Level Of Resolution Research Articles

The Effect of Resolution Level and Targeted Design in the Diagnostic Performance of Prenatal Chromosomal Microarray Analysis

Introduction: This study was performed to assess the optimal resolution for prenatal testing by array comparative genomic hybridization (aCGH), aiming to balance between maximum diagnostic yield and minimal detection of variants of uncertain significance (VOUS). Methods: This was a prospective study using data of 2,336 fetuses that underwent invasive prenatal diagnosis, and the samples were analyzed by aCGH. In total, six different aCGH platforms were studied; four different resolutions (0.18 Mb, 0.5 Mb, 1 Mb, and 2 Mb) and two platform designs (whole-genome [WG] and targeted). The results of these designs were compared based on their diagnostic yield and VOUS rate. The performance of the different designs was further analyzed according to indication for invasive testing. Results: The diagnostic yield of copy number variants increased with increasing level of analysis. The detection rates of clinically significant chromosomal abnormalities were almost the same across our targeted array designs; 7.2% with 0.18 Mb backbone/0.05 Mb versus 7.1% with 0.5 Mb backbone/0.05 Mb (p >0.05). However, a significant difference in the rate of VOUS was observed; 9.4% with 0.18 Mb backbone/0.05 Mb versus 6% with 0.5 Mb backbone/0.05 Mb (p <0.001). After analyzing the results across different indications for testing, we found that the application of non-targeted platform designs and lower levels of resolution analysis (such as 1 Mb WG or 0.5 MbL/1 MbG WG) would offer similar diagnostic yield in most cases with major congenital anomalies, with lower VOUS rates. However, the sample size for many indication groups was too small to extract robust associations. Conclusion: It appears that the targeted array platform with 0.5 Mb backbone resolution and 0.05 Mb on targeted gene-rich regions is optimal for routine chromosomal microarray analysis use in prenatal diagnosis. It may be beneficial to individualize the minimum resolution in specific referral indications as the indications for invasive prenatal testing may be quite heterogeneous.

Influence of dexamethasone on the interaction between glucocorticoid receptor and SOX9: A molecular dynamics study

The glucocorticoid receptor (GR) is a nuclear receptor that controls critical biological processes by regulating the transcription of specific genes. GR transcriptional activity is modulated by a series of ligands and coenzymes, where a ligand can act as an agonist or antagonist. GR agonists, such as the glucocorticoids dexamethasone (DEX) and prednisolone, are widely prescribed to patients with inflammatory and autoimmune diseases. DEX is also used to induce osteogenic differentiation in vitro. Recently, it has been highlighted that DEX induces changes in the osteogenic differentiation of human mesenchymal stromal cells by downregulating the transcription factor SRY-box transcription factor 9 (SOX9) and upregulating the peroxisome proliferator-activated receptor γ (PPARG). SOX9 is fundamental in the control of chondrogenesis, but also in osteogenesis by acting as a dominant-negative of RUNX2. Many processes remain to be clarified during cell fate determination, such as the interplay between the key transcription factors. The main objective pursued by this work is to shed light on the interaction between GR and SOX9 in the presence and absence of DEX at an atomic level of resolution using molecular dynamics simulations. The outcome of this research could help the understanding of possible molecular interactions between GR and SOX9 and their role in the determination of cell fate. The results highlight the key residues at the interface between GR and SOX9 involved in the complexation process and shed light on the mechanism through which DEX modulates GR-SOX9 binding and exerts its biological activity.

