Enriched Regions Research Articles

An enrichment system for glycoproteins using microfluidic paper-based analytical device with colorimetric detection

We introduce a facile method for glycoprotein enrichment, separation, and detection using microfluidic paper-based analytical devices (μPADs). The μPADs comprise two distinct components: the enrichment region (Chip I) and the detection section (Chip II). The reusable Chip I is fabricated by immobilizing 3-aminophenylboronic acid (APBA) onto a circular paper substrate, demonstrating exceptional glycoprotein affinity. In disposable Chip II, glycoproteins react with periodic acid, generating carbonyl compounds that produce a purple-colored product upon reacting with the Schiff reagent. Alterations in color intensity are captured using an ordinary cell phone and are subsequently analyzed using Photoshop software. Observations note a linear increase in average color intensities from 1.0 × 10−3 to 5.0 × 10−3 mol/L, with an R2 value of 0.9927. The relative standard deviations (RSDs) of inter-day (n = 5) and intra-day (n = 5) assessments stand at 1.5 % and 1.4 %, respectively. Our proposed approach can effectively enrich an ovalbumin (OVA) solution with concentrations as low as 1.0 × 10−11 mol/L, resulting in enrichment rates of 107 to 108 times. The interference deviations of five substances relative to OVA lie within the range of − 2.0 % to + 2.0 %. The methodology successfully enriches glycoproteins from egg white samples diluted by a factor of 1 × 106, demonstrating that the proposed method is remarkably suitable for enriching glycoproteins from authentic samples.

Abstract 2580: Targeting chromatin in ovarian cancer stem cells

Abstract The dynamic organization of chromatin, governed by epigenetic modifiers, critically regulates cell plasticity and determines cell fate in both normal and malignant stem cells. We hypothesized that chromatin architecture plays a role in regulating transcriptional heterogeneity in ovarian cancer stem cells (OCSCs) to maintain stemness and chemoresistance. PWS microscopy showed that ALDH+ OCSCs derived displayed higher nuclear fractal dimension D signals (P<0.05) than ALDH- non-OCSCs, indicating that chromatin in OCSCs possesses higher packing compared to non-OCSCs. Cut & TAG Sequencing showed that of the 3606-histone repressive H3K27m3 enriched regions (P<0.05, fold change >2), 3208 were detected in OCSCs while 398 peaks were present in non-OCSCs, consistent with findings supporting high D features in OCSCs. The active mark H3K4me3 was enriched at the promoter of stemness-associated genes, including SOX2, ALDH1A3, and FZD7 in OCSCs; and the repressive histone mark H3K27me3 was enriched at the promoter of the epithelial cell marker CDH1 in OCSCs. These results support that the chromatin of OCSCs contains open genomic regions, corresponding to stemness-associated genes and repressed regions associated with genes related to differentiation. RNA sequencing indicated that the coefficient of variance (COV) reflecting transcriptional heterogeneity in OCSCs was higher than in non-OCSCs at baseline. In response to platinum, genes with low baseline expression in OCSCs were most upregulated, supporting increased transcriptional heterogeneity in response to chemotherapy. Inhibitors of epigenetic modifiers (DNMTi, EZH2i, and Dot1Li) induced chromatin re-organization in OCSCs and promoted OCSCs transition toward differentiation, supporting that stemness-associated chromatin structure is targetable. We demonstrated that a Dot1L inhibitor (Dot1Li) targeted OCSCs by decreasing chromatin packing D, resulting in decreased transcriptional heterogeneity. In conclusion, OCSCs harbor highly packed chromatin, contributing to chemoresistance and cell plasticity. Epigenetic modifiers (such as Dot1Li) inhibit stemness by regulating chromatin organization and transcriptional malleability. Citation Format: Yinu Wang, Jane Frederick, Yaqi Zhang, Elizabeth Thomas Bartom, Greta Bauer, Edward Tanner, Vadim Backman, Daniela Matei. Targeting chromatin in ovarian cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2580.

