Hormone-dependent control of developmental timing through regulation of chromatin accessibility.

Specification of tissue identity during development requires precise coordination of gene expression in both space and time. Spatially, master regulatory transcription factors are required to control tissue-specific gene expression programs. However, the mechanisms controlling how tissue-specific gene expression changes over time are less well understood. Here, we show that hormone-induced transcription factors control temporal gene expression by regulating the accessibility of DNA regulatory elements. Using the Drosophila wing, we demonstrate that temporal changes in gene expression are accompanied by genome-wide changes in chromatin accessibility at temporal-specific enhancers. We also uncover a temporal cascade of transcription factors following a pulse of the steroid hormone ecdysone such that different times in wing development can be defined by distinct combinations of hormone-induced transcription factors. Finally, we show that the ecdysone-induced transcription factor E93 controls temporal identity by directly regulating chromatin accessibility across the genome. Notably, we found that E93 controls enhancer activity through three different modalities, including promoting accessibility of late-acting enhancers and decreasing accessibility of early-acting enhancers. Together, this work supports a model in which an extrinsic signal triggers an intrinsic transcription factor cascade that drives development forward in time through regulation of chromatin accessibility.

An unusual diarrheal outbreak in the community in Eastern Thailand caused by Norovirus GII.3[P25].

BACKGROUND: Sentinel laboratory surveillance for diarrheal disease determined norovirus to be the most common cause of non-bacterial gastroenteritis in people during the COVID-19 pandemic in Thailand. An increase in patients presenting with diarrhea and vomiting in hospitals across Chanthaburi province between December 2021 and January 2022 led to the need for the identification of viral pathogens that may be responsible for the outbreak. METHODS: Fecal samples (rectal swabs or stool) from 93 patients, of which 65 patients were collected during the December 2021 to January 2022 outbreak, were collected and screened for viral infection by real-time RT-PCR. Positive samples for norovirus GII were then genotyped by targeted amplification and sequencing of partial polymerase and capsid genes. Full genome sequencing was performed from the predominant strain, GII.3[P25]. RESULTS: Norovirus was the most common virus detected in human fecal samples in this study. 39 of 65 outbreak samples (60%) and 3 of 28 (10%) non-outbreak samples were positive for norovirus genogroup II. One was positive for rotavirus, and one indicated co-infection with rotavirus and norovirus genogroups I and II. Nucleotide sequences of VP1 and RdRp gene were successfully obtained from 28 of 39 positive norovirus GII and used for dual-typing; 25/28 (89.3%) were GII.3, and 24/28 (85.7) were GII.P25, respectively. Norovirus GII.3[P25] was the predominant strain responsible for this outbreak. The full genome sequence of norovirus GII.3[P25] from our study is the first reported in Thailand and has 98.62% and 98.57% similarity to norovirus found in China in 2021 and the USA in 2022, respectively. We further demonstrate the presence of multiple co-circulating norovirus genotypes, including GII.21[P21], GII.17[P17], GII.3[P12] and GII.4[P31] in our study. CONCLUSIONS: An unusual diarrhea outbreak was found in December 2021 in eastern Thailand. Norovirus strain GII.3[P25] was the cause of the outbreak and was first detected in Thailand. The positive rate during GII.3[P25] outbreak was six times higher than sporadic cases (GII.4), and, atypically, adults were the primary infected population rather than children.

Molecular autopsy for fetal structural anomaly: diagnostic and clinical utility of multidisciplinary team approach.

OBJECTIVES: In the West Midlands Regional Genetic Service, cases of perinatal death with a possible genetic diagnosis are evaluated by the Perinatal Pathology Genetic Multidisciplinary Team (MDT). The MDT assessed autopsy findings and considered genomic assessments. The objective of this retrospective service evaluation was to determine the clinical utility of the MDT. This is the first evaluation since the introduction of whole genome and whole exome sequencing in routine clinical care. METHOD: The outcomes for all the perinatal MDT cases from January 2021 to December 2021 were examined. All cases received a full or partial post-mortem examination (PM) and a chromosomal microarray. Demographics, phenotype, MDT recommendations, genetic testing, diagnoses, outcomes, impact of PM and impact of genetic testing were collected from patient case notes. RESULTS: One hundred and twenty-three cases were discussed at the MDT meeting in 2021. Genetic evaluation was recommended in 84 cases and accepted in 64 cases. A range of genetic tests were requested according to indication and availability. Thirty diagnoses were identified in 29 cases from 26 unrelated families. The diagnostic yield was 24% (29/123) of all cases or 45% (29/64) of the cases with a suspected genetic diagnosis who underwent genetic testing. PM examination added clinically actionable phenotype data in 79% of cases. A genetic diagnosis enabled accurate counselling of recurrence risk and provision of appropriate follow-up, including prenatal testing and preimplantation diagnosis for patients with inherited conditions. CONCLUSIONS: Genomic testing was a clinically useful addition to (but not a substitute for) PM examination in perinatal cases associated with structural anomalies. The MDT model helped assess cases and plan appropriate follow-up. Expedited whole genome sequencing or panel-agnostic analysis were most appropriate for heterogeneous presentations. This broad approach can also expand prenatal phenotypes and detect novel disease genes and should be a priority for future research. This article is protected by copyright. All rights reserved.

