bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrating cellular graph embeddings with tumor morphological features to predict in-silico spatial transcriptomics from H&E images
Authors: Prabhakar Vignesh , Warner Elisa , Liu Kai
Published: November 2023

Spatial transcriptomics allows precise RNA abundance measurement at high spatial resolution, linking cellular morphology with gene expression. We present a novel deep learning algorithm predicting local gene expression from histopathology images. Our approach employs a graph isomorphism neural network capturing cell-to-cell interactions in the tumor microenvironment and a Vision Transformer (CTransPath) for obtaining the tumor morphological features. Using a dataset of 30,612 spatially resolved gene expression profiles matched with histopathology images from 23 breast cancer patients, we identify 250 genes, including established breast cancer biomarkers, at a 100 µm resolution. Additionally, we co-train our algorithm on spatial spot-level transcriptomics from 10x Visium breast cancer data along with another variant of our algorithm on TCGA-BRCA bulk RNA Seq. data, yielding mutual benefits and enhancing predictive accuracy on both these datasets. This work enables image-based screening for molecular biomarkers with spatial variation, promising breakthroughs in cancer research and diagnostics.
A Cre-dependent reporter mouse for quantitative real-time imaging of Protein Kinase A activity dynamics
Authors: Tilden Elizabeth I. , Maduskar Aditi , Oldenborg Anna , Sabatini Bernardo L. , Chen Yao
Published: November 2023

Intracellular signaling dynamics play a crucial role in cell function. Protein kinase A (PKA) is a key signaling molecule that has diverse functions, from regulating metabolism and brain activity to guiding development and cancer progression. We previously developed an optical reporter, FLIM-AKAR, that allows for quantitative imaging of PKA activity via fluorescence lifetime imaging microscopy and photometry. However, using viral infection or electroporation for the delivery of FLIM-AKAR is invasive, cannot easily target sparse or hard-to-transfect/infect cell types, and results in variable expression. Here, we developed a reporter mouse,FL-AK, which expresses FLIM-AKAR in aCre-dependent manner from theROSA26locus.FL-AKprovides robust and consistent expression of FLIM-AKAR over time. Functionally, the mouse line reports an increase in PKA activity in response to activation of both Gαsand Gαq-coupled receptors in brain slices.In vivo, FL-AKreports PKA phosphorylation in response to neuromodulator receptor activation. Thus,FL-AKprovides a quantitative, robust, and flexible method to reveal the dynamics of PKA activity in diverse cell types.
VLIB: Unveiling insights through Visual and Linguistic Integration of Biorxiv data relevant to cancer via Multimodal Large Language Model
Authors: Prabhakar Vignesh , Liu Kai
Published: November 2023

The field of cancer research has greatly benefited from the wealth of new knowledge provided by research articles and preprints on platforms like Biorxiv. This study investigates the role of scientific figures and their accompanying captions in enhancing our comprehension of cancer. Leveraging the capabilities of Multimodal Large Language Models (MLLMs), we conduct a comprehensive analysis of both visual and linguistic data in biomedical literature. Our work introduces VLIB, a substantial scientific figure-caption dataset generated from cancer biology papers on Biorxiv. After thorough preprocessing, which includes figure-caption pair extraction, sub-figure identification, and text normalization, VLIB comprises over 500,000 figures from more than 70,000 papers, each accompanied by relevant captions. We fine-tune baseline MLLMs using our VLIB dataset for downstream vision-language tasks, such as image captioning and visual question answering (VQA), to assess their performance. Our experimental results underscore the vital role played by scientific figures, including molecular structures, histological images, and data visualizations, in conjunction with their captions, in facilitating knowledge translation through MLLMs. Specifically, we achieved a ROUGE score of 0.66 for VQA and 0.68 for image captioning, as well as a BLEU score of 0.72 for VQA and 0.70 for image captioning. Furthermore, our investigation highlights the potential of MLLMs to bridge the gap between artificial intelligence and domain experts in the field of cancer biology.
Large Language Model-Driven Evaluation of Medical Records Using MedCheckLLM
Authors: Schubert Marc Cicero , Wick Wolfgang , Venkataramani Varun
Published: November 2023

Large Language Models (LLMs) offer potential in healthcare, especially in the evaluation of medical documents. This research introduces MedCheckLLM, a multi-step framework designed for the systematic assessment of medical records against established evidence-based guidelines, a process termed ‘guideline-in-the-loop’. By keeping the guidelines separate from the LLM’s training data, this approach emphasizes validity, flexibility, and interpretability. Suggested evidence-based guidelines are externally accessed and fed back into the LLM for a evaluation. The method enables implementation of guideline updates and personalized protocols for specific patient groups without retraining. We applied MedCheckLLM to expert-validated simulated medical reports, focusing on headache diagnoses following International Headache Society guidelines. Findings revealed MedCheckLLM correctly extracted diagnoses, suggested appropriate guidelines, and accurately evaluated 87% of checklist items, with its evaluations aligning significantly with expert opinions. The system not only enhances healthcare quality assurance but also introduces a transparent and efficient means of applying LLMs in clinical settings. Future considerations must address privacy and ethical concerns in actual clinical scenarios.
Acute myeloid leukemia with mixed phenotype is characterized byRUNX1mutations, stemness features and limited lineage plasticity
Authors: Galera Pallavi , Dilip Deepika , Derkach Andriy , Chan Alexander , Zhang Yanming , Persuad Sonali , Mishera Tanmay , Liu Ying , Famulare Christopher , Gao Qi , Mata Douglas A. , Arcila Maria , Geyer Mark B. , Stein Eytan , Dogan Ahmet , Levine Ross L. , Roshal Mikhail , Glass Jacob , Xiao Wenbin
Published: November 2023

