Meaningful Discoveries Research Articles

Harnessing stem cell-based approaches for clinically meaningful discoveries in schizophrenia

Harnessing stem cell-based approaches for clinically meaningful discoveries in schizophrenia

Abstract LB396: The power of NetraAI: Precision medicine in oncology through sub-insight learning from small data sets

Abstract The capabilities of artificial intelligence (AI) and machine learning (ML) are pivotal for refining patient stratification and subtype discrimination in clinical trials. Conventional ML methods often rely on large data sets for meaningful discoveries. NetraAI is a novel ML approach designed and trained to work with smaller data sets. The challenge with smaller data sets is that they do not reflect the totality of the disease that they represent. NetraAI employs a novel approach termed “Sub-Insight Learning”, utilizing validated mathematical methods to analyze even small patient data sets. This allows the system to decompose the data sets into high and low confidence patient subpopulations, enhancing predictive model accuracy and reducing overfitting. Further, the system explains what variables are driving the etiology defining the subpopulations of patients. Using two non-small cell lung cancer (NSCLC) data sets (GSE18842 and GSE10245) consisting of only 104 samples from adenocarcinoma (ADC) and squamous cell carcinoma (SCC), NetraAI distinguished the two subtypes through unique genetic signatures. Notably, nine of the ten variables identified correlate with known NSCLC markers, with PIGX emerging as a novel target. Leveraging protein-protein interaction networks (PPI) revealed connections between PIGX and BACE1. BACE1 has been implicated as a driver of NSCLC brain metastasis. These findings shed light on the biology of membrane proteins and their post-translational modifications, a factor implicated in various diseases, prompting further exploration. NetraAI demonstrates a significant breakthrough in precision medicine for oncology, capable of generating meaningful insights from small data sets. The discovery of novel biomarkers and their implications in cancer and other diseases underline the potential of this AI-driven approach in advancing current research paradigms and patient-specific treatments. Citation Format: Bessi Qorri, Mike J. Tsay, Paul Leonchyk, Larry Alphs, Luca Pani, Joseph Geraci. The power of NetraAI: Precision medicine in oncology through sub-insight learning from small data sets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB396.

Searching and visualizing genetic associations of pregnancy traits by using GnuMoM2b.

Adverse pregnancy outcomes (APOs) are major risk factors for women's health during pregnancy and even in the years after pregnancy. Due to the heterogeneity of APOs, only few genetic associations have been identified. In this report, we conducted genome-wide association studies (GWASs) of 479 traits that are possibly related to APOs using a large and racially diverse study, Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b). To display extensive results, we developed a web-based tool GnuMoM2b (https://gnumom2b.cumcobgyn.org/) for searching, visualizing, and sharing results from a GWAS of 479 pregnancy traits as well as phenome-wide association studies of more than 17 million single nucleotide polymorphisms. The genetic results from 3 ancestries (Europeans, Africans, and Admixed Americans) and meta-analyses are populated in GnuMoM2b. In conclusion, GnuMoM2b is a valuable resource for extraction of pregnancy-related genetic results and shows the potential to facilitate meaningful discoveries.

The cluster D-trace loss for differential network analysis

ABSTRACT A growing literature suggests that gene expression can be greatly altered in disease conditions, and identifying those changes will improve the understanding of complex diseases such as cancers or diabetes. A prevailing direction in the analysis of gene expression studies the changes in gene pathways which include sets of related genes. Therefore, introducing structured exploration to differential analysis of gene expression networks may lead to meaningful discoveries. The topic of this paper is differential network analysis, which focuses on capturing the differences between two or more precision matrices. We discuss the connection between the thresholding method and the D-trace loss method on differential network analysis in the case that the precision matrices share the common connected components. Based on this connection, we further propose the cluster D-trace loss method which directly estimates the differential network and achieves model selection consistency. Simulation studies demonstrate its improved performance and computational efficiency. Finally, the usefulness of our proposed estimator is demonstrated by a real-data analysis on non-small cell lung cancer.

Ferroptosis-mediated immune responses in cancer.

