bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Linkable, Polycarbonate Gut Microbiome-Distal Tumor Chip Platform for Interrogating Cancer Promoting Mechanisms
Authors: Brasino Danielle S.K. , Speese Sean D. , Schilling Kevin , Schutt Carolyn E. , Barton Michelle C. 
Published: September 2023

AbstractGut microbiome composition has been tied to diseases ranging from arthritis to cancer to depression. However, mechanisms of action are poorly understood, limiting development of relevant therapeutics. Organ-on-chip platforms, which model minimal functional units of tissues and can tightly control communication between them, are ideal platforms to study these relationships. Many gut microbiome models have been published to date but devices are typically fabricated using oxygen permeable PDMS, requiring interventions to support anaerobic bacteria. To address this challenge, a novel platform was developed where the chips were fabricated entirely from gas-impermeable polycarbonate without tapes or gaskets. These chips replicated polarized villus-like structures of the native tissue. Further, they enabled co-cultures of commensal anaerobic bacteriaBlautia coccoideson the surface of gut epithelia for two days within a standard incubator. Another complication of PDMS devices is high ad-/absorption, limiting applications in high-resolution microscopy and biomolecule interaction studies. For future communication studies between gut microbiota and distal tumors, an additional polycarbonate chip design was developed to support hydrogel-embedded tissue culture. These chips enable high-resolution microscopy with all relevant processing done on-chip. Designed forfacilelinking, this platform will make a variety of mechanistic studies possible.
Pulmonary function and survival one year after dupilumab treatment of acute moderate to severe COVID-19: A follow up study from a Phase IIa trial
Authors: Hendrick Jennifer , Ma Jennie Z. , Haughey Heather M. , Coleman Rachael , Nayak Uma , Kadl Alexandra , Sturek Jeffrey M. , Jackson Patrick , Young Mary K. , Allen Judith E. , Petri William A. 
Published: September 2023

AbstractBackgroundWe previously conducted a Phase IIa randomized placebo-controlled trial of 40 subjects to assess the efficacy and safety of dupilumab use in those hospitalized with COVID-19 (NCT04920916). Based on our pre-clinical data suggesting downstream pulmonary dysfunction with COVID-19 induced type 2 inflammation, we contacted patients from our Phase IIa study at 1 year for assessment of Post Covid-19 Conditions (PCC).MethodsSubjects at 1 year after treatment underwent pulmonary function testing (PFTs), high resolution computed tomography (HRCT) imaging, symptom questionnaires, neurocognitive assessments, and serum immune biomarker analysis, with subject survival also monitored. The primary outcome was the proportion of abnormal PFTs, defined as an abnormal diffusion capacity for carbon monoxide (DLCO) or 6-minute walk testing (6MWT) at the 1-year visit.ResultsSixteen of the 29 one-year survivors consented to the follow up visit. We found that subjects who had originally received dupilumab were less likely to have abnormal PFTs compared to those who received placebo (Fisher’s exact p=0.011, adjusted p=0.058). We additionally found that 3 out of 19 subjects (16%) in the dupilumab group died by 1 year compared to 8 out of 21 subjects (38%) in the placebo group (log rank p=0.12). We did not find significant differences in neurocognitive testing, symptoms or CT chest imaging between treatment groups but observed evidence of reduced type 2 inflammation in those who received dupilumab.ConclusionsWe observed evidence of reduced long-term morbidity and mortality from COVID-19 with dupilumab treatment during acute hospitalization when added to standard of care regimens.
The mediating role of mammographic density in the protective effect of early-life adiposity on breast cancer risk: a multivariable Mendelian randomization study
Authors: Vabistsevits Marina , Smith George Davey , Richardson Tom G. , Richmond Rebecca C. , Sieh Weiva , Rothstein Joseph H. , Habel Laurel A. , Alexeeff Stacey E. , Lloyd-Lewis Bethan , Sanderson Eleanor 
Published: September 2023

AbstractObservational studies suggest that mammographic density (MD) may have a role in the unexplained protective effect of childhood adiposity on breast cancer risk. Here, we investigated a complex and interlinked relationship between puberty onset, adiposity, MD, and their effects on breast cancer using Mendelian randomization (MR).We estimated the effects of childhood and adulthood adiposity, and age at menarche on MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)) using MR and multivariable MR (MVMR), allowing us to disentangle their total and direct effects. Next, we examined the effect of MD on breast cancer risk, including risk of molecular subtypes, and accounting for genetic pleiotropy. Finally, we used MVMR to evaluate whether the protective effect of childhood adiposity on breast cancer was mediated by MD.Childhood adiposity had a strong inverse effect on mammographic DA, while adulthood adiposity increased NDA. Later menarche had an effect of increasing DA and PD, but when accounting for childhood adiposity, this effect attenuated to the null. DA and PD had a risk-increasing effect on breast cancer across all subtypes. The MD single-nucleotide polymorphism (SNP) estimates were extremely heterogeneous, and examination of the SNPs suggested different mechanisms may be linking MD and breast cancer. Finally, MR mediation analysis estimated that 56% (95% CIs [32% - 79%]) of the childhood adiposity effect on breast cancer risk was mediated via DA.In this work, we sought to disentangle the relationship between factors affecting MD and breast cancer. We showed that higher childhood adiposity decreases mammographic DA, which subsequently leads to reduced breast cancer risk. Understanding this mechanism is of great importance for identifying potential targets of intervention, since advocating weight gain in childhood would not be recommended.
A mathematical model for multiple COVID-19 waves applied to Kenya
Authors: Ogana Wandera , Juma Victor Ogesa , Bulimo Wallace D. , Chiteri Vincent Nandwa 
Published: September 2023