The interplay between adsorption and aggregation of von Willebrand factor chains in shear flows

Von Willebrand factor (VWF) is a giant extracellular glycoprotein that carries out a key adhesive function during primary hemostasis. Upon vascular injury and triggered by the shear of flowing blood, VWF establishes specific interactions with several molecular partners in order to anchor platelets to collagen on the exposed subendothelial surface. VWF also interacts with itself to form aggregates that, adsorbed on the surface, provide more anchor sites for the platelets. However, the interplay between elongation and subsequent exposure of cryptic binding sites, self-association, and adsorption on the surface remained unclear for VWF. In particular, the role of shear flow in these three processes is not well understood. In this study, we address these questions by using Brownian dynamics simulations at a coarse-grained level of resolution. We considered a system consisting of multiple VWF-like self-interacting chains that also interact with a surface under a shear flow. By a systematic analysis, we reveal that chain-chain and chain-surface interactions coexist nontrivially to modulate the spontaneous adsorption of VWF and the posterior immobilization of secondary tethered chains. Accordingly, these interactions tune VWF’s extension and its propensity to form shear-assisted functional adsorbed aggregates. Our data highlight the collective behavior VWF self-interacting chains have when bound to the surface, distinct from that of isolated or flowing chains. Furthermore, we show that the extension and the exposure to solvent have a similar dependence on shear flow, at a VWF-monomer level of resolution. Overall, our results highlight the complex interplay that exists between adsorption, cohesion, and shear forces and their relevance for the adhesive hemostatic function of VWF.

Genomic epidemiology and multilevel genome typing of Bordetella pertussis

ABSTRACT Bordetella pertussis causes pertussis (or whooping cough), a severe respiratory infectious disease in infants, although it can be prevented by whole cell and acellular vaccines. The recent pertussis resurgence in industrialised countries is partly attributed to pathogen adaptation to vaccines, while emergence of antimicrobial resistance, specifically to macrolides in China, has become a concern. Surveillance of current circulating and emerging strains is therefore vital to understand the risks they pose to public health. Although the use of genomics-based typing is increasing a genomic nomenclature for this pathogen has not been well established. Here, we implemented the multilevel genome typing (MGT) system for B. pertussis with five levels of resolution, which provide targeted typing of relevant lineages and discrimination of closely related strains at the finest scale. The lower resolution levels (MGT2 and MGT3) describe the distribution of major vaccine antigen alleles including ptxP, fim3, fhaB and prn, as well as temporal and spatial trends within the B. pertussis global population. Mid-resolution levels (MGT3 and MGT4) enable typing of antibiotic-resistant lineages and Prn deficient lineages within the ptxP3 clade. The high-resolution level (MGT5) can capture finer-scale epidemiology such as outbreaks and local transmission events, with comparable resolution to existing genomic methods of strain-relatedness assessment. The scheme offers stable MGT-type assignments aiding harmonisation of typing and communication between laboratories. The scheme is available at https://mgtdb.unsw.edu.au/pertussis, is regularly updated from global data repositories and accepts public submissions. The MGT scheme provides a comprehensive, robust, and scalable system for global surveillance of B. pertussis.

Redshifting galaxies from DESI to JWST CEERS: Correction of biases and uncertainties in quantifying morphology

Observations of high-redshift galaxies with unprecedented detail have now been rendered possible with the James Webb Space Telescope (JWST). However, accurately quantifying their morphology remains uncertain due to potential biases and uncertainties. To address this issue, we used a sample of 1816 nearby DESI galaxies, with a stellar mass range of 109.75 − 11.25 M⊙, to compute artificial images of galaxies of the same mass located at 0.75 ≤ z ≤ 3 and observed at rest-frame optical wavelength in the Cosmic Evolution Early Release Science (CEERS) survey. We analyzed the effects of cosmological redshift on the measurements of Petrosian radius (Rp), half-light radius (R50), asymmetry (A), concentration (C), axis ratio (q), and Sérsic index (n). Our results show that Rp and R50, calculated using non-parametric methods, are slightly overestimated due to PSF smoothing, while R50, q, and n obtained through fitting a Sérsic model does not exhibit significant biases. By incorporating a more accurate noise effect removal procedure, we improve the computation of A over existing methods, which often overestimate, underestimate, or lead to significant scatter of noise contributions. Due to PSF asymmetry, there is a minor overestimation of A for intrinsically symmetric galaxies. However, for intrinsically asymmetric galaxies, PSF smoothing dominates and results in an underestimation of A, an effect that becomes more significant with higher intrinsic A or at lower resolutions. Moreover, PSF smoothing also leads to an underestimation of C, which is notably more pronounced in galaxies with higher intrinsic C or at lower resolutions. We developed functions based on resolution level, defined as Rp/FWHM, for correcting these biases and the associated statistical uncertainties. Applying these corrections, we measured the bias-corrected morphology for the simulated CEERS images and we find that the derived quantities are in good agreement with their intrinsic values – except for A, which is robust only for angularly large galaxies where Rp/FWHM ≥ 5. Our correction functions can be applied to other surveys, offering valuable tools for future studies.