Cell death is a universal biological process in almost every physiological and pathological condition, including development, degeneration, inflammation, and cancer. In addition to apoptosis, increasing numbers of cell death types have been discovered in recent years. The biological significance of cell death has long been a subject of interest and exploration and meaningful discoveries continue to be made. Ferroptosis is a newfound form of programmed cell death and has been implicated intensively in various pathological conditions and cancer therapy. A few studies show that ferroptosis has the direct capacity to kill cancer cells and has a potential antitumor effect. As the rising role of immune cells function in the tumor microenvironment (TME), ferroptosis may have additional impact on the immune cells, though this remains unclear. In this study we focus on the ferroptosis molecular network and the ferroptosis-mediated immune response, mainly in the TME, and put forward novel insights and directions for cancer research in the near future.

Content Analysis On Consumer Complaints On Customer Service Among Agricultural Businesses

This research study employs the methodological approach of content analysis to examine consumer complaints related to service establishments involved in the sale of agricultural products. The primary objective of this study is to extract valuable insights from consumer feedback, identifying prominent concerns and issues. This analysis aims to reveal recurring patterns and pinpoint areas necessitating improvement within the realm of agricultural product retail. To achieve this objective, an extensive dataset of consumer complaints will be amassed from various sources, encompassing online platforms, consumer forums, and social media channels. Additionally, personal interviews were conducted with twenty-four (24) mothers to gather their perspectives on customer service within the agricultural business sector. The data gathered will then undergo a rigorous content analysis procedure. This involves methodically categorizing and subjecting the complaints to thematic analysis. Through the utilization of this methodology, the study seeks to unearth meaningful discoveries that can contribute to enriching the overall consumer experience. Moreover, the findings are intended to offer valuable recommendations for service establishments and stakeholders operating within the agricultural product retail industry.

Genome-wide CRISPR/Cas9 screen identifies etoposide response modulators associated with clinical outcomes in pediatric AML.

Etoposide is used to treat a wide range of malignant cancers, including acute myeloid leukemia (AML) in children. Despite the use of intensive chemotherapeutic regimens containing etoposide, a significant proportion of pediatric patients with AML become resistant to treatment and relapse, leading to poor survival. This poses a pressing clinical challenge to identify mechanisms underlying drug resistance to enable effective pharmacologic targeting. We performed a genome-wide CRISPR/Cas9 synthetic-lethal screening to identify functional modulators of etoposide response in leukemic cell line and integrated results from CRISPR-screen with gene expression and clinical outcomes in pediatric patients with AML treated with etoposide-containing regimen. Our results confirmed the involvement of well-characterized genes, including TOP2A and ABCC1, as well as identified novel genes such as RAD54L2, PRKDC, and ZNF451 that have potential to be novel drug targets. This study demonstrates the ability for leveraging CRISPR/Cas9 screening in conjunction with clinically relevant endpoints to make meaningful discoveries for the identification of prognostic biomarkers and novel therapeutic targets to overcome treatment resistance.

Simplicity: Web-Based Visualization and Analysis of High-Throughput Cancer Cell Line Screens.

High-throughput drug screens are a powerful tool for cancer drug development. However, the results of such screens are often made available only as raw data, which is intractable for researchers without informatics skills, or as highly processed summary statistics, which can lack essential information for translating screening results into clinically meaningful discoveries. To improve the usability of these datasets, we developed Simplicity, a robust and user-friendly web interface for visualizing, exploring, and summarizing raw and processed data from high- throughput drug screens. Importantly, Simplicity allows for easy recalculation of summary statistics at user-defined drug concentrations. This allows Simplicity's outputs to be used with methods that rely on statistics being calculated at clinically relevant doses. Simplicity can be freely accessed at https://oncotherapyinformatics.org/simplicity/.

Guidance on Processing the 10x Genomics Single Cell Gene Expression Assay.

