Specific Changes Research Articles

Key Account Management as a Differentiator in Trade-offs: The Case of Universal Heater Industries

The case narrates a typical business-to-business scenario wherein the customer (Bodha Constructions) calls for a fresh tender for the water heater supply. Universal Heater Industries (UHI), the current vendor, has won the price agreement for three years in the past, and seemingly has done a terrific job. UHI is surprised by the turn of events on the fresh tender, as their previous price agreement gave them an entitlement to a 15% price hike after three years. The new development of a fresh tender with a minor specification change put UHI’s plans in a quandary. The case depicts the tactics played by a large customer in pushing a vendor to align to new expectations despite a pre-agreed price hike.

Development of Risk Informed Aging Management Program in Decommissioning

Abstract This paper proposes to solve the issues related to aging management program (AMP) during the decommissioning phase by using risk information. The AMP for the decommissioning plants has not been established while the number of permanently shut down and decommissioned nuclear power plants are increasing in the world. The first issue is the change of the functional importance of the safety systems at the beginning of decommissioning. We propose to evaluate the importance using the probabilistic risk assessment (PRA) model with the change of specification in the decommissioning plant and to determine new importance grade. The second issue is to make the maintenance based on the appropriate risk information. This risk information should be based on the progress of decommissioning, reflected and evaluated in the PRA model, as well as information obtained from maintenance inspections, including the ROP process, and failure experience during routine operation. To address these issues, the maintenance program in decommissioning that uses the evaluation of risk information according to the decommissioning phase is proposed in this paper.

Embryo sac cellularization defects lead to supernumerary egg cells and twin embryos in Arabidopsis thaliana

Arabidopsis lines with loss-of-function mutation in Embryo sac-specific Pectin MethylEsterase Inhibitor (Atepmei) gene showed seed sterility with embryo sac cellularization defects. Examination of tissue-cleared mature ovules revealed irregularly positioned nuclei/embryos within the embryo sacs. Egg cell-specific marker (DD45) expression analysis confirmed the presence of multiple egg cells in the mutant embryo sacs. These supernumerary egg cells were functional as evident from the production of twin embryos when supernumerary sperm cells were provided. The results of ruthenium red and tannic acid-ferric chloride staining of developing Atepmei mutant ovules showed that cell wall formation and maintenance were altered around embryo sac nuclei, which also coincided with change in the gamete specification. This report implicates the role of cell walls in gamete cell fate determination by altering cell-cell communication. Our analysis of the twin-embryo phenotype of epmei mutants also sheds light on the boundary conditions for double fertilization in plant reproduction.

Introduction to CRISPR and Its Use in Drosophila.

The preeminence of Drosophila genetics has led to key discoveries in biology across a variety of fields and disciplines. The advent of CRISPR gene editing has expanded the toolkit of genetic reagents that can be applied to manipulate and observe genes, RNAs, and proteins in an in vivo context. This review describes CRISPR and its use as a transformative gene editing tool in Drosophila We focus on the canonical pathway in which the Cas9 nuclease is directed to specific sequences by guide RNA (gRNA), where cleavage leads to DNA repair by one of two main cellular pathways: nonhomologous end joining (NHEJ) or homology-directed repair (HDR). The error-prone NHEJ pathway can be appropriated to disrupt targeted sequences, enabling a variety of loss-of-function studies. Induction of the HDR pathway allows precise editing, including defined deletions, the introduction of specific sequence changes, and the incorporation of fluorescent and epitope tags. These approaches have increased the power of Drosophila genetics and been successfully used to conduct in vivo structure-function studies, study disease-associated variants, and follow protein dynamics.

Comapping Cellular Content and Extracellular Matrix with Hemodynamics in Intact Arterial Tissues Using Scanning Immunofluorescent Multiphoton Microscopy.