Abstract 6604: Spatial transcriptomics delineates tumor heterogeneity in NACT triple-negative breast cancer

Abstract BACKGROUND: Triple-Negative Breast Cancer (TNBC) is a highly aggressive subtype of breast cancer and only ~40% of TNBC patients achieve a pathological complete response (pCR) following neoadjuvant chemotherapy (NACT). Since molecular heterogeneity of TNBC may contribute to variable responses to NACT, we aimed to deconvolute TNBC’s histological and spatial transcriptomics (ST) patterns. METHODS: In total, 90 pre-treatment biopsies were collected from NACT-treated TNBC patients from archival samples and the ongoing FORCE (NCT03238144) clinical trial at Guy’s Hospital, London, UK. Of these, 38 achieved pCR (Responder), 46 had residual disease (Non-Responder) whilst 6 are currently undergoing NACT; 46 post-treatment surgical resections were collected from Non-Responders.Each sample was H&E stained, imaged, and annotated by a pathologist. A 6-digit classifier was designed to capture the histology of each region of interest (ROI), characterizing the tumour region, epithelial type and immune cell localization, population, distribution, and abundance.H&Es were used to guide ST profiling of serial sections which was performed on the GeoMx Digital Spatial Profiler. Tissues were stained with fluorescent antibodies against PanCK and CD45 to visualize the tissue, select ROIs and illuminate spatially resolved tumor and immune-enriched compartments, defined as PanCK+/CD45- and PanCK-/CD45+, respectively.Data analysis was performed in R 4.3.1 using the limma, dplyr, EdgeR, GeoMx Tools, GeoMx Workflows, RUV4, Spatial Experiment, SpatialDecon and GSVA packages, facilitating quality control, batch correction, differential and topographical gene expression, immune cell deconvolution and gene set enrichment analysis (GSEA), respectively. RESULTS: To date, we have performed ST profiling of 120 TNBC samples from 82 patients (46 Non-Responders; 36 Responders), totaling 3917 tumor or immune-cell enriched regions. Preliminary analyses revealed KEGG pathways involved in tissue adhesion are upregulated in tumor compartments of Non-Responders compared to Responders, whilst those involved in genomic integrity are suppressed. Unsupervised clustering of PanCK+CD45- regions in Non-Responders identified tumor clusters present in both pre- and post-NACT samples, suggesting potential chemo-resistant properties. Moreover, immune cell deconvolution of the PanCK-/CD45+ regions revealed spatially distinct patters of immune cell composition mapped to histological annotations identified by our ROI classifier. CONCLUSION: (S)Large scale ST of TNBC before and after NACT reveals novel patterns associated with response to treatment. We have designed a novel ROI classifier to spatially resolved transcriptomes of histological features, as such provide an in-depth characterization of the histo-genomics of TNBC. Citation Format: Isobelle Wall, Jelmar Quist, Sarah Pinder, KCL Cancer Biobank, Sheeba Irshad, Cheryl Gillet, Victoria Seewaldt, Kavitha Mukund, David Frankhouser, Shankar Subramaniam, Maddy Parsons, Anita Grigoriadis. Spatial transcriptomics delineates tumor heterogeneity in NACT triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6604.

Triboelectric Charging Properties of the Functional Groups of Common Pharmaceutical Materials Using Density Functional Theory Calculations.

Triboelectrification is a ubiquitous and poorly understood phenomenon in powder processing, particularly for pharmaceutical powders. Charged particles can adhere to vessel walls, causing sheeting; they can also cause agglomeration, threatening the stability of powder formulations, and in extreme cases electrostatic discharges, which present a serious fire and explosion hazard. Triboelectrification is highly sensitive to environmental and material conditions, which makes it very difficult to compare experimental results from different publications. In this work, density functional theory (DFT) is used to investigate the charge transfer characteristics of several functional groups of paracetamol in order to better understand the mechanisms of charging at the nanoscale and the influence of the environmental and material properties on charge transfer. This is achieved by studying the structure and electronic properties at the molecule-substrate interface. Using this molecule-substrate approach, the charging contributions of individual functional groups are explored by examining the Hirschfeld charges, the charge density difference between the molecule and substrate, the density of states, and the location of the frontier orbitals (HOMO and LUMO) of a paracetamol molecule. Charge density difference calculations indicate a significant transfer of charge from the molecule to the surface. Observable regions of electron density enrichment and depletion are evident around the electron-donating and -withdrawing groups, respectively. The density of states for the paracetamol molecule evolves as it approaches the surface, and the band gap disappears upon contact with the substrate. Hirshfeld charge analysis reveals asymmetry in the charge redistribution around the molecule, highlighting the varying charging tendencies of different atoms.