Correlated insulator behaviour at half-filling in magic-angle graphene superlattices.

A van der Waals heterostructure is a type of metamaterial that consists of vertically stacked two-dimensional building blocks held together by the van der Waals forces between the layers. This design means that the properties of van der Waals heterostructures can be engineered precisely, even more so than those of two-dimensional materials. One such property is the 'twist' angle between different layers in the heterostructure. This angle has a crucial role in the electronic properties of van der Waals heterostructures, but does not have a direct analogue in other types of heterostructure, such as semiconductors grown using molecular beam epitaxy. For small twist angles, the moiré pattern that is produced by the lattice misorientation between the two-dimensional layers creates long-range modulation of the stacking order. So far, studies of the effects of the twist angle in van der Waals heterostructures have concentrated mostly on heterostructures consisting of monolayer graphene on top of hexagonal boron nitride, which exhibit relatively weak interlayer interaction owing to the large bandgap in hexagonal boron nitride. Here we study a heterostructure consisting of bilayer graphene, in which the two graphene layers are twisted relative to each other by a certain angle. We show experimentally that, as predicted theoretically, when this angle is close to the 'magic' angle the electronic band structure near zero Fermi energy becomes flat, owing to strong interlayer coupling. These flat bands exhibit insulating states at half-filling, which are not expected in the absence of correlations between electrons. We show that these correlated states at half-filling are consistent with Mott-like insulator states, which can arise from electrons being localized in the superlattice that is induced by the moiré pattern. These properties of magic-angle-twisted bilayer graphene heterostructures suggest that these materials could be used to study other exotic many-body quantum phases in two dimensions in the absence of a magnetic field. The accessibility of the flat bands through electrical tunability and the bandwidth tunability through the twist angle could pave the way towards more exotic correlated systems, such as unconventional superconductors and quantum spin liquids.

Distinct single-component adjuvants steer human DC-mediated T-cell polarization via Toll-like receptor signaling toward a potent antiviral immune response.

The COVID-19 pandemic highlights the importance of efficient and safe vaccine development. Vaccine adjuvants are essential to boost and tailor the immune response to the corresponding pathogen. To allow for an educated selection, we assessed the effect of different adjuvants on human monocyte-derived dendritic cells (DCs) and their ability to polarize innate and adaptive immune responses. In contrast to commonly used adjuvants, such as aluminum hydroxide, Toll-like receptor (TLR) agonists induced robust phenotypic and functional DC maturation. In a DC-lymphocyte coculture system, we investigated the ensuing immune reactions. While monophosphoryl lipid A synthetic, a TLR4 ligand, induced checkpoint inhibitors indicative for immune exhaustion, the TLR7/8 agonist Resiquimod (R848) induced prominent type-1 interferon and interleukin 6 responses and robust CTL, B-cell, and NK-cell proliferation, which is particularly suited for antiviral immune responses. The recently licensed COVID-19 vaccines, BNT162b and mRNA-1273, are both based on single-stranded RNA. Indeed, we could confirm that the cytokine profile induced by lipid-complexed RNA was almost identical to the pattern induced by R848. Although this awaits further investigation, our results suggest that their efficacy involves the highly efficient antiviral response pattern stimulated by the RNAs' TLR7/8 activation.

For richer, for poorer: Financial behaviors, power (im)balance, and relational aggression among different-gender newlyweds in the U.S.