The demand for technologies that allow the study of gene expression at single cell resolution continues to increase. One such assay was launched in 2016 by the US-based company 10x Genomics Inc. Utilizing the power of the single cell on a large scale (Zheng et al. Nat Commun 8:14049, 2017)-capturing thousands of cells at once-has shaped life sciences ever since and allowed researchers to discover new insights within their respective fields of study such as oncology, neurobiology, and immunology (among others). Obtaining high-data quality is the key to being able to make these meaningful discoveries, which in turn is directly linked to the quality of the initial cell (or nuclei) suspension that is used to load the 10x Genomics Chromium Single Cell Gene Expression assay. A successful workflow relies on a cell suspension which is fully dissociated, extremely clean, and of high viability. While the workflow itself has been detailed elsewhere (De Simone et al. Methods Mol Biol 1979:87-110, 2019), in this chapter we will focus on the importance of the quality of the initial cell suspension, as well as common mistakes that can occur while running a Single Cell Gene Expression assay. The descriptions of these tips and tricks refer to the current version of the 10x Genomics User Guide (Chromium Single Cell 3' Reagent Kits User Guide (v3.1 Chemistry Dual Index). https://support10xgenomicscom/single-cell-gene-expression/index/doc/user-guide-chromium-single-cell-3-reagent-kits-user-guide-v31-chemistry-dual-index) which can be downloaded from the Support section on the 10x Genomics website (10x Genomics website. https://www10xgenomicscom). These documents and user guides are continuously improved and updated; hence, it is important to regularly check the company's website for the most recent version.

Swede Home Chicago: The Wallin's Svenska Records Story, 1923–27

According to the liner notes of this project, Chicago has the highest Swedish population of any city after Stockholm. Chicago is also “home to the first record label founded by a Nordic immigrant to the United States.” Archeophone Records’ compilation Swede Home Chicago: The Wallin's Svenska Records Story, 1923–27 tells the story of former crofter Gustaf Waldemar Wallin, founder of Wallin's Svenska Records, a record company that came into being as a subsidiary of Wallin's Music Shop. This company issued 56 tracks between 1923 and 1927. Swede Home Chicago encompasses the entire catalog and includes two discs, featuring 28 tracks each, and a robust 76-page CD booklet. The booklet includes introductory material, performers’ biographies, track notes, lyrics and translations, endnotes, and production credits, as well as a rich plethora of archival photos relating to the Wallin family, the record company, the performers, and more.Without any prior knowledge of the folklife of Swedish American immigrants, one can still appreciate the thought and care put into this project. The context provided by the CD booklet is absolutely unmatched by that of any other project I have engaged with, and was the highlight of reviewing this project. As a folklorist focusing on music, with an eye trained on accessibility and transparency, this is particularly meaningful. For a multiplicity of reasons, one cannot and should not separate music from its historical context. The music itself cannot provide this context, especially when songs are being sung in a language one does not understand. Luckily, folklorists Jim Leary and Marcus Cederström, along with Archeophone Records’ Richard Martin, have crafted a fulfilling and multifaceted narrative that includes detailed lyric translations and is guaranteed to address any questions or concerns the listener might have.The music itself—56 tracks spread out over two discs—features piano, piano accordion, violin, and vocals covering the entire spectrum of human emotion and artistic preference and encompassing “earthy comic songs,” “pious hymns and patriotic anthems,” “venerable folk tunes [intermingled] with hot jazz,” and more. It is striking that this collection is so musically diverse despite coming from one company; it utilizes almost every possible sonic avenue within the given musical heritage to create a truly dynamic and entertaining catalog. In a further testament to the importance of these recordings at the time they first appeared, it is worth noting that the 28 10-inch shellac discs originally issued by Wallin's Svenska Records were recorded by Homer Rodeheaver and Orlando Marsh, two venerable giants of the recording industry.Swede Home Chicago is a set that anyone who is interested in music and music history should own. Speaking as a “many-sectored” folklorist, I feel there is great potential for this collection. It is both deeply entertaining and richly engaging. This project could be used in Scandinavian, migration, and music studies courses as an educational tool. Given that the CD booklet is crucial to the understanding of the project as a whole, future creators of similar projects might look to Swede Home Chicago for guidance on creating something that is appropriately contextual. However, this project should not be construed as being solely historical in scope and content. This collection has implications for folkloristics as well. I was particularly struck by the last few words on the back cover asserting that Swede Home Chicago “[illuminates] a vibrant bygone musical scene that expands our understanding of America's perpetual musical pluralism.” This concept is a lesson for folklore as a discipline, not just for those of us who focus on American music.Just as these discs run the gamut musically despite coming from a singular cultural background, American music encompasses thousands of traditions that should be recognized as equally important parts of the whole. The parsing out of these threads is endless but worthy work that yields meaningful discoveries about American folklife. I send my thanks to Jim Leary, Marcus Cederström, Richard Martin, Archeophone Records, the Mills Music Library and the Center for the Study of Upper Midwestern Cultures at the University of Wisconsin–Madison, the National Endowment for the Humanities, and all other institutions and people involved in this project—a dynamic and powerful step forward in viewing folklife through a musical lens.