Genetic dissection of crossover mutants defines discrete intermediates in mouse meiosis

Crossovers (COs), the exchange of homolog arms, are required for accurate chromosome segregation during meiosis. Studies in yeast have described the single-end invasion (SEI) intermediate: a stabilized 3' end annealed with the homolog as the first detectible CO precursor. SEIs are thought to differentiate into double Holliday junctions (dHJs) that are resolved by MutLgamma (MLH1/MLH3) into COs. Currently, we lack knowledge of early steps of mammalian CO recombination or how intermediates are differentiated in any organism. Using comprehensive analysis of recombination in thirteen different genetic conditions with varying levels of compromised CO resolution, we infer CO precursors include asymmetric SEI-like intermediates and dHJs in mouse. In contrast to yeast, MLH3 is structurally required to differentiate CO precursors into dHJs. We verify conservation of aspects of meiotic recombination and show unique features in mouse, providing mechanistic insight into CO formation.

Angle Measurement Based on Second Harmonic Generation Using Artificial Neural Network

This article proposed an angle measurement method based on second harmonic generation (SHG) using an artificial neural network (ANN). The method comprises three sequential parts: SHG spectrum collection, data preprocessing, and neural network training. First, the referenced angles and SHG spectrums are collected by the autocollimator and SHG-based angle sensor, respectively, for training. The mapping is learned by the trained ANN after completing the training process, which solves the inverse problem of obtaining the angle from the SHG spectrum. Then, the feasibility of the proposed method is verified in multiple-peak Maker fringe and single-peak phase-matching areas, with an overall angle measurement range exceeding 20,000 arcseconds. The predicted angles by ANN are compared with the autocollimator to evaluate the measurement performance in all the angular ranges. Particularly, a sub-arcsecond level of accuracy and resolution is achieved in the phase-matching area.

Integrated single-cell chromatin and transcriptomic analyses of human scalp identify gene-regulatory programs and critical cell types for hair and skin diseases.

Genome-wide association studies have identified many loci associated with hair and skin disease, but identification of causal variants requires deciphering of gene-regulatory networks in relevant cell types. We generated matched single-cell chromatin profiles and transcriptomes from scalp tissue from healthy controls and patients with alopecia areata, identifying diverse cell types of the hair follicle niche. By interrogating these datasets at multiple levels of cellular resolution, we infer 50-100% more enhancer-gene links than previous approaches and show that aggregate enhancer accessibility for highly regulated genes predicts expression. We use these gene-regulatory maps to prioritize cell types, genes and causal variants implicated in the pathobiology of androgenetic alopecia (AGA), eczema and other complex traits. AGA genome-wide association studies signals are enriched in dermal papilla regulatory regions, supporting the role of these cells as drivers of AGA pathogenesis. Finally, we train machine learning models to nominate single-nucleotide polymorphisms that affect gene expression through disruption of transcription factor binding, predicting candidate functional single-nucleotide polymorphism for AGA and eczema.