Guided by an intersectional feminism framework, we used three-wave, dyadic survey data from a nationally representative sample of 1625 U.S. different-gender newlywed couples to test three research questions. First, as balanced power is considered a key concept for relational well-being in feminism, we examined developmental trajectories in husbands' and wives' perception of power (im)balance. Second, considering money as a major influence on power and aggression, we examined how financial behaviors relate to power (im)balance and in turn relational aggression-a type of intimate partner violence that is controlling and manipulative in nature. Third, informed by the intersectionality between gender and socioeconomic status (SES), we examined gender differences and SES disparities in the associations among financial behaviors, developmental trajectories of perception of power (im)balance, and relational aggression. Our findings demonstrate that newlywed different-gender couples are experiencing power struggles, where two partners diminish each other's influence over time. We also found that healthy financial behaviors are associated with balanced power and, in turn, less relational aggression (especially for wives and in lower-SES households). Taken collectively, we continue calling for efforts to facilitate money management skills and promote balanced marital power.

Phase Separation and Fibrillization of Human Annexin A7 Are Mediated by Its Proline-Rich Domain.

Human annexin A7, a calcium- and phospholipid-binding protein, governs calcium homeostasis, plasma membrane repair, apoptosis, and tumor progression. A7 contains an N-terminal proline-rich domain (PRD; 180 residues, ∼24% prolines) that determines its functional specificity. Using microscopy and dye-binding assays, we show that recombinant A7 and its isolated PRD spontaneously phase separate into spherical condensates, which subsequently transform into ß-sheet-rich fibrils. We demonstrate that fibrillization of A7-PRD proceeds via primary nucleation and fibril-catalyzed secondary nucleation processes, as determined by chemical kinetics, providing a mechanistic basis for its amyloid assembly. This study confirms and highlights a subclass of eukaryotic PRDs prone to forming aggregates with important physiological and pathological implications.

Avidity-Based Method for the Efficient Generation of Monoubiquitinated Recombinant Proteins.

Monoubiquitination of proteins governs diverse physiological processes, and its dysregulation is implicated in multiple pathologies. The difficulty of preparing sufficient material often complicates the biophysical studies of monoubiquitinated recombinant proteins. Here we describe a robust avidity-based method that overcomes this problem. As a proof-of-concept, we produced milligram quantities of two monoubiquitinated targets, Parkinson's protein α-synuclein and ESCRT-protein ALIX, using NEDD4-family E3 ligases. Monoubiquitination hotspots were identified by quantitative chemical proteomics. Using FRAP and dye-binding assays, we uncovered strikingly opposite effects of monoubiquitination on the phase separation and fibrillization properties of these two amyloidogenic proteins, reflecting differences in their intermolecular interactions, thereby providing unique insights into the impact of monoubiquitination on protein aggregation.

Expression of E93 provides an instructive cue to control dynamic enhancer activity and chromatin accessibility during development.

How temporal cues combine with spatial inputs to control gene expression during development is poorly understood. Here, we test the hypothesis that the Drosophila transcription factor E93 controls temporal gene expression by regulating chromatin accessibility. Precocious expression of E93 early in wing development reveals that it can simultaneously activate and deactivate different target enhancers. Notably, the precocious patterns of enhancer activity resemble the wild-type patterns that occur later in development, suggesting that expression of E93 alters the competence of enhancers to respond to spatial cues. Genomic profiling reveals that precocious E93 expression is sufficient to regulate chromatin accessibility at a subset of its targets. These accessibility changes mimic those that normally occur later in development, indicating that precocious E93 accelerates the wild-type developmental program. Further, we find that target enhancers that do not respond to precocious E93 in early wings become responsive after a developmental transition, suggesting that parallel temporal pathways work alongside E93. These findings support a model wherein E93 expression functions as an instructive cue that defines a broad window of developmental time through control of chromatin accessibility.

Vascular space occupancy asymmetric spin echo (VASO-ASE) for non-invasive quantification of cerebral oxygen extraction fraction.