Mixed phenotype (MP) in acute leukemias poses unique classification and management dilemmas and can be seen in entities other than de novo mixed phenotype acute leukemia (MPAL). Although WHO classification empirically recommends excluding AML with myelodysplasia related changes (AML-MRC) and therapy related AML (t-AML) with mixed phenotype (referred to as “AML-MP”) from MPAL, there is lack of studies investigating the clinical, genetic, and biologic features of AML-MP. We report the first cohort of AML-MP integrating their clinical, immunophenotypic, genomic and transcriptomic features with comparison to MPAL and AML without MP. Patients with AML-MP share similar clinical and genetic features to its AML counterpart but differs from MPAL. AML-MP harbors more frequentRUNX1mutations than AML without MP and MPAL.RUNX1mutations or complex karyotypes did not impact the survival of MPAL patients. Unsupervised hierarchal clustering based on immunophenotype identified biologically distinct clusters with phenotype/genotype correlation and outcome differences. Furthermore, transcriptomic analysis showed an enrichment for stemness signature in AML-MP and AML without MP as compared to MPAL. Lastly, MPAL but not AML-MP often switched to lymphoid only immunophenotype after treatment. Expression of transcription factors critical for lymphoid differentiation were upregulated only in MPAL, but not in AML-MP. Our study for the first time demonstrates that AML- MP clinically and biologically resembles its AML counterpart without MP and differs from MPAL, supporting the recommendation to exclude these patients from the diagnosis of MPAL. Future studies are needed to elucidate the molecular mechanism of mixed phenotype in AML.

Key points

AML-MP clinically and biologically differs from MPAL but resembles AML.

AML-MP showsRUNX1mutations, stemness and limited lineage plasticity.
Role of ablation therapy in conjunction with surgical resection for neuroendocrine tumors (NETs): Risks and benefits of multimodality surgical treatment for NETs involving liver
Authors: Ostapenko Alexander , Stroever Stephanie , Eyasu Lud , Kim Minha , Aploks Krist , Dong Xiang , Seshadri Ramanathan
Published: November 2023

Background

Resection of hepatic metastasis from neuroendocrine tumors (NETs) improves quality of life and prolongs 5-year survival. Ablation can be utilized with surgery to achieve complete resection. Although several studies report long-term outcomes for patients undergoing ablation, none have explored perioperative effects of ablation in patients with metastatic NETs. Our goal was to determine if intra-operative ablation during hepatectomy increases risk of adverse outcomes such as surgical site infections (SSIs), bleeding, and bile leak.

Methods

A retrospective analysis of the hepatectomy NSQIP database from 2015-2019 was performed to determine the odds of SSIs, bile leaks, or bleeding in patients undergoing intraoperative ablation when compared to hepatectomy alone.

Results

Of the 966 patients included in the study, 298(30.9%) underwent ablation during hepatectomy. There were 78(11.7%) patients with SSIs in the hepatectomy alone group and 39(13.1%) patients with a SSIs in the hepatectomy with ablation group. Bile leak occurred in 41(6.2%) and 14(4.8%) patients in the two groups, respectively; bleeding occurred in 117(17.5%) and 33(11.1%), respectively. After controlling for confounding variables, ablation did not increase risk of SSI (p=0.63), bile leak (p=0.34) or bleeding (p=0.07) when compared to patients undergoing resection alone on multivariate analysis.

Conclusions

Intraoperative ablation with hepatic resection for NETs is safe in the perioperative period without significant increased risk of infection, bleeding, or bile leak. Surgeons should utilize this modality when appropriate to achieve optimal disease control and outcomes.
AMEBIASIS: AN ANALYSIS OF ITS DISTINCTIVE PRESENTATION IN THE CONTEXT OF JORDANIAN CASES
Authors: Al-khlifeh Enas , Hasanat Ahmad B.
Published: November 2023