Mathematical Modeling of Gas-Solid Two-Phase Flows: Problems, Achievements and Perspectives (A Review)

Mathematical modeling is the most important tool for constructing theories of different kinds of two-phase flows. This review is devoted to the analysis of the introduction of mathematical modeling to two-phase flows, where solid particles mainly serve as the dispersed phase. The main problems and features of the study of gas-solid two-phase flows are included. The main characteristics of gas flows with solid particles are discussed, and the classification of two-phase flows is developed based on these characteristics. The Lagrangian and Euler approaches to modeling the motion of a dispersed phase (particles) are described. A great deal of attention is paid to the consideration of numerical simulation methods that provide descriptions of turbulent gas flow at different hierarchical levels (RANS, LES, and DNS), different levels of description of interphase interactions (one-way coupling (OWC), two-way coupling (TWC), and four-way coupling (FWC)), and different levels of interface resolution (partial-point (PP) and particle-resolved (PR)). Examples of studies carried out on the basis of the identified approaches are excluded, and they are also excluded for the mathematical modeling of various classes of gas-solid two-phase flows.

Underwater macrophotogrammetry to monitor in situ benthic communities at submillimetre scale

Abstract Larval settlement and recruitment of sessile organisms are key ecological processes for population recovery and maintenance that occur at scales invisible to the human eye. Accordingly, proxies of recruitment have commonly been quantified using artificial substrata such as settlement tiles made of diverse materials and shapes, which are typically transported to the laboratory for examination. However, it is unknown how much bias is introduced with this sampling strategy and how recruitment quantified on tiles relates to recruitment on nearby natural substrata. Here, we applied techniques that combine macrophotography with photogrammetry (macrophotogrammetry) underwater to monitor benthic communities at submillimetre scale. This application allows the investigation of recruitment and community succession of the earliest life‐history stages in situ and on natural substrata. We tested the use of four different imaging systems, varying in costs from US$ 1400 to US$ 5440. While the most expensive SONY αRiv system provided the best visual output and ground resolution (up to 5 μm/pixel with a + 4 close‐up lens); regardless of systems, 3D models always had a ground resolution ≤23 μm/pixel and errors in planar measurements of submillimetre features were similar among systems. This level of resolution compares well with stereomicroscopy in the range of 5:1 to 10:1 magnification, while providing detailed 3D digital records through time. Using a coral reef example, we apply this approach to demonstrate how it can be used to monitor small reef areas (~300–600 cm2) through time, including the quantification of biophysical metrics such as cover of small facilitative and competitive organisms and microhabitat complexity. We further show that organisms as small 0.5 mm in size, such as 2‐month‐old coral settlers, can be located accurately within the 3D models and measured with a good level of confidence. This method can be readily applied to other benthic environments to elucidate drivers of early recruitment and recovery of benthic organisms following disturbance impacts at very fine scales, directly on natural substrata, to avoid biases inherent with laboratory‐based analyses of artificial surfaces.

A Novel Light U-Net Model for Left Ventricle Segmentation Using MRI

MRI segmentation and analysis are significant tasks in clinical cardiac computations. A cardiovascular MR scan with left ventricular segmentation seems necessary to diagnose and further treat the disease. The proposed method for left ventricle segmentation works as a combination of the intelligent histogram-based image enhancement technique with a Light U-Net model. This technique serves as the basis for choosing the low-contrast image subjected to the stretching technique and produces sharp object contours with good contrast settings for the segmentation process. After enhancement, the images are subjected to the encoder–decoder configuration of U-Net using a novel lightweight processing model. Encoder sampling is supported by a block of three parallel convolutional layers with supporting functions that improve the semantics for segmentation at various levels of resolutions and features. The proposed method finally increased segmentation efficiency, extracting the most relevant image resources from depth-to-depth convolutions, filtering them through each network block, and producing more precise resource maps. The dataset of MICCAI 2009 served as an assessment tool of the proposed methodology and provides a dice coefficient value of 97.7%, accuracy of 92%, and precision of 98.17%.