Deviation of blood flow from an optimal range is known to be associated with the initiation and progression of vascular pathologies. Important open questions remain about how the abnormal flow drives specific wall changes in pathologies such as cerebral aneurysms where the flow is highly heterogeneous and complex. This knowledge gap precludes the clinical use of readily available flow data to predict outcomes and improve treatment of these diseases. As both flow and the pathological wall changes are spatially heterogeneous, a crucial requirement for progress in this area is a methodology for acquiring and comapping local vascular wall biology data with local hemodynamic data. Here, we developed an imaging pipeline to address this pressing need. A protocol that employs scanning multiphoton microscopy was developed to obtain three-dimensional (3D) datasets for smooth muscle actin, collagen, and elastin in intact vascular specimens. A cluster analysis was introduced to objectively categorize the smooth muscle cells (SMC) across the vascular specimen based on SMC actin density. Finally, direct quantitative comparison of local flow and wall biology in 3D intact specimens was achieved by comapping both heterogeneous SMC data and wall thickness to patient-specific hemodynamic results.

GO-DICE: Goal-Conditioned Option-Aware Offline Imitation Learning via Stationary Distribution Correction Estimation

Offline imitation learning (IL) refers to learning expert behavior solely from demonstrations, without any additional interaction with the environment. Despite significant advances in offline IL, existing techniques find it challenging to learn policies for long-horizon tasks and require significant re-training when task specifications change. Towards addressing these limitations, we present GO-DICE an offline IL technique for goal-conditioned long-horizon sequential tasks. GO-DICE discerns a hierarchy of sub-tasks from demonstrations and uses these to learn separate policies for sub-task transitions and action execution, respectively; this hierarchical policy learning facilitates long-horizon reasoning.Inspired by the expansive DICE-family of techniques, policy learning at both the levels transpires within the space of stationary distributions. Further, both policies are learnt with goal conditioning to minimize need for retraining when task goals change. Experimental results substantiate that GO-DICE outperforms recent baselines, as evidenced by a marked improvement in the completion rate of increasingly challenging pick-and-place Mujoco robotic tasks. GO-DICE is also capable of leveraging imperfect demonstration and partial task segmentation when available, both of which boost task performance relative to learning from expert demonstrations alone.

Recent advancements in the role of histone acetylation dynamics to improve stress responses in plants.

In eukaryotes, transcriptional regulation is determined by the DNA sequence and is facilitated through sophisticated and complex chromatin alterations and histone remodelling. Recent research has shown that the histone acetylation dynamic, an intermittent and reversible substitution, constitutes a prerequisite for chromatin modification. These changes in chromatin structure modulate genome-wide and specific changes in response to external and internal cues like cell differentiation, development, growth, light temperature, and biotic stresses. Histone acetylation dynamics also control the cell cycle. HATs and HDACs play a critical role in gene expression modulation during plant growth and response to environmental circumstances. It has been well established that HATs and HDACs interact with various distinct transcription factors and chromatin-remodelling proteins (CRPs) involved in the transcriptional regulation of several developmental processes. This review explores recent research on histone acyltransferases and histone deacetylases, mainly focusing on their involvement in plant biotic stress responses. Moreover, we also emphasized the research gaps that must be filled to fully understand the complete function of histone acetylation dynamics during biotic stress responses in plants. A thorough understanding of histone acetylation will make it possible to enhance tolerance against various kinds of stress and decrease yield losses in many crops.

Occupational challenges: burnout syndrome and brazilian legislation

The article addresses the intersection between Burnout Syndrome and changes in Brazilian legislation, offering a holistic view of the clinical, psychological and legal implications of this phenomenon in the workplace. By exploring the trajectory of Burnout Syndrome as a new occupational condition, the analysis highlights the evolution of legal perspectives in Brazil. Using a desk research approach, the study reviews Brazilian legislation and analyzes related studies, revealing increasing attention to mental health and specific changes in legislation to protect workers. Furthermore, the ethical discussion and employers' responsibilities are addressed, expanding the scope of the analysis. The research contributes to an ongoing dialogue about mental health, legislation and work practices, promoting a deeper understanding and prevention of Burnout in Brazilian professional environments.