PURPOSE: Asymmetric spin echo (ASE) MRI is a method for measuring regional oxygen extraction fraction (OEF); however, extravascular tissue models have been shown to under-estimate OEF. The hypothesis investigated here is that the addition of a vascular-space-occupancy (VASO) pre-pulse will more fully suppress blood water signal and provide global OEF values more consistent with physiological expectation and 15 O positron emission tomography (PET)-validated T2 -relaxation-under-spin-tagging (TRUST) OEF measures. METHODS: Healthy adults (n = 14; age = 27.7 ± 5.2 y; sex = 7/7 male/female) were scanned at 3.0T. Multi-echo ASE without inter-readout refocusing (ASERF- ), multi-echo ASE with inter-readout refocusing (ASERF+ ), and single-echo VASO-ASE were acquired twice each with common spatial resolution = 3.44 × 3.44 × 3.0 mm and τ = 0-20 ms (interval = 0.5 ms). TRUST was acquired twice sequentially for independent global OEF assessment (τCPMG  = 10 ms; effective TEs = 0, 40, 80, and 160 ms; spatial resolution = 3.4 × 3.4 × 5 mm). OEF intraclass-correlation-coefficients (ICC), summary statistics, and group-wise differences were assessed (Wilcoxon rank-sum; significance: two-sided p < 0.05). RESULTS: ASERF+ (OEF = 36.8 ± 1.9%) and VASO-ASE (OEF = 34.4 ± 2.3%) produced OEF values similar to TRUST (OEF = 36.5 ± 4.6%, human calibration model; OEF = 32.7 ± 4.9%, bovine calibration model); however, ASERF- yielded lower OEF (OEF = 26.1 ± 1.0%; p < 0.01) relative to TRUST. VASO-ASE (ICC = 0.61) yielded lower ICC compared to other ASE variants (ICC >0.89). CONCLUSION: VASO-ASE and TRUST provide similar OEF values; however, VASO-ASE spatial coverage and repeatability improvements are required.

A realist approach to understanding alliancing within Local Government public health and social care service provision.

BACKGROUND: Within the current context of continued austerity and post-pandemic recovery, it remains important that Local Government services address the increasing needs of residents as cost-effectively as possible. Alliancing, whereby services work collaboratively focusing on the 'whole-system', has gained popularity as a tool with the potential to support collaborative whole systems approaches. This synthesis aims to identify how alliancing can be successfully operationalised in the commissioning of public health, wider National Health Service (NHS) and social care-related services. METHODS: A realist literature synthesis was undertaken in order to identify underlying generative mechanisms associated with alliancing, the contextual conditions surrounding the implementation and operationalisation of the alliancing approach mechanisms, and the outcomes produced as a result. An iterative approach was taken, using a recent systematic review of the effectiveness of Alliancing, online database searches, and grey literature searches. RESULTS: Three mechanistic components were identified within the data as being core to the successful implementation of alliances in public health and social care-related services within Local Government: (i) Achieving a system-level approach; (ii) placing local populations at the heart of the system; and (iii) creating a cultural shift. Programme theories were postulated within these components. CONCLUSIONS: The alliancing approach offers an opportunity to achieve system-level change with the potential to benefit local populations. The realist synthesis approach taken within this study has provided insights into the necessary contextual and mechanistic factors of the Alliancing approach, above and beyond effectiveness outcomes typically collected through more conventional evaluation methodologies.

Durability of Antibody Response and Frequency of SARS-CoV-2 Infection 6 Months after COVID-19 Vaccination in Healthcare Workers.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies decay but persist 6 months postvaccination; lower levels of neutralizing titers persist against Delta than wild-type virus. Of 227 vaccinated healthcare workers tested, only 2 experienced outpatient symptomatic breakthrough infections, despite 59/227 exhibiting serologic evidence of SARS-CoV-2 infection, defined as presence of nucleocapsid protein antibodies.

Memes: A motif analysis environment in R using tools from the MEME Suite.

Identification of biopolymer motifs represents a key step in the analysis of biological sequences. The MEME Suite is a widely used toolkit for comprehensive analysis of biopolymer motifs; however, these tools are poorly integrated within popular analysis frameworks like the R/Bioconductor project, creating barriers to their use. Here we present memes, an R package that provides a seamless R interface to a selection of popular MEME Suite tools. memes provides a novel "data aware" interface to these tools, enabling rapid and complex discriminative motif analysis workflows. In addition to interfacing with popular MEME Suite tools, memes leverages existing R/Bioconductor data structures to store the multidimensional data returned by MEME Suite tools for rapid data access and manipulation. Finally, memes provides data visualization capabilities to facilitate communication of results. memes is available as a Bioconductor package at https://bioconductor.org/packages/memes, and the source code can be found at github.com/snystrom/memes.

Marital quality over the life course and child well-being from childhood to early adolescence.