Amebiasis is a serious health problem, particularly in economically disadvantaged countries. However, unresolved questions remain regarding the clinical symptoms and laboratory results of amebiasis in Jordan, a developing country. Therefore, we assessed the prevalence and severity of amebiasis in a sizable population in the center of Jordan in relation to potential risk variables such as environment, age and sex of the patients, collecting data from the medical records of the patients treated at the Al-Hussein Hospital in Al-Salt city between 2020 and 2022. Clinical manifestations and laboratory findings, including fecal red blood cell and leukocyte counts, total and differential leukocyte counts by age, and other information were included in this report. This study showed that amebiasis is a common problem in Al-Salt city, accounting for 16.8% of all gastroenteritis cases. Amebiasis affects individuals of all sexes and ages. When comparing males of different ages to females of similar ages, both age and male sex showed an increased risk of amebiasis (P=0.014). Infants and toddlers accounted for more than one-quarter of the cases, with more than half of them diagnosed with watery diarrhea. Numerous patients of all age groups displayed age-related neutrophilic leukocytosis and atypical WBC counts. The findings of this study suggest that amebiasis is highly prevalent, affects a significant proportion of infants and toddlers, and causes severe clinical symptoms. This is the first study on Al-Salt city population with respect to multiple variables and demographic factors. These data are crucial for the decision-making of medical professionals. The epidemiology of amebiasis in Jordan must be determined, and preventive measures must be developed, especially for childcare at educational facilities.
Pathological claustrum activity drives aberrant cognitive network processing in human chronic pain
Authors: Stewart Brent W. , Keaser Michael L. , Lee Hwiyoung , Margerison Sarah M. , Cormie Matthew A. , Moayedi Massieh , Lindquist Martin A. , Chen Shuo , Mathur Brian N. , Seminowicz David A.
Published: November 2023

Aberrant cognitive network activity and cognitive deficits are established features of chronic pain. However, the nature of cognitive network alterations associated with chronic pain and their underlying mechanisms require elucidation. Here, we report that the claustrum, a subcortical nucleus implicated in cognitive network modulation, is activated by acute painful stimulation and pain-predictive cues in healthy participants. Moreover, we discover pathological activity of the claustrum and a lateral aspect of the right dorsolateral prefrontal cortex (latDLPFC) in migraine patients. Dynamic causal modeling suggests a directional influence of the claustrum on activity in this latDLPFC region, and diffusion weighted imaging (DWI) verifies their structural connectivity. These findings advance understanding of claustrum function during acute pain and provide evidence of a possible circuit mechanism driving cognitive impairments in chronic pain.
Development of a high throughput system to screen compounds that revert the activated hepatic stellate cells to a quiescent-like state
Authors: Nakano Yasuhiro , Itoh Tohru , Tanaka Minoru , Miyajima Atsushi , Kido Taketomo
Published: November 2023

Chronic liver injury induces fibrosis that often proceeds to cirrhosis and hepatocellular carcinoma, indicating that prevention and/or resolution of fibrosis is a promising therapeutic target. Hepatic stellate cells (HSCs) are the major driver of fibrosis by expressing extracellular matrices (ECM). HSCs, in the normal liver, are quiescent and activated by liver injury to become myofibroblasts that proliferate and produce ECM. It has been shown that activated HSCs (aHSCs) become a “quiescent-like” state by removal of liver insults. Therefore, deactivation agents can be a therapeutic drug for advanced liver fibrosis. Using aHSCs prepared from human induced pluripotent stem cells, we found that aHSCs were reverted to a quiescent-like state by a combination of chemical compounds that either inhibit or activate a signaling pathway, Lanifibranor, SB431542, Dorsomorphin, retinoic acid, palmitic acid and Y27632,in vitro. Based on these results, we established a high throughput system to screen agents that induce deactivation and demonstrate that a single chemical compound can induce deactivation.
DeLoop: a deep learning model for chromatin loop prediction from sparse ATAC-seq data
Authors: Luo Yihai , Zhang Zhihua
Published: November 2023

Deciphering gene regulation and understanding the functional implications of disease-associated non-coding variants require the identification of cell-type-specific 3D chromatin interactions. Current chromosome conformation capture technologies fall short in resolution when handling limited cell inputs. To address this limitation, we introduce DeLoop, a deep learning model designed to predict CTCF-mediated chromatin loops from sparse ATAC-seq data by leveraging multitask learning techniques and attention mechanisms. Our model utilizes ATAC-seq data and DNA sequence features, showcasing superior performance compared to existing state-of-the-art models, particularly under low read depth conditions, enabling accurate chromatin loop inference when sufficient cells are infeasible. In addition, generalizing across cell types, DeLoop proves effective in de novo prediction tasks and its potential for predicting functional interactions.
Reinstatement ofRIG-Iin chickens via genetic modification reveals new insights into the dynamic evolution of avian immune sensors
Authors: Sid Hicham , von Heyl Theresa , Schleibinger Sabrina , Klinger Romina , Guabiraba Rodrigo , Guillory Vanaique , Schade Benjamin , Elleder Daniel , Sives Samantha , Vervelde Lonneke , Trapp Sascha , Schusser Benjamin
Published: November 2023

Retinoic acid-inducible gene I(RIG-I) activates mitochondrial antiviral signaling proteins, initiating the antiviral response.RIG-IandRNF135, a ubiquitin ligase regulator, are missing in domestic chickens but conserved in mallard ducks. It was long believed that chickens’RIG-Iloss was linked to increased avian influenza susceptibility. We reinstated both genes in chickens and examined their susceptibility to the avian influenza virus H7N1. UninfectedRIG-I-expressing chickens exhibited shifts in T and B cells, while the H7N1 infection led to severe disease, persistent weight loss, and increased viral replication. Conversely, the co-expression ofRIG-IandRNF135reduced the viral replication and was associated with high inflammatory response. Our data indicate that the loss ofRIG-Iin chickens likely evolved to counteract deleterious inflammation caused by viral infection. We highlight the effects of restoring evolutionary lost genes in birds and suggest a new immunological approach to reduce viral replication and prevent infection.