YEvo: experimental evolution in high school classrooms selects for novel mutations that impact clotrimazole resistance in Saccharomyces cerevisiae.

Antifungal resistance in pathogenic fungi is a growing global health concern. Nonpathogenic laboratory strains of Saccharomyces cerevisiae are an important model for studying mechanisms of antifungal resistance that are relevant to understanding the same processes in pathogenic fungi. We have developed a series of laboratory modules in which high school students used experimental evolution to study antifungal resistance by isolating azole-resistant S. cerevisiae mutants and examining the genetic basis of resistance. We have sequenced 99 clones from these experiments and found that all possessed mutations previously shown to impact azole resistance, validating our approach. We additionally found recurrent mutations in an mRNA degradation pathway and an uncharacterized mitochondrial protein (Csf1) that have possible mechanistic connections to azole resistance. The scale of replication in this initiative allowed us to identify candidate epistatic interactions, as evidenced by pairs of mutations that occur in the same clone more frequently than expected by chance (positive epistasis) or less frequently (negative epistasis). We validated one of these pairs, a negative epistatic interaction between gain-of-function mutations in the multidrug resistance transcription factors Pdr1 and Pdr3. This high school-university collaboration can serve as a model for involving members of the broader public in the scientific process to make meaningful discoveries in biomedical research.

Reconciliation with the pain through embracing the past: Message of hope and resilience via the Ugaritic alphabet

After witnessing my home country suffering through a vicious civil war, this inquiry initially intended to represent Syria in a positive light, as a place of civilization, differently to what we have been constantly seeing in the news in recent years. However, the research led me to more meaningful discoveries. With the help of Syrian participants, I discovered not only a way to promote the country as a place of peace and prosperity, but also a way to invite the viewer to reconcile with grief and adversity they have experienced by embracing the word ‘hope’. In this visual essay, I share an invitation to reconcile with one’s self, past and hardship through the Ugaritic alphabet.

Transcriptome-module phenotype association study implicates extracellular vesicles biogenesis in Plasmodium falciparum artemisinin resistance.