HEAT STRESS IN CITRUS: A MOLECULAR FUNCTIONAL AND BIOCHEMICAL PERCEPTION

Misfortunes caused by high temperatures compel us to more readily comprehend the physiological, hormonal, and sub-atomic systems of reactions, particularly in humid and subhumid yields such as citrus organic products that are accustomed to specific conditions. Heat stress is accustomed to drought and many other environmental factors affecting Citriculture. We observe the role of Rubisco, antioxidant enzymes, HSPs, physiological changes in plasma membranes, and the role of ABA and SA under heat stress in citrus. Not-with-standing essential exploration, developing and utilizing new and well-developed citrus rootstocks is an essential element for the regulation, according to ecological circumstances. Rootstocks are essential in controlling how plants react to changing environmental factors, such as heat stress. They transfer beneficial features and increase stress tolerance, which helps citrus plants be more resilient overall. The duration of growth, yield, fruit quality, and tolerance to biotic and abiotic challenges are only a few of the characteristics of citrus horticulture that can be significantly improved using the right rootstocks. Enhancing citrus fruits' resistance to unfavorable environmental circumstances is urgently needed due to climate change. We can learn more about how different rootstocks affect the scion's capacity to withstand abiotic pressures by examining the metabolic responses caused by those rootstocks. Because of its increased antioxidant capacity, improved stomatal control, and storage of protective proteins, Carrizo citrange, for instance, demonstrates superior resilience to heat stress when compared to Cleopatra mandarin. The combined impacts of heat and drought on citrus vegetation differ from the effects of each stress alone. Specific metabolic changes are occur, which agree with findings from other plant research looking at the combined impacts of stress on physiology, transcriptome, proteome, and metabolome. When using rootstocks like Sunki Maravilha mandarin under drought stress, important metabolites such as galactinol, raffinose, and SA can be enhanced in scions through grafting. On the other hand, the Cleopatra rootstock alters the metabolism of the scion, resulting in lower quantities of the amino acids galactinol, raffinose, proline, phenylalanine, and tryptophan, which could lead to undesired characteristics. These results highlight the value of continued research to solve the problems brought on by climate change and provide light on the role of rootstocks in citriculture.

Ribosome profiling reveals downregulation of UMP biosynthesis as the major early response to phage infection.

The ribosome profiling technology has provided invaluable insights for understanding cellular translation and eukaryotic viral infections. However, its potential for investigating host-phage interactions remains largely untapped. Here, we applied ribosome profiling to Lactococcus cremoris cultures infected with sk1, a major infectious agent in dairy fermentation processes. This revealed a profound downregulation of genes involved in pyrimidine nucleotide synthesis at an early stage of phage infection, suggesting an anti-phage program aimed at restricting nucleotide availability and, consequently, phage propagation. This is consistent with recent findings and contributes to our growing appreciation for the role of nucleotide limitation as an anti-viral strategy. In addition to capturing rapid alterations in gene expression levels, we identified translation occurring outside annotated regions, as well as signatures of non-standard translation mechanisms. The gene profiles revealed specific changes in ribosomal densities upon infection, reflecting alterations in the dynamics of the translation process.

Comparative analysis of in-silico tools in identifying pathogenic variants in dominant inherited retinal diseases.

Inherited retinal diseases (IRDs) are a group of rare genetic eye conditions that cause blindness. Despite progress in identifying genes associated with IRDs, improvements are necessary for classifying rare autosomal dominant (AD) disorders. AD diseases are highly heterogenous, with causal variants being restricted to specific amino acid changes within certain protein domains, making AD conditions difficult to classify. Here, we aim to determine the top-performing in-silico tools for predicting the pathogenicity of AD IRD variants. We annotated variants from ClinVar and benchmarked 39 variant classifier tools on IRD genes, split by inheritance pattern. Using area-under-the-curve (AUC) analysis, we determined the top-performing tools and defined thresholds for variant pathogenicity. Top-performing tools were assessed using genome sequencing on a cohort of participants with IRDs of unknown etiology. MutScore achieved the highest accuracy within AD genes, yielding an AUC of 0.969. When filtering for AD gain-of-function and dominant negative variants, BayesDel had the highest accuracy with an AUC of 0.997. Five participants with variants in NR2E3, RHO, GUCA1A, and GUCY2D were confirmed to have dominantly inherited disease based on pedigree, phenotype, and segregation analysis. We identified two uncharacterized variants in GUCA1A (c.428T>A, p.Ile143Thr) and RHO (c.631C>G, p.His211Asp) in three participants. Our findings support using a multi-classifier approach comprised of new missense classifier tools to identify pathogenic variants in participants with AD IRDs. Our results provide a foundation for improved genetic diagnosis for people with IRDs.

The Specific Molecular Changes Induced by Diabetic Conditions in Valvular Endothelial Cells and upon Their Interactions with Monocytes Contribute to Endothelial Dysfunction.

