a H-bonded water chain binds linearly to the nitrile nitrogen similar to the monohydrated benzonitrile-water complex. In the other observed isomer, the water dimer forms a ring-type structure, where a H-bonded water dimer simultaneously interacts with the nitrile nitrogen and the adjacent ortho CH group. Finally, we compare the water-binding motif in the neutral benzonitrile-water complex with the corresponding positively and negatively charged benzonitrile-water monohydrates to comprehend the charge-induced alteration of the solvent binding motif.

Attention Aggregation Encoder-Decoder Network Framework for Stereo Matching

In the stereo matching networks based on deep learning, current cost aggregation networks lack the means to aggregate cost volume to the utmost extent. Therefore, different from the standard encoder-decoder structures, we propose an attention aggregation encoder-decoder network framework for stereo matching that contains three modules. Specifically, we design a sub-branch and cross-stage aggregation encoding module, which aggregate context information of different sub-branches and cross-stages to achieve the mutual utilization of different deep cost volumes. Meanwhile, we introduce a three-dimensional attention recoding module to obtain the robust discriminative cost volume through recalibrating the high-level semantic information of the sub-branches. In addition, we construct a stepwise aggregation decoding module to decode the cost volume via the stepwise fusion upsampling strategy, which further enhances the learning ability of the network model. The experimental results on Scene Flow and KITTI benchmark datasets show that the proposed network framework is superior to other similar methods in aggregating information.

A selective and stepwise aggregation of a new fluorescent probe for dinitrate explosive differentiation by self-adaptive host-guest interaction

Nitrate explosive is hard to detect due to lack of aromatic ring and weak interaction with fluorescence probe. More challenging is even to differentiate the dinitrates with multiple nitrate explosives based on photo induced electron transfer or aggregation caused fluorescence change mechanism. A highly selective dinitrate explosive probe was designed based on a new strategy ¾ stepwise aggregation of multiple anchored fluorene dimer 8Py-2F . Compared with its monomer counterpart 2Py-F , 8Py-2F showed a selective and stepwise fluorescence quenching to dinitrate explosives—ethylene glycol (EGDN) and triethylene glycol dinitrate (TEGDN). The limits of detection (LODs) are 2.72 μM for TEGDN and 0.46 μM for EGDN, which is three orders of magnitude lower than those of 2Py-F . The stepwise quenching process is well matched with the stepwise aggregation process as evidence by scanning electron microscopy (SEM). Nuclear magnetic resonance (NMR) and quantum chemical calculation proved the interaction force between the dinitrate and 8Py-2F is hydron bonding interaction, and interaction distance is far less than that of the multiple nitrates coming from the flexibility of the chain and steric hinderance, which resulted in a self-adaptive interaction and higher selectivity. The new strategy is beneficial for the differentiation of the chemicals with similar energy level which is difficult to realize via other method, and the new method provides fluorometric probe for dinitrate explosive detection and makes it an ideal candidate for chemical detection and analysis in public safety and environmental monitoring.

Alpha-synuclein stepwise aggregation reveals features of an early onset mutation in Parkinson\u2019s disease

Amyloid formation is a process involving interconverting protein species and results in toxic oligomers and fibrils. Aggregated alpha-synuclein (αS) participates in neurodegenerative maladies, but a closer understanding of the early αS polymerization stages and polymorphism of heritable αS variants is sparse still. Here, we distinguished αS oligomer and protofibril interconversions in Thioflavin T polymerization reactions. The results support a hypothesis reconciling the nucleation-polymerization and nucleation-conversion-polymerization models to explain the dissimilar behaviors of wild-type and the A53T mutant. Cryo-electron microscopy with a direct detector shows the polymorphic nature of αS fibrils formed by heritable A30P, E46K, and A53T point mutations. By showing that A53T rapidly nucleates competent species, continuously elongates fibrils in the presence of increasing amounts of seeds, and overcomes wild-type surface requirements for growth, our findings place A53T with features that may explain the early onset of familial Parkinson’s disease cases bearing this mutation.

Merging Shaker K+ channel electrophysiology with structural data by a nucleation and growth mechanism

The ON and OFF ionic and gating currents of the Shaker K+ channel were simulated with a kinetic model that predicts stepwise outward movement and aggregation of the four subunits of its tetrameric structure during depolarization, followed by their downward movement and disaggregation during repolarization. Only a maximum of three free parameters is required for the simulation. The model provides explanations for the Cole-Moore effect, the rising phase of the ON gating current and the long-term (C-type) inactivation of the OFF gating current, with gating charge immobilization. The latter phenomenon is explained by a gradual strengthening of the interaction between the ball-and-chain blocker and its receptor just below the selectivity filter. This strengthening, which stems from conformational changes around the outer mouth of the pore, determines a slow release of the gating charge during repolarization. By merging the model predictions based on the interpretation of electrophysiological data with the available structural data, a detailed description of the consecutive series (C/O)→(O/O)→(O/I)→(C/I) of channel states is proposed, where the first letter refers to the closed (C) or open (O) activation gate, and the second to the open (O) or inactivated (I) selectivity filter. The role of electrostatic attractions within the channel is emphasized.