Plasmodium falciparum malaria is still an important disease in sub-Saharan Africa (sSA). Great strides have been made in its control spear-headed by artemisinin (ART)-based combination therapies (ACTs). However, concerns about the imminent spread of ART-resistant (ARTr) malaria parasites to sSA threaten gains already made. Attempts to mitigate this risk have highlighted the need to discover novel P. falciparum drug targets. Therefore, studies to deepen our understanding of the biology of P. falciparum are needed. The role of extracellular vesicles (EVs) in the biology of malaria parasites is not fully understood. Recently, the ART resistance-associated transcriptional profile has been reported to involve several biological processes connected to vesicular trafficking, proteotoxic stress, erythrocyte remodelling, and mitochondrial metabolism. We explored a role for EVs in developing the P. falciparum ARTr phenotype using bulk RNA sequencing of unsynchronized parasite cultures under untreated, 0.1% dimethyl sulfoxide and 700nM dihydroartemisinin treated conditions for six hours. As pathway and gene ontology analysis is limited in its curated knowledge repertoire on EVs biogenesis in P. falciparum, we used a modular (gene set) analysis approach to explore whether an EVs biogenesis module is associated with the ARTr phenotype in P. falciparum. We first generated well-defined EVs modules of interest and used statistical tools to determine differences in their expression among the parasite and treatment conditions. Then we used gene set enrichment analysis to determine the strength of the association between each EVs module of interest and the ARTr phenotype. This transcriptome-module phenotype association study (TMPAS) represents a well-powered approach to making meaningful discoveries out of bulk gene expression data. We identified four EVs module of interest and report that one module representing gene sets with correlated expression to PF3D7_1441800 – involved with EVs biogenesis in P. falciparum - is associated with the ARTr phenotype (R539T_DHA_treated versus R539T_untreated: normalized enrichment score (NES) = 1.1830174, FDR q-value < 0.25; C580R_DHA_treated versus C580R_untreated: NES = 1.2457103, FDR q-value < 0.25). PF3D7_1441800 has been reported to reduce EVs production when knocked out in P. falciparum. Altogether, our findings suggest a role for EVs in developing ART resistance and warrant further studies interrogating this association.

OpenVar: functional annotation of variants in non-canonical open reading frames

BackgroundRecent technological advances have revealed thousands of functional open reading frames (ORF) that have eluded reference genome annotations. These overlooked ORFs are found throughout the genome, in any reading frame of transcripts, mature or non-coding, and can overlap annotated ORFs in a different reading frame. The exploration of these novel ORFs in genomic datasets and of their role in genetic traits is hindered by a lack of software.ResultsHere, we present OpenVar, a genomic variant annotator that mends that gap and fosters meaningful discoveries. To illustrate the potential of OpenVar, we analysed all variants within SynMicDB, a database of cancer-associated synonymous mutations. By including non-canonical ORFs in the analysis, OpenVar yields a 33.6-fold, 13.8-fold and 8.3-fold increase in high impact variants over Annovar, SnpEff and VEP respectively. We highlighted an overlapping non-canonical ORF in the HEY2 gene where variants significantly clustered.ConclusionsOpenVar integrates non-canonical ORFs in the analysis of genomic variants, unveiling new research avenues to better understand the genotype–phenotype relationships.

A systematic evaluation of the computational tools for ligand-receptor-based cell-cell interaction inference.

Cell–cell interactions (CCIs) are essential for multicellular organisms to coordinate biological processes and functions. One classical type of CCI interaction is between secreted ligands and cell surface receptors, i.e. ligand-receptor (LR) interactions. With the recent development of single-cell technologies, a large amount of single-cell ribonucleic acid (RNA) sequencing (scRNA-Seq) data has become widely available. This data availability motivated the single-cell-resolution study of CCIs, particularly LR-based CCIs. Dozens of computational methods and tools have been developed to predict CCIs by identifying LR-based CCIs. Many of these tools have been theoretically reviewed. However, there is little study on current LR-based CCI prediction tools regarding their performance and running results on public scRNA-Seq datasets. In this work, to fill this gap, we tested and compared nine of the most recent computational tools for LR-based CCI prediction. We used 15 well-studied scRNA-Seq samples that correspond to approximately 100K single cells under different experimental conditions for testing and comparison. Besides briefing the methodology used in these nine tools, we summarized the similarities and differences of these tools in terms of both LR prediction and CCI inference between cell types. We provided insight into using these tools to make meaningful discoveries in understanding cell communications.

Research priority setting for paediatric rheumatology in the UK.

The evidence base that underlies the management of children and young people with paediatric rheumatic diseases is deficient. In this field, there are many crucial unanswered questions. The UK Paediatric Rheumatology Clinical Studies Group, supported by UK National Institute for Health Research Clinical Research Network: children and Versus Arthritis, elicited ideas for research priorities from paediatric rheumatologists, trainees, allied health-care professionals, nurse specialists, patients, parents of patients, carers, and charities. These ideas were collected through online surveys and face-to-face meetings. A modified Delphi process was used, which included online research priority ranking surveys and a consensus workshop. A longlist of 55 disease-specific research priorities and 37 general research priorities were voted on in the first survey. A list of 11 top general research priorities was produced. The top ten disease-specific research priorities were discussed in depth at a Delphi workshop to determine their final ranking. This Health Policy paper will help to guide clinicians, academics, and funding bodies to prioritise research in paediatric rheumatic diseases, specifically in areas of unmet patient needs.