Enrichment of the element free Galerkin method for cracks and notches without a priori knowledge of the analytical singularity order

We introduce a novel enrichment technique for the element free Galerkin (EFG) method to capture the infinite stress field around the crack or notch tip. The singular enrichment bases are built through a weighted residual application of the governing partial differential equation. A special mapping is used to adapt the bases with the singularities. These bases are used in a moving least squares approximation to enrich the smooth polynomial bases of the EFG within the singularity-dominated zone in an intrinsic approach. The novelty of the method is that no a priori knowledge of the analytical singularity order is required to reproduce the singular bases, but they are automatically built during the solution procedure. The diffraction technique has been used to model the discontinuity of the notch tip. The effect of various parameters, including the enriched region size, enrichment factors, nodal distribution and irregularities, has been examined. Validation of the method using available analytical solutions or finite element modeling, revealed that the proposed enrichment is quite effective and accurate for displacement and stress components.

Extended Enrichment for Ultrasensitive Detection of Low‐Frequency Mutations by Long Blocker Displacement Amplification

AbstractDetecting low‐frequency DNA mutations hotspots cluster is critical for cancer diagnosis but remains challenging. Quantitative PCR (qPCR) is constrained by sensitivity, and allele‐specific PCR is restricted by throughput. Here we develop a long blocker displacement amplification (LBDA) coupled with qPCR for ultrasensitive and multiplexed variants detection. By designing long blocker oligos to perfectly match wildtype sequences while mispairing with mutants, long blockers enable 14–44 nt enrichment regions which is 2‐fold longer than normal BDA in the experiments. For wild template with a specific nucleotide, LBDA can detect different mutation types down to 0.5 % variant allele frequency (VAF) in one reaction, with median enrichment fold of 1,000 on 21 mutant DNA templates compared to the wild type. We applied LBDA‐qPCR to detect KRAS and NRAS mutation hotspots, utilizing a single plex assay capable of covering 81 mutations and tested in synthetic templates and colorectal cancer tissue samples. Moreover, the mutation types were verified through Sanger sequencing, demonstrating concordance with results obtained from next generation sequencing. Overall, LBDA‐qPCR provides a simple yet ultrasensitive approach for multiplexed detection of low VAF mutations hotspots, presenting a powerful tool for cancer diagnosis and monitoring.

Enriched Regions of 228Ra Along the U.S. GEOTRACES Pacific Meridional Transect (GP15)

AbstractThe half‐life of 228Ra (5.7 years) aligns well with near‐surface and near‐bottom ocean mixing timescales. Because 228Ra is sourced from sediments, regions of enhanced activity represent water that has recently interacted with sediments on the continental margin or seabed. The GP15 meridional transect from Alaska to Tahiti along152°W encountered several regions in the upper ocean where 228Ra was enriched. These enrichments follow surface and subsurface ocean current patterns and pair with earlier measurements of 228Ra and transient radionuclides to reveal the origins of these enriched regions. An enriched region at Alaska margin stations 1–3 was sourced locally but did not extend to the Alaskan trench at station 4. A large shallow region between 47° and 32°N. was sourced from the west by the North Pacific Current; another shallow enriched region between 11° and 5° N was also sourced from the west by the North Equatorial Countercurrent. Subsurface enrichments (100–400 m) between 18 and 47°N were associated with Central Mode Water and North Pacific Intermediate Water. The 228Ra activities in the upper Pacific were six times lower than activities in the Atlantic. In deep waters the primary enrichment was 27°–47°N. Two stations (32° and 37°N) were especially enriched, having near‐bottom inventories several times greater than other stations. With these two exceptions the remaining Pacific stations exhibited averaged inventories lower than those in the Atlantic. There was one region of enriched 223Ra (half‐life = 11 days) above the Puna Ridge near Hawaii.