Aortic valve disease (AVD) represents a global public health challenge. Research indicates a higher prevalence of diabetes in AVD patients, accelerating disease advancement. Although the specific mechanisms linking diabetes to valve dysfunction remain unclear, alterations of valvular endothelial cells (VECs) homeostasis due to high glucose (HG) or their crosstalk with monocytes play pivotal roles. The aim of this study was to determine the molecular signatures of VECs in HG and upon their interaction with monocytes in normal (NG) or high glucose conditions and to propose novel mechanisms underlying valvular dysfunction in diabetes. VECs and THP-1 monocytes cultured in NG/HG conditions were used. The RNAseq analysis revealed transcriptomic changes in VECs, in processes related to cytoskeleton regulation, focal adhesions, cellular junctions, and cell adhesion. Key molecules were validated by qPCR, Western blot, and immunofluorescence assays. The alterations in cytoskeleton and intercellular junctions impacted VEC function, leading to changes in VECs adherence to extracellular matrix, endothelial permeability, monocyte adhesion, and transmigration. The findings uncover new molecular mechanisms of VEC dysfunction in HG conditions and upon their interaction with monocytes in NG/HG conditions and may help to understand mechanisms of valvular dysfunction in diabetes and to develop novel therapeutic strategies in AVD.

Onychoscopy and nailfold capillaroscopy in leprosy: A case–control study

Objectives: Studies have reported significant number of individuals with leprosy develop nail changes of heterogeneous variety. Direct or indirect damage secondary to neural damage, repeated trauma, vascular injury, anemia or following drug therapy have been implicated. In this study, we compared nail changes in cases of leprosy with controls to determine leprosy specific nail changes through detailed onychoscopic evaluation along with nailfold capillaroscopy. Materials and Methods: We performed a case–control study in a tertiary care institute with 30 leprosy patients and 30 age- and sex-matched controls. The study was done over a period of three months from June 2023 to August 2023. Patients were classified as per Ridley-Jopling classification. A detailed clinical examination followed by onychoscopy and proximal nailfold (PNF) capillaroscopy using Dermlite DL4 was done in all the nails of cases and controls. Results: A total of 600 nails of 30 leprosy patients on treatment attending our outpatient department were studied over a span of three months. Nail changes were seen in 26 (86.6%) out of 30 patients of leprosy disease compared to 10 (33.3%) of the controls. The most common nail finding seen in leprosy patients was longitudinal melanonychia followed by leukonychia. Transverse lines, leukonychia, subungual hyperkeratosis, nail discoloration, nail pallor, onychochauxis, subungual hematoma, splinter hemorrhage, and brachyonychia were seen more in cases than in controls, and the difference was statistically significant. The PNF capillaroscopy showed microhemorrhages in eight patients of leprosy while none in controls. Conclusion: Nail changes seen in leprosy are multifactorial. The PNF capillaroscopy showed microhemorrhages, which could be an early feature of vascular changes in leprosy.

Abstract PR-006: Brain metastases roadmap reveals conserved regulatory dynamics rooted in dormant tumor cells