Research on marital quality and child well-being is currently limited by its common use of geographically constrained, homogenous, and often cross-sectional (or at least temporally limited) samples. We build upon previous work showing multiple trajectories of marital quality and data from the National Longitudinal Survey of Youth-1979 (NLSY79) regarding mothers and their children (inclusive of ages 5-14). We examine how indicators of child well-being are linked to parental trajectories of marital quality (happiness, communication, and conflict). Results showed children whose parents had consistently poor marital quality over the life course exhibited more internalizing and externalizing problems, poorer health, lower quality home environments, and lower math and vocabulary scores than children of parents in consistently higher-quality marriages. Group differences remained stable over time for child health, home environment, and vocabulary scores. Group differences for internalizing problems declined over time, whereas group differences increased for externalizing problems and math scores. Initial advantages for females across nearly all indicators of child well-being tended to shrink over time, with boys often moving slightly ahead by mid adolescence. We discuss the implications of these findings in regard to children's development and well-being and suggest treating marriage as a monolithic construct betrays important variation within marriage itself.

Disconnection description of triple-junction motion.

Grain boundary (GB) migration in polycrystalline materials necessarily implies the concurrent motion of triple junctions (TJs), the lines along which three GBs meet. Today, we understand that GB migration occurs through the motion of disconnections in the GB plane (line defects with both step and dislocation character). We present evidence from molecular dynamics grain growth simulations and idealized microstructures that demonstrates that TJ motion and GB migration are coupled through disconnection dynamics. Based on these results, we develop a theory of coupled GB/TJ migration and use it to develop a physically based, disconnection mechanism-specific continuum model of microstructure evolution. The continuum approach provides a means of reducing the complexity of the discrete disconnection picture to extract the features of disconnection dynamics that are important for microstructure evolution. We implement this model in a numerical, continuum simulation and demonstrate that it is capable of reproducing the molecular dynamics (MD) simulation results.

Structural and functional analyses reveal promiscuous and species specific use of ephrin receptors by Cedar virus.

Cedar virus (CedV) is a bat-borne henipavirus related to Nipah virus (NiV) and Hendra virus (HeV), zoonotic agents of fatal human disease. CedV receptor-binding protein (G) shares only ∼30% sequence identity with those of NiV and HeV, although they can all use ephrin-B2 as an entry receptor. We demonstrate that CedV also enters cells through additional B- and A-class ephrins (ephrin-B1, ephrin-A2, and ephrin-A5) and report the crystal structure of the CedV G ectodomain alone and in complex with ephrin-B1 or ephrin-B2. The CedV G receptor-binding site is structurally distinct from other henipaviruses, underlying its capability to accommodate additional ephrin receptors. We also show that CedV can enter cells through mouse ephrin-A1 but not human ephrin-A1, which differ by 1 residue in the key contact region. This is evidence of species specific ephrin receptor usage by a henipavirus, and implicates additional ephrin receptors in potential zoonotic transmission.

LocalZProjector and DeProj: a toolbox for local 2D projection and accurate morphometrics of large 3D microscopy images.

BACKGROUND: Quantitative imaging of epithelial tissues requires bioimage analysis tools that are widely applicable and accurate. In the case of imaging 3D tissues, a common preprocessing step consists of projecting the acquired 3D volume on a 2D plane mapping the tissue surface. While segmenting the tissue cells is amenable on 2D projections, it is still very difficult and cumbersome in 3D. However, for many specimen and models used in developmental and cell biology, the complex content of the image volume surrounding the epithelium in a tissue often reduces the visibility of the biological object in the projection, compromising its subsequent analysis. In addition, the projection may distort the geometry of the tissue and can lead to strong artifacts in the morphology measurement. RESULTS: Here we introduce a user-friendly toolbox built to robustly project epithelia on their 2D surface from 3D volumes and to produce accurate morphology measurement corrected for the projection distortion, even for very curved tissues. Our toolbox is built upon two components. LocalZProjector is a configurable Fiji plugin that generates 2D projections and height-maps from potentially large 3D stacks (larger than 40 GB per time-point) by only incorporating signal of the planes with local highest variance/mean intensity, despite a possibly complex image content. DeProj is a MATLAB tool that generates correct morphology measurements by combining the height-map output (such as the one offered by LocalZProjector) and the results of a cell segmentation on the 2D projection, hence effectively deprojecting the 2D segmentation in 3D. In this paper, we demonstrate their effectiveness over a wide range of different biological samples. We then compare its performance and accuracy against similar existing tools. CONCLUSIONS: We find that LocalZProjector performs well even in situations where the volume to project also contains unwanted signal in other layers. We show that it can process large images without a pre-processing step. We study the impact of geometrical distortions on morphological measurements induced by the projection. We measured very large distortions which are then corrected by DeProj, providing accurate outputs.