Quantification of Large Transmural Biopsies Reveals Heterogeneity in Innervation Patterns in Chronic Myocardial Infarction

BackgroundAbnormal cardiac innervation plays an important role in arrhythmogenicity after myocardial infarction (MI). Data regarding reperfusion models and innervation abnormalities in the medium to long term after MI are sparse. Histologic quantification of the small-sized cardiac nerves is challenging, and transmural analysis has not been performed. ObjectivesThis study sought to assess cardiac innervation patterns in transmural biopsy sections in a porcine reperfusion model of MI (MI-R) using a novel method for nerve quantification. MethodsTransmural biopsy sections from 4 swine (n = 83) at 3 months after MI-R and 3 controls (n = 38) were stained with picrosirius red (fibrosis) and beta-III-tubulin (autonomic nerves). Biopsy sections were classified as infarct core, border zone, or remote zone. Each biopsy section was analyzed with a custom software pipeline, allowing calculation of nerve density and classification into innervation types at the 1 × 1–mm resolution level. Relocation of the classified squares to the original biopsy position enabled transmural quantification and innervation heterogeneity assessment. ResultsCoexisting hyperinnervation, hypoinnervation, and denervation were present in all transmural MI-R biopsy sections. The innervation heterogeneity was greatest in the infarct core (median: 0.14; IQR: 0.12-0.15), followed by the border zone (median: 0.05; IQR: 0.04-0.07; P = 0.02) and remote zone (median: 0.02; IQR: 0.02-0.03; P < 0.0001). Only in the border zone was a positive linear relation between fibrosis and innervation heterogeneity observed (R = 0.79; P < 0.0001). ConclusionsThis novel method allows quantification of nerve density and heterogeneity in large transmural biopsy sections. In the chronic phase after MI-R, alternating innervation patterns were identified within the same biopsy section. Persistent innervation heterogeneity, in particular in the border zone biopsy sections, may contribute to late arrhythmogenicity.

Activation of N-Methyl-D-aspartate receptor contributed to the ultrasonic modulation of neurons in vitro

Ultrasound stimulation is increasingly used to investigate brain function and treat brain diseases due to its high level of safety and precise spatiotemporal resolution. Therefore, it is crucial to understand the underlying mechanisms involved in ultrasound brain stimulation. In this study, we investigate the role of NMDA receptors in mediating the effects of ultrasound on primary hippocampal neurons in mice. Our results show that ultrasound alone can activate heterologous NMDA receptor subunits, including NR1A, NR2A, and NR2B, in 293T cells, as well as endogenous NMDA receptors in primary neurons. This activation leads to an influx of calcium and an increase in nuclear c-Fos expression in primary neurons that have not been pre-treated with an NMDA receptor inhibitor. In conclusion, our findings demonstrate that NMDA receptors contribute to neuronal activation by ultrasound stimulation in vitro, providing insight into the molecular mechanisms of ultrasound neuromodulation and a new mediator for the sonogenetics technique.

Localization of unlabeled bepirovirsen antisense oligonucleotide in murine tissues using in situ hybridization and CARS imaging.