Double inclined cracks overlapping effect on mixed stress intensity factors using XFEM object-oriented implementation

The object of research is the Mixed Mode Stress Intensity Factor (MMSIF) of a two-dimensional (2D) plate. With the emergence of modern technologies and advanced innovations which contribute to the development and improvement of the design, implementation and management of construction projects, it has become easier. However, it is very difficult to manufacture components free from unavoidable defects, such as cracks, which lead to material deterioration and ultimately shorten its service life. Based on the process of local enrichment region using partition of unity concept, the extended finite element method (XFEM) has overcome the limitations of the standard FEM method in terms of modeling and numerical simulation of discontinuities (cracks) while gaining its general advantages. This makes XFEM a powerful and widely used digital tool in recent years. One of the most frequently raised problems in the discontinuities field (cracks) is the phenomenon of juxtaposition of multiple cracks in a cracked isotropic plate, which must be studied to determine the extent of its effect on the crack stress intensity factor in order to obtain higher safety reliability. On this basis, an improved object-oriented programming (OOP) with extended finite elements was used because of its great importance and well-known benefits. In this paper, the MMSIF of a 2D plate is determined to show the effect of the out-of-phase orientation of the angle, as well as the effect of the juxtaposition of two inclined cracks. As a result of the research, it is shown that, the convergence between the results obtained in this study with those reported in the literature, and to theoretical values is remarkable, and their close agreement was noted. In the future, based on the object-oriented approach characteristics represented by flexibility, scalability, and modularity, which were explained in this research, this proposed approach can be enriched to include heterogeneous materials modeling, whether linear or nonlinear, crack propagation in dynamics, in addition to Complex 3D industrial problems.

CO2 selective adsorption over O2 on N−doped activated carbon: Experiment and quantum chemistry study

Utilizing flue gas as feedstock for CO2 electro−reduction systems is a promising technology to address problems caused by excessive CO2 emissions. However, the O2 contained in the flue gas has a significant adverse effect on the CO2 reduction. Herein, a facile strategy was proposed to suppress the influence of O2 by constructing a CO2−enriched region. N−doping was demonstrated to be an efficient way to enhance CO2 adsorption selectivity over O2 on activated carbon. The N−doped activated carbon achieved 3.7 times increase in CO2 adsorption selectivity over O2 than that before modification under simulated flue gas atmosphere (75 %N2 + 15 %CO2 + 10 %O2). The distinction in adsorption mechanism between CO2 and O2 was revealed by quantum chemistry study. The increased polarity of the carbon materials favored CO2 adsorption and had less impact on O2 adsorption. The electrostatic interaction between CO2 and carbon material was demonstrated to be enhanced after the introduction of pyridinic N and pyrrolic N, which led to an improvement in the CO2 adsorption capacity. The dispersion interaction, which fully regulated O2 adsorption, was weakened due to the deviation of the O2 adsorption position. This study provided a reference for the subsequent development of CO2 selective adsorption materials.

Clustered surface amino acid residues modulate the acid stability of GH10 xylanase in fungi