Abstract Capturing comprehensive brain metastasis landscape is critical to the establishment of effective anti-tumor strategies. This study took advantage of single cell multiomics sequencing to profile the molecular and cellular dynamics in tumor cells and associated microenvironment during brain metastasis. Among different primary cancer types, our data suggest that there are conserved yet distinct tumor cell subpopulations, governed by specific changes in gene expression, chromatin accessibility and tumor-stroma interactions. We characterized the conserved tumor subpopulations of brain metastasis with features of: (1) dormancy, (2) enhanced translation and migration, (3) epithelial to mesenchymal transition and (4) high proliferation rate. In line with previous observations, dormant cells exhibit distinct stimulation for interferon and oxidative phosphorylation. Furthermore, our data suggest that dormant tumor cells increase amino acids metabolism and antigen presentation by upregulating HLA class molecules. Stromal and tumor cells interaction network analysis predicted most active ligands that might shape intratumoral heterogeneity. For example, TGFβ signaling induced by immune cells and astrocytes is associated with tumor cell epithelial to mesenchymal transition. Additionally, results suggest the vascular endothelial niche supports brain metastasis proliferation. Interestingly, dormant tumor cells appear to limit cell-cell interactions with the surrounding microenvironment when compared to other tumor cells subpopulations. Despite pronounced cell plasticity, trajectory analysis uncovered a cell progression pattern and its major sequential states and driving genes. Notably, the trajectory embarked with dormant tumor cells at its root and ended with a prevalence of rapidly proliferating tumor cells. As cycling cancer cells arise, we observed a disruption in circadian rhythm regulators activities, indicating that altered circadian regulation may contribute to brain metastasis progression. This work demonstrated that despite a pronounced intratumoral heterogeneity, brain metastases present conserved tumor subpopulations regardless of the patient and primary type. Importantly, the tumor trajectory provides new insights into the regulatory landscape controlling the transition from dormant to proliferating tumor cells. A novel and key finding in this study is the multiomics characterization of the regulatory landscape shaping human brain metastases. Thus, we believe further understanding of these key regulatory elements could lead to novel tumor targets with broad translational potential. Citation Format: Remi Klotz, Yiru Jess Wang, Alexis Zukowski, Frank Attenelo, Srinivas Ramachandran, Min Yu. Brain metastases roadmap reveals conserved regulatory dynamics rooted in dormant tumor cells [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr PR-006.

Abstract A003: Characterizing DNA methylation patterns driving chemotherapy resistance in ovarian high-grade serous carcinoma

Abstract To characterize the role of DNA methylation (DNAm) in chemotherapy response, we analyzed whole-genome DNAm data integrated with transcriptome from 67 samples of 17 patients with ovarian high grade serous carcinoma (HGSC) belonging to the prospective, longitudinal, multi-region DECIDER trial (NCT04846933). We used a novel decomposition method, which allows separating the effects of tumor microenvironment and treatment, tissue, and patient specific changes, facilitating the integration of the heterogeneous collection of samples. We firstly characterized DNAm alterations between tissue sites. Our results show that the cancer spread from tubo-ovarian sites to metastatic deposits is accompanied by moderate changes that employ cell junctions and focal adhesions. The most drastic change in the tissue intrinsic DNAm profiles implicated upregulation of members of the ATP-binding-cassette (ABC) family of transporters, including such multidrug resistance-associated genes as ABCC2, ABCC3, and ABCC4 in omentum. We then proceeded to characterize the DNAm changes during treatment. Our results reveal that DNAm plays a distinct role in emergence, driving, and regulation of both preexisting and acquired resistance to chemotherapy. We observed that patient-specific DNAm background shows enormous intra- and intertumor heterogeneity and sustains multiple driver mechanisms to resist chemotherapy-induced cell death already prior to treatment. We also observed that neoadjuvant chemotherapy (NACT) results in emergence of resistance via acquired, tissue specific DNAm alterations in DNA damage repair, apoptosis, cellular senescence, and drug efflux. Pathway analyses show that treatment-naïve tumors from patients with poor treatment outcome have DNAm-induced upregulation of key resistance promoting signaling pathways, such as PI3K/Akt, mTOR, and Rap1 cascades. Hypoxic transcriptional program activated via HIF-1 signaling was significantly altered in poorly responding patients, accompanied by changes in extracellular matrix instigated by integrins ITGB1 and ITGA5. Tumors of patients with refractory disease demonstrated DNAm changes in genes involved in tumor-promoting chronic inflammation driven by elevation of tumor necrosis factor. NACT treatment resulted in very few changes to these DNA aberrations and no acquired mechanisms, suggesting that intrinsic DNAm patient profiles accommodate multiple drivers for tumor progression and chemoresistance. In conclusion, using a large whole-sequencing DNAm dataset we elucidated the major underlying mechanisms of acquired platinum resistance, which provide possible targets for improving platinum sensitivity. Validation of these results and the intrinsic ability of HGSC to resist platinum-based treatment is currently on-going in our recently sequenced DNAm batch consisting of 400 samples of 135 HGSC patients. Citation Format: Alexandra Lahtinen, Giovanni Marchi, Kari Lavikka, Giulia Micoli, Susanna Holmström, Elsi Pöllänen, Ilari Maarala, Daria Afenteva, Yilin Li, Taru A. Muranen, Jaana Oikkonen, Kaisa Huhtinen, Anni Virtanen, Johanna Hynninen, Antti Häkkinen, Sampsa Hautaniemi. Characterizing DNA methylation patterns driving chemotherapy resistance in ovarian high-grade serous carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A003.