Current methods for detecting unlabeled antisense oligonucleotide (ASO) drugs rely on immunohistochemistry (IHC) and/or conjugated molecules, which lack sufficient sensitivity, specificity, and resolution to fully investigate their biodistribution. Our aim was to demonstrate the qualitative and quantitative distribution of unlabeled bepirovirsen, a clinical stage ASO, in livers and kidneys of dosed mice using novel staining and imaging technologies at subcellular resolution. ASOs were detected in formalin-fixed paraffin-embedded (FFPE) and frozen tissues using an automated chromogenic in situ hybridization (ISH) assay: miRNAscope. This was then combined with immunohistochemical detection of cell lineage markers. ASO distribution in hepatocytes versus nonparenchymal cell lineages was quantified using HALO AI image analysis. To complement this, hyperspectral coherent anti-Stokes Raman scattering (HS-CARS) imaging microscopy was used to specifically detect the unique cellular Raman spectral signatures following ASO treatment. Bepirovirsen was localized primarily in nonparenchymal liver cells and proximal renal tubules. Codetection of ASO with distinct cell lineage markers of liver and kidney populations aided target cell identity facilitating quantification. Positive liver signal was quantified using HALO AI, with 12.9% of the ASO localized to the hepatocytes and 87.1% in nonparenchymal cells. HS-CARS imaging specifically detected ASO fingerprints based on the unique vibrational signatures following unlabeled ASO treatment in a totally nonperturbative manner at subcellular resolution. Together, these novel detection and imaging modalities represent a significant increase in our ability to detect unlabeled ASOs in tissues, demonstrating improved levels of specificity and resolution. These methods help us understand their underlying mechanisms of action and ultimately improve the therapeutic potential of these important drugs for treating globally significant human diseases.

The role of magnetic resonance cholangiopancreatography in evaluation of etiological spectrum of obstructive jaundice

Jaundice is a commonly encountered problem in society. Discrimination between obstructive and non-obstructive causes is important to imply surgical intervention in cases of obstructive jaundice whereas medical management in non-obstructive jaundice. Nowadays diagnostic endoscopic retrograde cholangiopancreatography (ERCP) may be replaced by Magnetic resonance cholangiopancreatography (MRCP) as it has high level of resolution and reliability. We studied the role of MRCP in obstructive jaundice to evaluate its etiological spectrums and radiological findings. To evaluate the role of MRCP in the determination of aetiologies in obstructive jaundice, to assess degree and level of biliary obstruction and to correlate MRCP findings with post surgical follow-ups / ERCP/ histopathology. Total sixty-eight patients with a clinical diagnosis of obstructive jaundice referred for MRCP were included in our study. We correlated MRCP findings with the final diagnosis made by post-surgical follow-up / ERCP/ histopathology as a gold standard. For benign lesions, overall sensitivity of MRCP was 97.73%, specificity was 95.83% with an accuracy of 97.06%. MRCP had 94.74% sensitivity, 93.88% specificity, 94.12% accuracy in the diagnosis of choledocholithiasis, and 66.67% sensitivity, 98.39% specificity, and 95.59% accuracy in the diagnosis of benign strictures. For malignant lesions, accuracy, sensitivity, and specificity of MRCP were 97.06%, 95.83%, and 97.73%. MRCP is a highly reliable, accurate, non-invasive imaging technique and has a high sensitivity for the evaluation of aetiologies of obstructive jaundice.

The Fluorescence in situ hybridization (FISH): types and application: a review

The macromolecule identification method known as fluorescence in situ hybridization (FISH) is regarded as a recent development in the study of cytology. It was first created as a physical mapping method to identify genes inside chromosomes. Later, biological and medical studies benefited from the precision and adaptability of FISH. This attractive method offers a level of resolution in between chromosomal studies and DNA analysis. A hybridizing DNA probe used in FISH can either be directly or indirectly labeled. Fluorescent nucleotides are employed in direct labeling, whereas reporter molecules used in indirect labeling are afterwards recognized through affinity molecules, fluorescent antibodies, or other means. An excessively high number of chromosomes in a cell, unique gene fusions, or the loss of a chromosomal segment or an entire chromosome are examples of genetic disorders that can be detected with FISH. It is also used in a variety of scientific projects, including gene mapping and the discovery of fresh oncogenes. This article examines the FISH idea, its use, and its benefits in medical research.