Acidic xylanases are widely used in industries such as biofuels, animal feeding, and fruit juice clarification due to their tolerance to acidic environments. However, the factors controlling their acid stability, especially in GH10 xylanases, are only partially understood. In this study, we identified a series of thermostable GH10 xylanases with optimal temperatures ranging from 70 to 90 °C, and among these, five enzymes (Xyn10C, Xyn10RE, Xyn10TC, Xyn10BS, and Xyn10PC) exhibited remarkable stability at pH 2.0. Our statistical analysis highlighted several factors contributing to the acid stability of GH10 xylanases, including electrostatic repulsion, π-π stacking, ionic bonds, hydrogen bonds, and Van der Waals interactions. Furthermore, through mutagenesis studies, we uncovered that acid stability is influenced by a complex interplay of amino acid residues. The key amino acid sites determining the acid stability of GH10 xylanases were thus elucidated, mainly concentrated in two surface regions behind the enzyme active center. Notably, the critical residues associated with acid stability markedly enhanced Xyn10RE’s thermostability by more than sixfold, indicating a potential acid-thermal interplay in GH10 xylanases. This study not only reported a series of valuable genes but also provided a range of modification targets for enhancing the acid stability of GH10 xylanases.Key points• Five acid stable and thermostable GH10 xylanases were reported.• The key amino acid sites, mainly forming two enriched surface regions behind the enzyme active center, were identified responsible for acid stability of GH10 xylanases.• The finding revealed interactive amino acid sites, offering a pathway for synergistic enhancement of both acid stability and thermostability in GH10 xylanase modifications.

Unveiling remarkable hydrogen accumulation near ferrite crack tip: Role of unloading effect

We investigate the effect of stress state and hydrogen traps on hydrogen distribution proximity to ferrite crack tip. The results of hydrogen microprint and microstructure characterization indicate that diffusible hydrogen accumulates within crack wake, but the region of hydrogen enrichment ahead of crack tip is tiny according to Ag distribution. By comparing experimental data and numerical calculations, we conclude that the unloading-induced compressive stress region ahead of the crack tip leads to the formation of an overall diffusible H-depleted zone, thereby inhibiting the forward progression of the Ag enrichment zone ahead of the crack tip, whereas the extended size of Ag clustering area within crack plastic wake is primarily attributed to the level of crack plasticity generating dislocation and vacancy traps.

The effect of site-specific recombinases XerCD on the removal of over-replicated chromosomal DNA through outer membrane vesicles in bacteria.

Outer membrane vesicles (OMVs) are universally produced by Gram-negative bacteria and play important roles in symbiotic and pathogenic interactions. The DNA from the lumen of OMVs from the Alphaproteobacterium Dinoroseobacter shibae was previously shown to be enriched for the region around the terminus of replication ter and specifically for the recognition sequence dif of the two site-specific recombinases XerCD. These enzymes are highly conserved in bacteria and play an important role in the last phase of cell division. Here, we show that a similar enrichment of ter and dif is found in the DNA inside OMVs from Prochlorococcus marinus, Pseudomonas aeruginosa, Vibrio cholerae, and Escherichia coli. The deletion of xerC or xerD in E. coli reduced the enrichment peak directly at the dif sequence, while the enriched DNA region around ter became broader, demonstrating that either enzyme influences the DNA content inside the lumen of OMVs. We propose that the intra-vesicle DNA originated from over-replication repair and the XerCD enzymes might play a role in this process, providing them with a new function in addition to resolving chromosome dimers.IMPORTANCEImprecise termination of replication can lead to over-replicated parts of bacterial chromosomes that have to be excised and removed from the dividing cell. The underlying mechanism is poorly understood. Our data show that outer membrane vesicles (OMVs) from diverse Gram-negative bacteria are enriched for DNA around the terminus of replication ter and the site-specific XerCD recombinases influence this enrichment. Clearing the divisome from over-replicated parts of the bacterial chromosome might be a so far unrecognized and conserved function of OMVs.