Graphical abstract
Cultivation, chemistry, and genome ofPsilocybe zapotecorum
Authors: Miller Dusty Rose , Jacobs Jordan Taylor , Rockefeller Alan , Singer Harte , Bollinger Ian M. , Conway James , Slot Jason C. , Cliffel David E.
Published: November 2023

Psilocybe zapotecorumis a strongly blue-bruising psilocybin mushroom used by indigenous groups in southeastern Mexico and beyond. While this species has a rich history of ceremonial use, research into its chemistry and genetics have been limited. Herein, we detail mushroom morphology and report on cultivation parameters, chemical profile, and the full genome sequence ofP. zapotecorum. First, growth and cloning methods are detailed that are simple, and reproducible. In combination with high resolution microscopic analysis, the strain was barcoded, confirming species-level identification. Full genome sequencing reveals the architecture of the psilocybin gene cluster inP. zapotecorum,and can serve as a reference genome for Psilocybe Clade I. Characterization of the tryptamine profile revealed a psilocybin concentration of 17.9±1.7 mg/g, with a range of 10.6-25.7 mg/g (n=7), and similar tryptamines (psilocin, baeocystin, norbaeocystin, norpsilocin, aeruginascin, 4-HO-tryptamine, and tryptamine) in lesser concentrations for a combined tryptamine concentration of 22.5±3.2 mg/g. These results showP. zapotecorumto be a potent – and variable –Psilocybemushroom. Chemical profiling, genetic analysis, and cultivation assist in demystifying these mushrooms. As clinical studies with psilocybin gain traction, understanding the diversity of psilocybin mushrooms will assure that psilocybin therapy does not become synonymous with psilocybin mushrooms.
Immunosuppressive tumor microenvironment of osteosarcoma
Authors: Taylor Aaron Michael , Sheng Jianting , Ng Patrick Kwok Shing , Harder Jeffrey M. , Kumar Parveen , Ahn Ju Young , Cao Yuliang , Dzis Alissa M. , Jillette Nathaniel L. , Goodspeed Andrew , Bodlak Avery , Wu Qian , Isakoff Michael S. , George Joshy , Grassmann Jessica D.S. , Luo Diane , Flynn William F. , Courtois Elise T. , Robson Paul , Hayashi Masanori , Paolillo Alini Trujillo , Petrilli Antonio Sergio , de Toledo Silvia Regina Caminada , Balarezo Fabiola Sara , Lindsay Adam D. , Hoang Bang , Wong Stephen T.C. , Lau Ching C.
Published: November 2023

Osteosarcoma is the most common malignant bone tumor in children, characterized by a high degree of genomic instability, resulting in copy-number alterations and genomic rearrangements without disease-defining recurrent mutations. Clinical trials based on molecular characterization have failed to find new effective therapies or improve outcomes over the last 40 years. To better understand the immune microenvironment of osteosarcoma, we performed single-cell RNA sequencing on six tumor biopsy samples, combined with a previously-published cohort of six samples. Additional osteosarcoma samples were profiled using spatial transcriptomics for validation of discovered subtypes and to add spatial context. Analysis revealed immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs), regulatory and exhausted T-cells, and LAMP3+ dendritic cells. Using cell-cell communication modeling, we identified robust interactions between MDSCs and other cells, leading to NF-κB upregulation and an immunosuppressive microenvironment, as well as interactions involving regulatory T-cells and osteosarcoma cells that promoted tumor progression and a proangiogenic niche.

Statement of Significance

Osteosarcoma patient survival has remained stagnant for several decades due to lack of successful therapy for high-risk patients, including those with metastatic disease. Identifying novel therapeutics including immunotherapies is of great clinical importance. Our study highlights several important immunosuppressive mechanisms within osteosarcoma that should be considered when developing future immunotherapies.
The complete diploid reference genome of RPE-1 identifies human phased epigenetic landscapes
Authors: Volpe Emilia , Corda Luca , Di Tommaso Elena , Pelliccia Franca , Ottalevi Riccardo , Licastro Danilo , Guarracino Andrea , Capulli Mattia , Formenti Giulio , Tassone Evelyne , Giunta Simona
Published: November 2023

Comparative analysis of recent human genome assemblies highlights profound sequence divergence that peaks within polymorphic loci such as centromeres. This raises the question about the adequacy of relying on human reference genomes to accurately analyze sequencing data derived from experimental cell lines. Here, we generated the complete diploid genome assembly for the human retinal epithelial cells (RPE-1), a widely used non-cancer laboratory cell line with a stable karyotype, to use as matched reference for multi-omics sequencing data analysis. Our RPE1v1.0 assembly presents completely phased haplotypes and chromosome-level scaffolds that span centromeres with ultra-high base accuracy (>QV60). We mapped the haplotype-specific genomic variation specific to this cell line including t(Xq;10q), a stable 73.18 Mb duplication of chromosome 10 translocated onto the microdeleted chromosome X telomere t(Xq;10q). Polymorphisms between haplotypes of the same genome reveals genetic and epigenetic variation for all chromosomes, especially at centromeres. The RPE-1 assembly as matched reference genome improves mapping quality of multi-omics reads originating from RPE-1 cells with drastic reduction in alignments mismatches compared to using the most complete human reference to date (CHM13). Leveraging the accuracy achieved using a matched reference, we were able to identify the kinetochore sites at base pair resolution and show unprecedented variation between haplotypes. This work showcases the use of matched reference genomes for multi-omics analyses and serves as the foundation for a call to comprehensively assemble experimentally relevant cell lines for widespread application.