Molecular insights into the effects of focused ultrasound mechanotherapy on lipid bilayers: Unlocking the keys to design effective treatments

Administration of focused ultrasounds (US) represents an attractive complement to classical therapies for a wide range of maladies, from cancer to neurological pathologies, as they are non-invasive, easily targeted, their dosage is easy to control, and they involve low risks. Different mechanisms have been proposed for their activity but the direct effect of their interaction with cell membranes is not well understood at the molecular level. This is in part due to the difficulty of designing experiments able to probe the required spatio-temporal resolutions. Here we use Molecular Dynamics (MD) simulations at two resolution levels and machine learning (ML) classification tools to shed light on the effects that focused US mechanotherapy methods have over a range of lipid bilayers. Our results indicate that the dynamic-structural response of the membrane models to the mechanical perturbations caused by the sound waves strongly depends on the lipid composition. The analyses performed on the MD trajectories contribute to a better understanding of the behavior of lipid membranes, and to open up a path for the rational design of new therapies for the long list of diseases characterized by specific lipid profiles of pathological membrane cells.

A registry-based population study of the HLA in Québec, Canada.

As part of the worldwide effort to better characterize HLA diversity in populations, we have studied the population of Québec in Canada. This province has been defined by a complex history with multiple founder effects and migration patterns. We analyzed the typing data of 3806 individuals registered in Héma-Québec's Registry, which covered most administrative regions in Québec. Typing information was resolved at the second field level of resolution by next-generation sequencing (NGS) or by Sanger sequencing. We used the HLA-net.eu GENE[RATE] tools to estimate allele and two-locus haplotype frequencies for HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1, as well as Hardy-Weinberg equilibrium (HWE), selective neutrality, and linkage disequilibrium. The chord genetic distance was also calculated between administrative regions and was visualized using non-metric multidimensional scaling (NMDS) analysis. While most individual regions were in HWE, HWE was rejected for the province considered as a whole. Some regions exhibited signatures of selection, mostly toward an excess of heterozygotes. Allele and haplotype frequencies revealed outlier regions that strongly differed from the other regions. NMDS plots also showed differences between regions. The administrative regions of the province of Québec displayed heterogeneity in their HLA profiles. This heterogeneity was attributable to differing allele and haplotype specificities by region. In particular, regions 02-Saguenay-Lac-Saint-Jean and 01-Bas-St-Laurent diverged from the rest of the regions. The urban regions 06-Montréal and 13-Laval were very diversified in their HLA profiles. Together, these results will help optimize donor recruitment strategies in Québec.

SEESAW: detecting isoform-level allelic imbalance accounting for inferential uncertainty

Detecting allelic imbalance at the isoform level requires accounting for inferential uncertainty, caused by multi-mapping of RNA-seq reads. Our proposed method, SEESAW, uses Salmon and Swish to offer analysis at various levels of resolution, including gene, isoform, and aggregating isoforms to groups by transcription start site. The aggregation strategies strengthen the signal for transcripts with high uncertainty. The SEESAW suite of methods is shown to have higher power than other allelic imbalance methods when there is isoform-level allelic imbalance. We also introduce a new test for detecting imbalance that varies across a covariate, such as time.

Two structurally defined Aβ polymorphs promote different pathological changes in susceptible mice.

Misfolded Aβ is involved in the progression of Alzheimer's disease (AD). However, the role of its polymorphic variants or conformational strains in AD pathogenesis is not fully understood. Here, we study the seeding properties of two structurally defined synthetic misfolded Aβ strains (termed 2F and 3F) using in vitro and in vivo assays. We show that 2F and 3F strains differ in their biochemical properties, including resistance to proteolysis, binding to strain-specific dyes, and in vitro seeding. Injection of these strains into a transgenic mouse model produces different pathological features, namely different rates of aggregation, formation of different plaque types, tropism to specific brain regions, differential recruitment of Aβ40 /Aβ42 peptides, and induction of microglial and astroglial responses. Importantly, the aggregates induced by 2F and 3F are structurally different as determined by ssNMR. Our study analyzes the biological properties of purified Aβ polymorphs that have been characterized at the atomic resolution level and provides relevant information on the pathological significance of misfolded Aβ strains.