Abstract B057: Oncogenic Foxl2 directs enhancer reprogramming and changes in 3D genome structure in ovarian granulosa cell tumors

Abstract Background: Adult-type granulosa cell tumors (aGCTs) are a rare monogenic disease. Nearly all aGCTs carry a missense point mutation in the Forkhead domain containing FOXL2 (Foxl2 p.C134W) transcription factor, but the oncogenic mechanism of this mutation is unknown. Other Forkhead family transcription factors have well-described “pioneer” activity, binding to compacted, nucleosome-bound DNA and increasing accessibility for other regulatory proteins. Objectives: To investigate if oncogenic Foxl2-C134W has pioneering activity and if mutant Foxl2 operates its oncogenic activity through enhancer reprogramming. Methods: CRISPR/Cas9 editing was used to generate isogenic granulosa cell tumor cells lacking either the FOXL2 wild-type allele (single knock-out; SKO) or both the mutant and wild-type FOXL2 alleles (double knock-out; DKO). ATAC-Seq and endogenous Foxl2 ChIP-Seq were performed on these isogenic lines to determine the differential chromatin accessibility at Foxl2-bound regulatory regions across genotypes. Promoter capture HiC was performed using a bespoke genome-wide hybrid capture probe set, CHiCAGO was used to identify significant HiC interactions, and an activity-by-contact model was constructed to identify enhancer elements bound by endogenous Foxl2-C134W and determine their target promoter contact frequency (promoter capture HiC) and enhancer activity (geometric mean of H3K27ac and ATACseq signal. Results: Endogenous ChIP-seq of Foxl2-C134W from the SKO cell line identified 1147 high-confidence peaks. De novo motif discovery identified the canonical Foxl2 binding motif (TGTTTACATT, P = 1.4 × 10−7) in 44.9% of peaks, as well as a novel variant motif (TGTTTTGTCT, P = 6.7 × 10−15) in 68.5% of peaks. Median chromatin accessibility at Foxl2-C134W peak regions, as measured by ATAC-seq, was significantly decreased in the DKO cells compared to either SKO or parental cell lines (P < 2 × 10-16 for both comparisons). Decreased chromatin accessibility at Foxl2-C134W ChIP-seq peaks in the DKO cells was driven by peaks containing the novel variant Foxl2 binding motif. Promoter capture HiC through activity-by-contact model identified promoter-enhancer interactions lost in the DKO cell line involving several genes, including ADAMTS5, FOXF2, and PRICKLE1 (adjusted P < 0.05). Conclusion: Foxl2-C134W exhibits “pioneering” activity, increasing chromatin accessibility at key gene regulatory elements with associated re-programming of promoter-enhancer interactions. The oncogenic mechanism of Foxl2-C134W in granulosa cell tumors may involve changes in DNA binding specificity, re-directing this pioneering function to sites containing a novel variant Foxl2 binding motif. Citation Format: Veena K. Vuttaradhi, Eleonora Khlebus, Thomas Welte, Barrett Lawson, Robert Tyler Hillman. Oncogenic Foxl2 directs enhancer reprogramming and changes in 3D genome structure in ovarian granulosa cell tumors [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B057.

Abstract B089: Intratumoral expression analysis of mast cells in high grade serous ovarian cancer