Highlights

We generated the complete phased genome assembly of one of the most widely used non-cancer cell lines (RPE-1) with a stable diploid karyotype

We used this genome as a matched reference to analyze sequencing data from RPE-1

Mapping to the RPE1v1.0 genome improves alignment quality, faithful assignment of reads to each haplotype, and epigenome peak calling accuracy uncovering inter-haplotype variation

Use of the matched reference genome enables epigenetic precision in identifying for the first time the kinetochore site at base pair resolution for each haplotype

The RPE-1 genome represents a new telomere-to-telomere (T2T) human diploid reference for the scientific community that will advance genetic and epigenetic research across fields using this cell line
Predictability of ecological and evolutionary dynamics in a changing world
Authors: Bozzuto Claudio , Ives Anthony R.
Published: November 2023

Ecological and evolutionary predictions are being increasingly employed to inform decision-makers confronted with intensifying pressures menacing life on Earth. For these efforts to effectively guide conservation actions, knowing the limit of predictability is pivotal. In this study, we provide realistic expectations about the enterprise of predicting changes in ecological and evolutionary observations through time. We begin with an intuitive explanation of predictability (that is, the extent to which predictions are possible) employing an easy-to-use metric, predictive powerPP(t). To illustrate the challenge of forecasting, we then show that among insects, birds, fishes, and mammals (i) 50% of the populations are predictable at most one year in advance, and (ii) the median one-year-ahead predictive power corresponds to a sobering predictionR2of approximately 20%. Nonetheless, predictability is not an immutable property of ecological systems. For example, different harvesting strategies can impact the predictability of exploited populations to varying degrees. Moreover, considering multivariate time series, incorporating explanatory variables or accounting for time trends (environmental forcing) can enhance predictability. To effectively address the urgent challenge of biodiversity loss, researchers and practitioners must be aware of the predictive information within the available data and explore efficient ways to leverage this information for environmental stewardship.
Going with the flow: evidence for phenotypic variation in cooperative plasticity during predator inspection in Trinidadian guppies (Poecilia reticulata)
Authors: Dimitriadou Sylvia , Padget Rebecca F.B. , Jack Tegen , Darden Safi K.
Published: November 2023

Assortative interactions can be key for the evolution and maintenance of cooperation. The propensity for cooperative behaviour to be met with equal cooperativeness can arise from partner conditional responses or fixed cooperative traits, but also a combination of both; something that has yet to be investigated outside of humans. We explored whether individuals differing in trait cooperativeness also differed in plasticity of their conditional response to partner cooperativeness. To identify when selection may favour high or low plasticity as a function of cooperativeness, we also developed an evolutionary simulation model, where individuals’ probability of cooperating was modelled alongside their plasticity. Our empirical results suggest that guppies (Poecilia reticulata) bred to make high cooperative investments in the context of predator inspection exhibit greater conditional response plasticity than guppies bred to make lower investments. Our agent-based model found that more cooperative individuals will show greater plasticity in their propensity to cooperate, compared to less cooperative individuals, except when there are no consequences of nobody cooperating. Combined, our findings show that more cooperative individuals might benefit from a greater capacity to adjust behaviour than less cooperative individuals – this could have implications for assortment by cooperative behaviour.
Benchmarking and integrating human B-cell receptor genomic and antibody proteomic profiling
Authors: Lê Quý Khang , Chernigovskaya Maria , Stensland Maria , Singh Sachin , Leem Jinwoo , Revale Santiago , Galson Jacob D. , Nyman Tuula A. , Snapkow Igor , Greiff Victor
Published: November 2023

Immunoglobulins (Ig), which exist either as B-cell receptors (BCR) on the surface of B cells or as antibodies when secreted, play a key role in the recognition and response to antigenic threats. The capability to jointly characterize the BCR and antibody repertoire is crucial in understanding human adaptive immunity. From peripheral blood, bulk BCR sequencing (bulkBCR-seq) currently provides the highest sampling depth, single-cell BCR sequencing (scBCR-seq) allows for paired chain characterization, and antibody peptide sequencing by tandem mass spectrometry (Ab-seq) provides information on the composition of secreted antibodies in the serum. Although still rare, studies combining these three technologies would comprehensively capture the humoral immune response. Yet, it has not been benchmarked to what extent the datasets generated by these three technologies overlap and complement each other. To address this question, we isolated peripheral blood B cells from healthy donors and sequenced BCRs at bulk and single-cell level, in addition to utilizing publicly available sequencing data. Integrated analysis was performed on these datasets, resolved by replicates and across individuals. Simultaneously, serum antibodies were isolated, digested with multiple proteases, and analyzed with Ab-seq. Systems immunology analysis showed high concordance in repertoire features between bulk and scBCR-seq within individuals, especially when replicates were utilized. In addition, Ab-seq identified clonotype-specific peptides using both bulk and scBCR-seq library references, demonstrating the feasibility of combining scBCR-seq and Ab-seq for reconstructing paired-chain Ig sequences from the serum antibody repertoire. Collectively, our work serves as a proof-of-principle for combining bulk sequencing, single-cell sequencing, and mass spectrometry as complementary methods towards capturing humoral immunity in its entirety.
A New Paradigm for Applying Deep Learning to Protein-Ligand Interaction Prediction
Authors: Wang Zechen , Wang Sheng , Li Yangyang , Guo Jingjing , Wei Yanjie , Mu Yuguang , Zheng Liangzhen , Li Weifeng
Published: November 2023