Integrative genomic analyses reveal putative cell type-specific targets of the Drosophila ets transcription factor Pointed

The Ets domain transcription factors direct diverse biological processes throughout all metazoans and are implicated in development as well as in tumor initiation, progression and metastasis. The Drosophila Ets transcription factor Pointed (Pnt) is the downstream effector of the Epidermal growth factor receptor (Egfr) pathway and is required for cell cycle progression, specification, and differentiation of most cell types in the larval eye disc. Despite its critical role in development, very few targets of Pnt have been reported previously. Here, we employed an integrated approach by combining genome-wide single cell and bulk data to identify putative cell type-specific Pnt targets. First, we used chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) to determine the genome-wide occupancy of Pnt in late larval eye discs. We identified enriched regions that mapped to an average of 6,941 genes, the vast majority of which are novel putative Pnt targets. Next, we integrated ChIP-seq data with two other larval eye single cell genomics datasets (scRNA-seq and snATAC-seq) to reveal 157 putative cell type-specific Pnt targets that may help mediate unique cell type responses upon Egfr-induced differentiation. Finally, our integrated data also predicts cell type-specific functional enhancers that were not reported previously. Together, our study provides a greatly expanded list of putative cell type-specific Pnt targets in the eye and is a resource for future studies that will allow mechanistic insights into complex developmental processes regulated by Egfr signaling.

Optimal configuration of energy storage for alleviating transmission congestion in renewable energy enrichment region

High-penetration renewable energy development causes transmission congestion in power system operation. Such transmission congestion in short period can be alleviated by energy storage configuration, instead of investing and expanding new transmission lines. This paper presents an optimal configuration method of energy storage for alleviating transmission congestion in renewable energy enrichment region. In order to obtain the characteristics of renewable energy outputs, a scenario generation technique for renewable energy outputs considering spatio-temporal correlation is first proposed. A Monte Carlo-based approach for evaluating the transmission congestion is proposed for identifying the potential locations of energy storage installation. Finally, an optimal configuration method of energy storage based on stochastic programming is proposed for alleviating transmission congestion. Numerical experiments are carried out on a modified IEEE-RTS 24-bus system and a practical 129-bus system. Numerical results show that energy storage can improve the flexibility of power system operation and the utilization of renewable energy generation. Especially, in the practical 129-bus system, the proposed method reduces renewable energy curtailment by 625.26 MWh and 444.43 MWh under fall and winter typical scenarios, respectively. And, investing some energy storage devices is more economical when the duration of transmission congestion is relatively short.

Abstract B032: Spatial proteomics and transcriptomics reveal early immune cell organization in human pancreatic intraepithelial neoplasia

Abstract A common precursor of pancreatic adenocarcinoma (PDAC) are microscopic lesions, termed pancreatic intraepithelial neoplasia (or PanIN). These lesions are initiated at least a decade before overt PDAC forms, thus providing a large window of opportunity to modulate the immune microenvironment before significant pro-carcinogenic signals prevail. To best inform strategies for interception of these precursor lesions, it is critical to understand the quantity and spatial localization of the lymphoid compartment recruited to PanINs compared to PDAC. Here, we report the use of spatial–omics (proteomic and transcriptomics) to evaluate the recruitment of lymphoid cells to PanIN lesions compared to immune–enriched regions of PDAC in a unique cohort of 5 treatment–naïve PDAC patients who underwent resection of their primary pancreas tumor. Using imaging mass cytometry, we found lymphoid populations recruited preferentially to low–grade PanINs compared with normal tissue. This population of predominantly CD4+ T cells in low–grade PanINs was markedly different from the increased Treg and exhausted CD4+ T cell populations found infiltrating in the tumor. Interestingly, our approach to evaluate the spatial localization of these recruited lymphoid populations uncovered their capacity to organize into tertiary lymphoid structures (TLSs). Structurally and functionally immature TLSs were associated with PanIN lesions, while mature TLSs were found adjacent to the invasive tumor border of PDAC. Mature TLSs restricted to the outside of the tumor had markers of proliferation indicating functional capabilities; however, these aggregates also contained immunosuppressive lymphoid subtypes. Signatures of immature PanIN associated TLSs and mature PDAC associated TLSs were recapitulated by the spatial transcriptomics analysis performed on this same cohort. Additionally, the proteomic analysis identified that the immune population restricted to the periphery of the tumor was substantially denser and enriched with greater numbers of naïve CD4+ T cells and central memory T cells than the intra–tumoral population. Together, these data demonstrate that PanINs are capable of recruiting a substantial lymphoid population that can organize into immature TLSs. The quality and quantity of lymphoid cells recruited to PanINs compared to regions inside and surrounding PDAC provides evidence of the dynamic immune microenvironment in response to PanIN–to–PDAC progression. These data provide insight into the immunological landscape of PDAC development and will inform the next generation of strategies to prevent PanIN lesions from progressing to overt PDAC. Citation Format: Melissa R. Lyman, Jacob T. Mitchell, Luciane T. Kagohara, Amanda L. Huff, Daniel Haldar, Sarah Shin, Samantha Guinn, Benjamin Barrett, Gabriella Longway, Alexei Hernandez, Erin Coyne, Xuan Yuan, Lalitya Andaloori, Jiaying Lai, YunZhou Liu, Rachel Karchin, Anuj Gupta, Ashley Kiemen, André Forjaz, Denis Wirtz, Pei-Hsun Wu, Atul Deshpande, Todd Armstrong, Nilofer S. Azad, Elizabeth Thompson, Robert Anders, Won Jin Ho, Elizabeth Jaffee, Elana Fertig, Neeha Zaidi. Spatial proteomics and transcriptomics reveal early immune cell organization in human pancreatic intraepithelial neoplasia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B032.