Improved kinetic description of fast relaxation of cylindrical micelles

On the basis of the linearized analytical and numerical kinetic description of stepwise aggregation of surfactant aggregates, the hierarchical relaxation times have been found for a polydisperse micellar system close and above the critical micellar concentration. The description was based on the difference and differential Becker–Döring kinetic equations with using a specific boundary condition and improved models for the attachment rates of surfactant monomers to cylindrical aggregates. Two models have been considered: the linear model for cylindrical aggregates and the attachment rate to elongated spheroidal aggregates. The rate of attachment of monomers to an elongated spheroidal aggregate was found explicitly as a function of the aggregation number. With applying the truncation techniques, the analytical solution of differential kinetic equations for fast relaxation of polydisperse micellar systems has been obtained for a linear model of the aggregation rate. In the case of the attachment rate for an elongated spheroidal aggregate, the semi-analytical solution has been found.

Modeling squid axon Na+ channel by a nucleation and growth kinetic mechanism

A kinetic model accounting for all salient features of the Na+ channel of the squid giant axon is provided. The model furnishes explanations for the Cole-Moore-like effect, the rising phase of the ON gating current and the slow ‘intermediate component’ of its decaying phase, as well as the gating charge immobilization. Experimental ON ionic currents are semi-quantitatively simulated by the use of only three free parameters, upon assuming that the Na+ channel opening proceeds along with the stepwise aggregation of its four domains, while they are moving their gating charge outward under depolarizing conditions. The inactivation phase of the ON ionic current is interpreted by a progressive electrostatic attraction between the positively charged ‘hinged lid’ containing the hydrophobic IFM triad and its receptor inside the channel pore, as the stepwise outward movement of the S4 segments of the Na+ channel progressively increases the negative charge attracting the triad to its receptor. The Na+ channel closing is assumed to proceed by repolarization-induced disaggregation of its domains, accompanied by inward movement of their gating charge. The phenomenon of ‘gating charge immobilization’ can be explained by assuming that gradual structural changes of the receptor over the time course of depolarization strengthen the interaction between the IFM triad and its receptor, causing a slow release of the gating charge during the subsequent repolarization.

Stepwise Aggregation of Cholate and Deoxycholate Dictates the Formation and Loss of Surface-Available Chirally Selective Binding Sites.

Bile salts are facially amphiphilic, naturally occurring chemicals that aggregate to perform numerous biochemical processes. Because of their unique intermolecular properties, bile salts have also been employed as functional materials in medicine and separation science (e.g., drug delivery, chiral solubilization, purification of single-walled carbon nanotubes). Bile micelle formation is structurally complex, and it remains a topic of considerable study. Here, the exposed functionalities on the surface of cholate and deoxycholate micelles are shown to vary from one another and with the micelle aggregation state. Collectively, data from NMR and capillary electrophoresis reveal preliminary, primary, and secondary stepwise aggregation of the salts of cholic (CA) and deoxycholic (DC) acid in basic conditions (pH 12, 298 K), and address how the surface availability of chirally selective binding sites is dependent on these sequential stages of aggregation. Prior work has demonstrated sequential CA aggregation (pH 12, 298 K) including a preliminary CMC at ca. 7 mM (no chiral selection), followed by a primary CMC at ca. 14 mM that allows chiral selection of binaphthyl enantiomers. In this work, DC is also shown to form stepwise preliminary and primary aggregates (ca. 3 mM DC and 9 mM DC, respectively, pH 12, 298 K) but the preliminary 3 mM DC aggregate is capable of chirally selective solubilization of the binaphthyl enantiomers. Higher-order, secondary bile aggregates of each of CA and DC show significantly degraded chiral selectivity. Diffusion NMR reveals that secondary micelles of CA exclude the BNDHP guests, while secondary micelles of DC accommodate guests, but with a loss of chiral selectivity. These data lead to the hypothesis that secondary aggregates of DC have an exposed binding site, possibly the 7α-edge of a bile dimeric unit, while secondary CA micelles do not present binding edges to the solution, potentially instead exposing the three alcohol groups on the hydrophilic α-face to the solution.

The 17-residue-long N terminus in huntingtin controls stepwise aggregation in solution and on membranes via different mechanisms

Aggregation of huntingtin protein arising from expanded polyglutamine (polyQ) sequences in the exon-1 region of mutant huntingtin plays a central role in the pathogenesis of Huntington's disease. The huntingtin aggregation pathways are of therapeutic and diagnostic interest, but obtaining critical information from the physiologically relevant htt exon-1 (Httex1) protein has been challenging. Using biophysical techniques and an expression and purification protocol that generates clean, monomeric Httex1, we identified and mapped three distinct aggregation pathways: 1) unseeded in solution; 2) seeded in solution; and 3) membrane-mediated. In solution, aggregation proceeded in a highly stepwise manner, in which the individual domains (N terminus containing 17 amino acids (N17), polyQ, and proline-rich domain (PRD)) become ordered at very different rates. The aggregation was initiated by an early oligomer requiring a pathogenic, expanded Gln length and N17 α-helix formation. In the second phase, β-sheet forms in the polyQ. The slowest step is the final structural maturation of the PRD. This stepwise mechanism could be bypassed by seeding, which potently accelerated aggregation and was a prerequisite for prion-like spreading in vivo Remarkably, membranes could catalyze aggregation even more potently than seeds, in a process that caused significant membrane damage. The N17 governed membrane-mediated aggregation by anchoring Httex1 to the membrane, enhancing local concentration and promoting collision via two-dimensional diffusion. Considering its central roles in solution and in membrane-mediated aggregation, the N17 represents an attractive target for inhibiting multiple pathways. Our approach should help evaluate such inhibitors and identify diagnostic markers for the misfolded forms identified here.