Protein-ligand interaction prediction poses a significant challenge in the field of drug design. Numerous machine learning and deep learning models have been developed to identify the most accurate docking poses of ligands and active compounds against specific targets. However, the current models often suffer from inadequate accuracy and lack practical physical significance in their scoring systems. In this research paper, we introduce IGModel, a novel approach that leverages the geometric information of protein-ligand complexes as input for predicting the root mean square deviation (RMSD) of docking poses and the binding strength (the negative value of the logarithm of binding affinity, pKd) with the same prediction framework. By incorporating the geometric information, IGModel ensures that its scores carry intuitive meaning. The performance of IGModel has been extensively evaluated on various docking power test sets, including the CASF-2016 benchmark, PDBbind-CrossDocked-Core, and DISCO set, consistently achieving state-of-the-art accuracies. Furthermore, we assess IGModel's generalization ability and robustness by evaluating it on unbiased test sets and sets containing target structures generated by AlphaFold2. The exceptional performance of IGModel on these sets demonstrates its efficacy. Additionally, we visualize the latent space of protein-ligand interactions encoded by IGModel and conduct interpretability analysis, providing valuable insights. This study presents a novel framework for deep learning-based prediction of protein-ligand interactions, contributing to the advancement of this field.
Inspiring Diverse Researchers in Virginia: Cultivating Research Excellence Through a Career Building Program
Authors: Mata-McMurry Lina V. , Phillips Jennifer V. , Burks Sandra G. , Greene Adam , Syed Sana , Johnston Karen C.
Published: November 2023

Historically underrepresented groups in biomedical research have continued to experience low representation despite shifting demographics. Diversity fosters inclusive, higher quality, and innovative team science. One avenue for diversifying research teams is integrating diversity-focused initiatives into Clinical and Translational Science Award (CTSA) Programs, such as the integrated Translational Health Research Institute of Virginia (iTHRIV). In 2020, iTHRIV participated in Building Up, developed by the University of Pittsburgh CTSA, intended to increase representation and improve career support for underrepresented groups in the biomedical workforce. Drawing lessons from this study, iTHRIV implemented the “inspiring Diverse Researchers in Virginia” (iDRIV) program. This year-long program provided education, coaching, mentoring, and sponsorship for underrepresented early-career investigators in the biomedical workforce. To date, 24 participants have participated in the program across three cohorts. Participants have been predominantly female (92%), with 33% identifying as Hispanic/Latinx, 29% as Black, and 13% Asian. Notably, 38% of scholars have subsequently achieved at least one accomplishment, such as receiving a local research honor or award and an extramural funding award from a foundation or federal agency. The iTHRIV iDRIV program serves as a model for providing career support to developing investigators from underrepresented backgrounds, with the overall goal of improving patient health.
Naturalistic drug cue reactivity in heroin use disorder: orbitofrontal synchronization as a marker of craving and recovery
Authors: Kronberg Greg , Ceceli Ahmet O. , Huang Yuefeng , Gaudreault Pierre-Olivier , King Sarah G. , McClain Natalie , Alia-Klein Nelly , Goldstein Rita Z.
Published: November 2023

Movies captivate groups of individuals (the audience), especially if they contain themes of common motivational interest to the group. In drug addiction, a key mechanism is maladaptive motivational salience attribution whereby drug cues outcompete other reinforcers within the same environment or context. We predicted that while watching a drug-themed movie, where cues for drugs and other stimuli share a continuous narrative context, fMRI responses in individuals with heroin use disorder (iHUD) will preferentially synchronize during drug scenes. Results revealed such drug-biased synchronization in the orbitofrontal cortex (OFC), ventromedial and ventrolateral prefrontal cortex, and insula. After 15 weeks of inpatient treatment, there was a significant reduction in this drug-biased shared response in the OFC, which correlated with a concomitant reduction in dynamically-measured craving, suggesting synchronized OFC responses to a drug-themed movie as a neural marker of craving and recovery in iHUD.
Adenine base editing corrects point mutation in mitochondrial single-stranded binding protein (SSBP1) to improve mitochondrial function
Authors: Cha Ju Hyuen , Lee Seok-Hoon , Yun Yejin , Choi Won Hoon , Koo Hansol , Jung Sung Ho , Chae Ho Byung , Lee Dae Hee , Lee Seok Jae , Jo Dong Hyun , Kim Jeong Hun , Song Jae-Jin , Chae Jong-Hee , Lee Jun Ho , Oh Seung Ha , Park Jiho , Kang Jin Young , Bae Sangsu , Lee Sang-Yeon
Published: November 2023