The effect of micromechanical stresses on vacancy formation and stress-driven mass-transport in polycrystalline Fe–Au alloy

In recent years, a new class of super saturated binary and ternary alloys have demonstrated the ability for the self-healing of creep-induced voids formed at the grain boundaries. However, a clear understanding of the parameters affecting the self-healing mechanism is still not yet complete. One of the main challenges is understanding the effect of microstructure and micromechanical stresses on the redistribution of the healing-solute and vacancies. To this end, we address this issue using a CALPHAD-informed diffusion model coupled with crystal plasticity. In principle, the approach is general and can be used for any binary Fe–X alloy, but in this work Fe–Au binary system is used since it experimentally showed the best healing efficiency. First, we present a multicomponent diffusion model considering cross and stress-driven diffusion. The effect of stress was also considered on the equilibrium vacancy concentration. To investigate the effect of the micromechanical stresses, a representative volume element (RVE) was obtained using the phase-field method. The results showed that the maximum vacancy concentration is at the grain boundaries (GBs) with the highest hydrostatic tensile stresses. These were also the regions of the highest Au enrichment. A crucial factor to achieve this is the high diffusivity of Au compared to the Fe matrix. Increasing the stresses, lead to an increase both in vacancy and Au concentration. The accompanying increased stress triaxiality is suggested to be the reason for the reduced self-healing efficiency observed in previous experimental studies.

Genome-wide association and functional genomic analyses for body conformation traits in North American Holstein cattle.

Body conformation traits are directly associated with longevity, fertility, health, and workability in dairy cows and have been under direct genetic selection for many decades in various countries worldwide. The main objectives of this study were to perform genome-wide association studies and functional enrichment analyses for fourteen body conformation traits using imputed high-density single nucleotide polymorphism (SNP) genotypes. The traits analyzed include body condition score (BCS), body depth (BD), bone quality (BQ), chest width (CW), dairy capacity (DC), foot angle (FAN), front legs view (FLV), heel depth (HDe), height at front end (HFE), locomotion (LOC), rear legs rear view (RLRV), rear legs side view (RLSV), stature (ST), and a composite feet and legs score index (FL) of Holstein cows scored in Canada. De-regressed estimated breeding values from a dataset of 39,135 North American Holstein animals were used as pseudo-phenotypes in the genome-wide association analyses. A mixed linear model was used to estimate the SNP effects, which ranged from 239,533 to 242,747 markers depending on the trait analyzed. Genes and quantitative trait loci (QTL) located up to 100Kb upstream or downstream of the significant SNPs previously cited in the Animal QTLdb were detected, and functional enrichment analyses were performed for the candidate genes identified for each trait. A total of 20, 60, 13, 17, 27, 8, 7, 19, 4, 10, 13, 15, 7, and 13 genome-wide statistically significant SNPs for Bonferroni correction based on independent chromosomal segments were identified for BCS, BD, BQ, CW, DC, FAN, FLV, HDe, HFE, LOC, RLRV, RLSV, ST, and FL, respectively. The significant SNPs were located across the whole genome, except on chromosomes BTA24, BTA27, and BTA29. Four markers (for BCS, BD, HDe, and RLRV) were statistically significant when considering a much stricter threshold for the Bonferroni correction for multiple tests. Moreover, the genomic regions identified overlap with various QTL previously reported for the trait groups of exterior, health, meat and carcass, milk, production, and reproduction. The functional enrichment analyses revealed 27 significant gene ontology terms. These enriched genomic regions harbor various candidate genes previously reported as linked to bone development, metabolism, as well as infectious and immunological diseases.