HYGIEIA: HYpothesizing the Genesis of Infectious Diseases and Epidemics through an Integrated Systems Biology Approach.

More than two years on, the COVID-19 pandemic continues to wreak havoc around the world and has battle-tested the pandemic-situation responses of all major global governments. Two key areas of investigation that are still unclear are: the molecular mechanisms that lead to heterogenic patient outcomes, and the causes of Post COVID condition (AKA Long-COVID). In this paper, we introduce the HYGIEIA project, designed to respond to the enormous challenges of the COVID-19 pandemic through a multi-omic approach supported by network medicine. It is hoped that in addition to investigating COVID-19, the logistics deployed within this project will be applicable to other infectious agents, pandemic-type situations, and also other complex, non-infectious diseases. Here, we first look at previous research into COVID-19 in the context of the proteome, metabolome, transcriptome, microbiome, host genome, and viral genome. We then discuss a proposed methodology for a large-scale multi-omic longitudinal study to investigate the aforementioned biological strata through high-throughput sequencing (HTS) and mass-spectrometry (MS) technologies. Lastly, we discuss how a network medicine approach can be used to analyze the data and make meaningful discoveries, with the final aim being the translation of these discoveries into the clinics to improve patient care.

Uniting diversity to create a more inclusive academic environment.

Uniting diversity to create a more inclusive academic environment.

A study of customer perception of visual information in food stands through eye-tracking

PurposeThe study selected five small-scale food operations as visual stimuli and eye-tracking experiment was conducted with 36 female participants in a laboratory setting. Heat maps were used to visualize viewers' visual attention on the storefronts. The eye-movement data were analyzed using one-way repeated ANOVA to identify a significant difference between stimuli in terms of average fixation duration, fixation counts and revisits. An independent t-test was also used to examine statistical difference among text and image in menu board. The significance cut-off of p-value was set to &lt;0.05.Design/methodology/approachThe exteriors of food-service establishments are major business representation. However, few studies have been conducted to examine customers' visual processing toward small-scale restaurants. The present study accordingly aims to discover customers' different levels of attention to the frontage in food stands through eye tracking, which would be practical for future owners to plan their exterior shop design.FindingsThe findings can be summarized as follows: First, upper board shows the highest level of attention, suggesting an optimal location of menu board for grasping customers' attention. Second, customers also gaze the inside of a store along with the food on display, which are related with food hygiene and the perception. Third, textual information on menu boards tends to attract more visual attention than those of images. Overall, the current study indicates various customers' attention toward the location of menu boards as well as the type of visual information on menu board.Originality/valueThe results of this study make a new insight into customers' viewing behavior toward exteriors of food-service establishments. This study is one of the first attempts to explore how customers distribute visual attention to the exterior images of food stand by using eye-tracking technology. The findings of this research thus enrich the food-service literature and offer meaningful discoveries on customers' visual behaviors. For example, this study suggests that customers tend to be attracted to textual information on menu boards rather than graphical ones.

The problematics of gender and power in Lumban traditional hand embroidery

Embroidery provides meaningful discoveries through interactions and relations connected in the lived experiences of women hand embroiderers. A woman’s performance of her embroidery skills indicates the intimate connection of her womanhood, her daily life, and the kind of labor and effort she places upon it. Interviews, focus group discussions, and creative workshop reveal that social conditions from the past to the present, allow her to continuously construct her identity and negotiate her role in society. Embroidery has offered the women in this study an opportunity to create not only their identity as individuals but also as a community, and has helped them develop their capacities beyond realizing their womanhood. The presence of the problematics of gender and power is evident through the obvious contradictions of the empowered under disempowering conditions thus rendering their power and empowerment, symbolic.