Mutations in nuclear genes that regulate the mitochondrial DNA (mtDNA) replication machinery have been linked to mtDNA depletion syndromes. Through whole-genome sequencing, we identified a heterozygous missense mutation (c.272G>A:p.Arg91Gln) in single-stranded binding protein 1 (SSBP1), a crucial protein involved in mtDNA replication. The proband manifested symptoms including sensorineural deafness, congenital cataract, optic atrophy, macular dystrophy, and myopathy, all of which are compatible with mtDNA depletion disease. We found that thisSSBP1mutation impeded multimer formation and DNA-binding affinity, which led to reduced efficiency of mtDNA replication and altered mitochondria dynamics. To correct this mutation, we tested two adenine base editor (ABE) variants using patient-derived fibroblasts. One variant, NG-Cas9-based ABE8e (NG-ABE8e), exhibited higher editing efficacy (up to 30% editing), and edited cells showed signs of improved mitochondrial replication and function, including increased mtDNA and ATP production. However, these cells also had higher frequencies of off-target editing of nearby nucleotides, but the risks from bystander editing were limited due to mostly silent mutations and off-target sites in non-translated regions. The other variant, NG-Cas9-based ABE8eWQ (NG-ABE8eWQ), had a safer therapeutic profile with very few off-target effects, but this came at the cost of lower editing efficacy (up to 10% editing). Despite this, NG-ABE8eWQ-edited cells still restored replication and improved mtDNA copy number, which in turn recovery of compromised mitochondrial function. As these therapeutic strategies make their way into the clinic, our research suggests that base editing-based gene therapies may be a promising treatment for mitochondrial diseases, including those associated withSSBP1mutations.
The qMini assay identifies an overlooked class of splice variants
Authors: Guan Bin , Bender Chelsea , Pantrangi Madhulatha , Moore Nia , Reeves Melissa , Naik Amelia , Li Huirong , Goetz Kerry , Blain Delphine , Agather Aime , Cukras Catherine , Zein Wadih M. , Huryn Laryssa A. , Brooks Brian P. , Hufnagel Robert B.
Published: November 2023

Splice variants are known to cause diseases by utilizing alternative splice sites, potentially resulting in protein truncation or mRNA degradation by nonsense-mediated decay. Splice variants are verified when altered mature mRNA sequences are identified in RNA analyses or minigene assays. Using a quantitative minigene assay, qMini, we uncovered a previously overlooked class of disease-associated splice variants that did not alter mRNA sequence but decreased mature mRNA level, suggesting a potentially new pathogenic mechanism.
The provision of information on time-lapse imaging: A systematic analysis of UK fertility clinics websites
Authors: Perrotta Manuela , Zampino Letizia , Geampana Alina , Bhide Priya
Published: November 2023

Structured Abstract

Research Question

This study aims to systematically analyse the provision of information on Time-lapse Imaging (TLI) by UK fertility clinic websites.

Design

We conducted an analysis of 106 clinic websites that offer fertility treatment to self-funded patients. The analysis aimed to examine whether these clinics offer TLI, the associated cost for patients, and the clarity and quality of the provided information.

Results

Out of the 106 websites analysed, 71 (67%) claimed to offer TLI, with 17 being NHS clinics and 54 being private clinics. Among these websites, 25 (35.2%) mentioned charging patients between £300 and £850, 25 (35.8%) claimed not to charge patients, and 21 (29.6%) did not provide any cost information for TLI. Although TLI is generally considered safe for patients and embryos, only 21 (29.6%) websites provided information on the associated risks. Furthermore, 64 (90.1%) websites made claims or implied that TLI leads to improved clinical outcomes by enhancing embryo selection. Notably, 34 (47.9%) websites did not mention or provide any links to the HFEA traffic light system. Additionally, 30 (42.2%) websites made claims regarding the effectiveness of TLI that contradicted the assessment of the HFEA, referring to early, mostly unspecified, studies.

Conclusions

It is crucial to provide patients with clear and accurate information to enable them to make fully informed decisions about TLI, particularly when they are responsible for the associated costs. The findings of this study raise concerns about the reliability and accuracy of the information available on fertility clinic websites, which are typically the primary source of information for patients.
Implementation of One Health surveillance systems: opportunities and challenges - Lessons learned from the OH-EpiCap application
Authors: Tegegne Henok Ayalew , Freeth Frederick T. A. , Bogaardt Carlijn , Taylor Emma , Reinhardt Johana , Collineau Lucie , Prada Joaquin M , Hénaux Viviane
Published: November 2023