Dual enhancement in strength and ductility of Fe-rich medium-entropy alloys via an in situ formed heterogeneous multi-phase structure.

In this work, we successfully achieved an exceptional strength-ductility synergy in the brittle Ni0.6CoFe1.4 medium-entropy alloy (MEA) via in situ formation of a heterogeneous structure by doping with Si. The newly developed Ni0.6CoFe1.4Six (x = 0.1, 0.2 and 0.3) MEAs exhibited a multi-phase heterogeneous structure consisting of face-centered cubic (FCC), body-centered cubic (BCC) and NiSi phases, with some B2 nanoparticles precipitated inside the BCC matrix. This multi-phase heterogeneous structure combined with precipitation hardening resulted in a dual enhancement in the strength and ductility of the alloys. Notably, the tensile strength and strain of the Ni0.6CoFe1.4Si0.3 MEA were significantly increased to 1096.9 ± 39.0 MPa and 31.7 ± 0.3%, respectively, which were about 39.9% and 456.1% higher than those of the Ni0.6CoFe1.4 base alloy. Furthermore, density functional theory (DFT) results indicated that the charge redistribution caused by the addition of Si led to the presence of local charge enrichment and depletion regions, which facilitate plastic deformation and increase the ductility. The current study would provide valuable guidance to produce low-cost yet high-performance BCC-structured MEAs.

Failure analysis of large and complex engine blades based on experimental research

On a certain day in December 2022, a GE90 engine equipped by an airline experienced a surge during flight. Ground inspection revealed broken blades of the 9-stage high-pressure compressor. To identify the cause of its fracture failure, the macroscopic fracture surface was first analyzed. Obvious fatigue crack propagation characteristics were found at the blade cross-section. Small pits formed by the impact were observed at the crack source location, indicating that the blade was first formed into a circular arc-shaped impact wound after being impacted by an external object. In the subsequent service process, under continuous vibration, fatigue cracks are formed at the impact point as the crack source and gradually propagate, ultimately leading to blade fracture and failure. To further explore the source of foreign objects causing impact damage, the surface scanning method using energy spectrum analysis was used. An enriched region of C element was found near the impact point. However, due to the lack of conditions for the formation of C combustion products at the compressor location, it can be considered that the foreign object may have come from external sources.

Use of Anomaly Detection algorithms to unveil new physics in Vector Boson Scattering

A new methodology to improve the sensitivity to new physics contributions to the Standard Model processes at LHC is presented. A Variational AutoEncoder trained on Standard Model processes is used to identify Effective Field Theory contributions as anomalies. While the output of the model is supposed to be very similar to the inputs for Standard Model events, it is expected to deviate significantly for events generated through new physics processes. The reconstruction loss can then be used to select a signal enriched region which is by construction independent of the nature of the chosen new physics process. In order to improve further the discrimination power, an adversarial layer is introduced with a cross entropy term added to the loss function, optimizing at the same time the reconstruction of the input variables of the Standard Model and classification of new physics processes. This procedure ensures that the model is optimized for discrimination, with a small price in terms of model dependency to physics process. In this work I will discuss in detail the above-mentioned method using generator level Vector Boson Scattering events produced at LHC assuming an integrated luminosity of 350/fb.