Abstract Objective: The goal of this study is to examine intratumoral expression and phenotypic changes in mast cells following neoadjuvant chemotherapy (NACT) exposure in high grade serous ovarian cancer (HGSOC). Methods: 37 HGSOC matched pre-and post-NACT patient tumors were stained with a commercially available mast cell hemotoxic-based kit and both intratumoral and stromal mast cells were quantified. Immunohistochemistry was employed to stain for histamine in 19 matched HGSOC patient tumors and mean intensity and integrated optical density was quantified using Image J. Kaplan Meier curve analysis was employed to determine the relationship between mast cells levels and progression-free survival (PFS). Immortalized human mast cells, LUVA were treated with carboplatin and paclitaxel and specific genomic changes were measured by quantitative PCR (qPCR). Results. Mast cells were more prominently expressed in intraepithelial regions compared to stromal cells, however both populations were significantly (p<0.05) increased following NACT. Total mast cells stratified by upper and lower quartile demonstrated that higher levels were significantly (p<0.05) associated with improved PFS. Furthermore, histamine, a marker of mast cell degranulation was significantly (p<0.05) increased in HGSOC tumors post-NACT and significantly correlated (r=0.553, p=0.013) with the change in total mast cells. Following chemotherapy treatment LUVA cells demonstrated an over 7-fold increase in amphiregulin (AREG) expression (p<0.01), a key marker of mast cell activation. Interestingly, angiogenic and pro-tumorigenic factors IL-10, IL-8, and VEGFA exhibited no significant differences in expression following chemotherapy exposure. Conclusions: Overall, our findings suggest a correlation in NACT exposure and intratumoral mast cell recruitment, degranulation, and activation. Further studies include investigating differences in specific tumorigenic genes and cell signaling pathways in mast cells pre- and post- NACT, as well as determining if mast cells can impact HGSOC chemotherapy response. Citation Format: Julia McAdams, Jasmine Ebott, Payton De La Cruz, Nicole E. James. Intratumoral expression analysis of mast cells in high grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B089.

Psychosis in Alzheimer’s disease is associated with specific changes in brain MRI volume, cognition and neuropathology

Psychosis in Alzheimer’s Disease (AD) is prevalent and indicates poor prognosis. However, the neuropathological, cognitive and brain atrophy patterns underlying these symptoms have not been fully elucidated. In this study, we evaluated 178 patients with AD neuropathological change (ADNC) and ante-mortem volumetric brain magnetic resonance imaging (MRI). Presence of psychosis was determined using the Neuropsychiatric Inventory Questionnaire. Clinical Dementia Rating Sum-of-boxes (CDR-SB) was longitudinally compared between groups with a follow-up of 3000 days using mixed-effects multiple linear regression. Neuropsychological tests closest to the time of MRI and brain regional volumes were cross-sectionally compared. Psychosis was associated with lower age of death, higher longitudinal CDR-SB scores, multi-domain cognitive deficits, higher neuritic plaque severity, Braak stage, Lewy Body pathology (LB) and right temporal lobe regional atrophy. Division according to the presence of LB showed differential patterns of AD-typical pathology, cognitive deficits and regional atrophy. In conclusion, psychosis in ADNC with and without LB has clinical value and associates with subgroup patterns of neuropathology, cognition and regional atrophy.

Effect of non-thermal effects in microwave heating on the rheology and chemical properties of petroleum asphalt

This study systematically analyses the rheological properties of typical petroleum asphalt heated by microwaves at different temperatures through viscosity, penetration, dynamic shear, low-temperature bending, and other rheological tests. The results show that the non-thermal effect of microwaves enhances the fluidity of petroleum asphalt in the high-temperature viscous flow state, becomes softer in the medium-temperature viscoelastic state, and becomes hard and brittle in the low-temperature glassy state. The effect of microwaves also causes some specific changes in the properties of bitumen, including softening point and glass transition temperature in the opposite direction, as well as a large difference in the response of bitumen of different viscosities. The chemical changes in microwave-heated bitumen were analyzed using component tests and microscopic observation. It was found that microwave heating homogenized and dispersed the asphaltene aggregates into small particles, with the heavy components significantly reduced and the light components increased.

Evolutionary change in flight-to-light response in urban moths comes with changes in wing morphology.

Moths and other insects are attracted by artificial light sources. This flight-to-light behaviour disrupts their general activity focused on finding resources, such as mating partners, and increases predation risk. It thus has substantial fitness costs. In illuminated urban areas, spindle ermine moths Yponomeuta cagnagella were reported to have evolved a reduced flight-to-light response. Yet, the specific mechanism remained unknown, and was hypothesized to involve either changes in visual perception or general flight ability or overall mobility traits. Here, we test whether spindle ermine moths from urban and rural populations-with known differences in flight-to-light responses-differ in flight-related morphological traits. Urban individuals were found to have on average smaller wings than rural moths, which in turn correlated with a lower probability of being attracted to an artificial light source. Our finding supports the reduced mobility hypothesis, which states that reduced mobility in urban areas is associated with specific morphological changes in the flight apparatus.