As the complexity of health systems has increased over time, there is an urgent need for developing multi-sectoral and multi-disciplinary collaboration within the domain of One Health (OH). Despite the efforts to promote collaboration in health surveillance and overcome professional silos, implementing OH surveillance systems in practice remains challenging for multiple reasons. In this study, we describe the lessons learned from the evaluation of OH surveillance using OH-EpiCap (an online evaluation tool for One Health epidemiological surveillance capacities and capabilities), the challenges identified with the implementation of OH surveillance, and the main barriers that contribute to its sub-optimal functioning, as well as possible solutions to address them. We conducted eleven case studies targeting the multi-sectoral surveillance systems for antimicrobial resistance in Portugal and France,Salmonellain France, Germany, and the Netherlands,Listeriain The Netherlands, Finland and Norway,Campylobacterin Norway and Sweden, and psittacosis in Denmark. These evaluations facilitated the identification of common strengths and weaknesses, focusing on the organization and functioning of existing collaborations and their impacts on the surveillance system. Lack of operational and shared leadership, adherence to FAIR data principles, sharing of techniques, and harmonized indicators led to poor organization and sub-optimal functioning of OH surveillance systems. In most cases, the effectiveness of OH surveillance over traditional surveillance, operational costs, behavioural changes, and population health outcomes brought by the OH surveillance have not been evaluated. To this end, the establishment of a formal governance body with representatives from each sector could assist in overcoming long-standing barriers. Moreover, demonstrating the impacts of OH-ness of surveillance may facilitate the implementation of OH surveillance systems.
A retrospective analysis of the diagnostic performance of an FDA approved software for the detection of intracranial hemorrhage
Authors: Pourmussa Bianca , Gorovoy David
Published: November 2023

Objective

To determine the sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of Rapid ICH, a commercially available AI model, in detecting intracranial hemorrhage (ICH) on non-contrast computed tomography (NCCT) examinations of the head at a single regional medical center.

Methods

RapidAI’s Rapid ICH is incorporated into real time hospital workflow to assist radiologists in the identification of ICH on NCCT examinations of the head. 412 examinations from August 2022 to January 2023 were pulled for analysis. Scans in which it was unclear if ICH was present or not, as well as scans significantly affected by motion artifact were excluded from the study. The sensitivity, specificity, accuracy, PPV, and NPV of the software were then assessed retrospectively for the remaining 406 NCCT examinations using prior radiologist report as the ground-truth. A two tailedztest with α = 0.05 was preformed to determine if the sensitivity and specificity of the software in this study were significantly different from Rapid ICH’s reported sensitivity and specificity. Additionally, the software’s performance was analyzed separately for the male and female populations and a chi-square test of independence was used to determine if model correctness significantly depended on sex.

Results

Of the 406 scans assessed, Rapid ICH flagged 82 ICH positive cases and 324 ICH negative cases. There were 80 examinations (19.7%) truly positive for ICH and 326 examinations (80.3%) negative for ICH. This resulted in a sensitivity of 71.3%, 95% CI [61.3%-81.2%], a specificity of 92.3%, 95% CI [89.4%-95.2%], an accuracy of 88.2%, 95% CI [85.0%-91.3%], a PPV of 69.5%, 95% CI [59.5%-79.5%], and an NPV of 92.9%, 95% CI [90.1%-95.7%]. Two examinations were excluded due to no existing information on patient sex in the electronic medical record. The resulting sensitivity was significantly different from the sensitivity reported by Rapid ICH (95%),z= 2.60,p= .009 although the resulting specificity was not significantly different from the specificity reported by Rapid ICH (94%),z= 0.65,p= .517. The model performance did not depend on sex per the chi-square test of independence:X2(1 degree of freedom,N= 404) = 1.95,p= .162 (p> 0.05).

Conclusion

Rapid ICH demonstrates exceptional capability in the identification of ICH, but its performance when used at this site differs from the values advertised by the company, and from assessments of the model’s performance by other research groups. Specifically, the sensitivity of the software at this site is significantly different from the sensitivity reported by the company. These results underscore the necessity for independent evaluation of the software at institutions where it is implemented.
An exploration into the impact of the COVID-19 pandemic on maternal mental health in high-and middle-income countries with a case study in East Sussex
Authors: Sabesan Abbeishna , Ackley Caroline , Stone Sophia
Published: November 2023

Background

The physical isolation that the Coronavirus pandemic enforced resulted in a decline in mental health that disproportionally affected higher risk individuals, including women in the perinatal period. The wellbeing of perinatal women was, at times, neglected due to hospital and governmental isolation regulations. The aim of this study was to conduct a scoping review and Key Informant Interviews (KII) to identify gaps and opportunities for further research, and to distinguish discrepancies and correlations between the two sources of information.

Methods

Two methods were utilised: a scoping review and KIIs. The scoping review identified relevant articles through a database search on Google Scholar, PubMed and EBSCO. The KIIs were conducted virtually with counsellors working in a maternal mental health charity in South-East England. Both methods collected qualitative data and were thematically analysed.

Results

95 articles were eligible for the review and 5 participants were recruited for the KIIs. Thematic analysis revealed 6 themes in both sources (1) demographics; (2) support; (3) policy; (4) insecurity; (5) anxiety; and (6) milestones. Between the two datasets there were no disparities in the impacts of changing policies, fear of the virus, and the grief caused by missing perinatal milestones on mental health. Significant discrepancies were identified in the influence of demographic characteristics, which was a risk factor for adverse mental health outcomes.

Conclusion

The most prominent theme in the review is the reduced support available, whilst the KIIs indicate that changing hospital policies are the main cause of harm to perinatal mental health. Birth trauma is deemed to be of significance in the interviews but not in the literature. Further research should focus on the impact of the pandemic on recovery following birth trauma to identify long-term implications and facilitate policy changes to reduce the risk of birth trauma/ post-traumatic stress disorder.