Outpatient Practice Reactivation in an Integrated Community Practice During the COVID-19 Pandemic.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has impacted health care organizations throughout the world. The Southwest Minnesota Region of Mayo Clinic Health System, a community-based health care system, was not immune, and in March 2020, our outpatient services were deferred and decreased by 90%. Method: This article is a review of the approach we used to safely reactivate outpatient care, the tools that we developed, and the outcomes of these reactivation efforts. A novel Outpatient Practice Reactivation Framework was established and used that included Outpatient Clinic Appointment Dashboard, Decision Matrix, Access Management, Virtual Care, and Patient Safety. This framework was guided by patient demand for care and by safety principles, as recommended by state and federal agencies and our internal infectious disease department guidelines. Results and Conclusions: Over the course of 9 weeks, ambulatory visit volumes and clinic utilization rates returned to pre-COVID levels (Pre-COVID fill rate range: 87% to 94%, post-COVID fill rate range: 86% to 89%) exceeding target fill rate of 80%, as a result of establishing the initiative as a shared priority, committing to a robust schedule and decisive actions, creating and maintaining a well-defined structure, taking an inclusive approach, overcommunicating and providing sufficient data for transparency, developing guiding principles, and training and educating staff.

[Lung cancer at a Chilean public hospital]. / Cáncer pulmonar: caracterización, estadificación y supervivencia en una cohorte de una década en un hospital del sistema público de salud de Chile.

BACKGROUND: Lung cancer is the world's leading cause of cancer death. AIM: To describe the clinical, staging and survival characteristics of lung cancer in a public Chilean regional hospital. MATERIAL AND METHODS: Analysis of a prospective database of a thoracic surgery service, retrieving histologically confirmed lung cancer cases from January 2010 to December 2019 and reviewing their medical records. Cases were re-staged by the TNM-8 system and variables were compared between periods 2010-2014 and 2015-2019. RESULTS: We retrieved 551 lung cancer cases, 333 (60 %) men, with a mean age of 65 years. Distant metastases were found in 72% of cases (excluding lymphatic metastases). Of the non-small cell lung cancers (NSCLC), 50 (10%) cases were in stage I, 18 (4%) in stage II, 81 (16%) in stage III and 347 (70%) in stage IV. Global five-year survival was 18%, 20% for NSCLC, 71% for excised NSCLC, 8% for non-excised NSCLC, 88% for stage I and 92% for subgroup IA. Resective surgery was performed in 81 (14%) cases. When comparing 2010-2014 and 2015-2019 periods, the frequency of resective surgery increased from 7% to 20%. CONCLUSIONS: The diagnosis of lung cancer was frequently made in advanced stages. There was a significant increase in early diagnosis and frequency of surgeries with curative intent in the second observation period.

Quantitative NMR Study of Insulin-Degrading Enzyme Using Amyloid-ß and HIV-1 p6 Elucidates Its Chaperone Activity.

Insulin-degrading enzyme (IDE) hydrolyzes monomeric polypeptides, including amyloid-ß (Aß) and HIV-1 p6. It also acts as a nonproteolytic chaperone to prevent Aß polymerization. Here we compare interactions of Aß and non-amyloidogenic p6 with IDE. Although both exhibited similar proteolysis rates, the binding kinetics to an inactive IDE characterized using relaxation-based NMR were remarkably different. IDE and Aß formed a sparsely populated complex with a lifetime of milliseconds in which a short hydrophobic cleavage segment of Aß was anchored to IDE. Strikingly, a second and more stable complex was significantly populated with a subsecond lifetime owing to multiple intermolecular contacts between Aß and IDE. By selectively sequestering Aß in this nonproductive complex, IDE likely increases the critical concentration required for fibrillization. In contrast, IDE and p6 formed a transient, submillisecond complex involving a single anchoring p6 motif. Modulation of intermolecular interactions, thus, allows IDE to differentiate between non-amyloidogenic and amyloidogenic substrates.