AbstractThe COVID-19 pandemic, which began in December 2019, prompted governments to implement non-pharmaceutical interventions (NPIs) to curb its spread. Despite these efforts and the discovery of vaccines and treatments, the disease continued to circulate globally, evolving into multiple waves, largely driven by emerging COVID-19 variants. Mathematical models have been very useful in understanding the dynamics of the pandemic. Mainly, their focus has been limited to individual waves without easy adaptability to multiple waves. In this study, we propose a compartmental model that can accommodate multiple waves, built on three fundamental concepts. Firstly, we consider the collective impact of all factors affecting COVID-19 and express their influence on the transmission rate through piecewise exponential-cum-constant functions of time. Secondly, we introduce techniques to model the fore sections of observed waves, that change infection curves with negative gradients to those with positive gradients, hence, generating new waves. Lastly, we implement a jump mechanism in the susceptible fraction, enabling further adjustments to align the model with observed infection curve. By applying this model to the Kenyan context, we successfully replicate all COVID-19 waves from March 2020 to January 2023. The identified change points align closely with the emergence of dominant COVID-19 variants, affirming their pivotal role in driving the waves. Furthermore, this adaptable approach can be extended to investigate any new COVID-19 variant or any other periodic infectious diseases, including influenza.
Pathway-Specific Polygenic Scores Improve Cross-Ancestry Prediction of Psychosis and Clinical Outcomes
Authors: Tubbs Justin D. , Leung Perry B.M. , Zhong Yuanxin , Zhan Na , Hui Tomy C.K. , Ho Karen K.Y. , Hung Karen S.Y. , Cheung Eric F.C. , So Hon-Cheong , Lui Simon S.Y. , Sham Pak C. 
Published: September 2023

AbstractPsychotic disorders are debilitating conditions with disproportionately high public health burden. Genetic studies indicate high heritability, but current polygenic scores (PGS) account for only a fraction of variance in psychosis risk. PGS often show poor portability across ancestries, performing significantly worse in non-European populations. Pathway-specific PGS (pPGS), which restrict PGS to genomic locations within distinct biological units, could lead to increased mechanistic understanding of pathways that lead to risk and improve cross-ancestry prediction by reducing noise in genetic predictors. This study examined the predictive power of genome-wide PGS and nine pathway-specific pPGS in a unique Chinese-ancestry sample of deeply-phenotyped psychosis patients and non-psychiatric controls. We found strong evidence for the involvement of schizophrenia-associated risk variants within “nervous system development” (p=2.5e-4) and “regulation of neuron differentiation” pathways (p=3.0e-4) in predicting risk for psychosis. We also found the “ion channel complex” pPGS, with weights derived from GWAS of bipolar disorder, to be strongly associated with the number of inpatient psychiatry admissions a patient experiences (p=1.5e-3) and account for a majority of the signal in the overall bipolar PGS. Importantly, although the schizophrenia genome-wide PGS alone explained only 3.7% of the variance in liability to psychosis in this Chinese ancestry sample, the addition of the schizophrenia-weighted pPGS for “nervous system development” and “regulation of neuron differentiation” increased the variance explained to 6.9%, which is on-par with the predictive power of PGS in European ancestry samples. Thus, not only can pPGS provide greater insight into mechanisms underlying genetic risk for disease and clinical outcomes, but may also improve cross-ancestry risk prediction accuracy.
Spatial and temporal relationship between focal and rotational drivers and their relationship to structural remodeling in patients with persistent AF
Authors: Honarbakhsh Shohreh , Roney Caroline , Wharmby Amy , Vidal Horrach Caterina , Hunter Ross J. 
Published: September 2023

ABSTRACTBackgroundFocal and rotational activations have been demonstrated in AF, but their relationship to each other and to structural remodeling remains unclear.MethodsPatients undergoing catheter ablation for persistent AF were included. All patients underwent pulmonary vein isolation. Unipolar signals were collected to identify focal and rotational drivers using a wavefront propagation algorithm. Aim was to assess the relationship of drivers to underlying low voltage zones (LVZs; <0.5mV) and to determine whether there was a temporal (≤500ms) and spatial (≤12mm) relationship between focal and rotational drivers.ResultsIn 40 patients, 86 drivers were identified (57, 66.3% focal and 29, 33.7% rotational). Rotational drivers showed co-localized to LVZs (21/29, 72.4%) whilst focal drivers did not (11/57 in LVZ, 19.3%; p<0.001). The proportion of the left atrium (LA) occupied by LVZs predicted rotational driver occurrence (AUC 0.96, 95%CI 0.90-1.00; p<0.001). In patients with a relatively healthy atrium, where the atrium was made up of ≤15% LVZs, only focal drivers were identified. Eighteen of the 21 (85.7%) rotational drivers located in LVZs also showed a temporal and spatial relationship to a focal driver. The presence of a LVZ within 12 mm of the focal driver was a strong predictor for whether a paired rotational driver would also occur in that vicinity.ConclusionsRotational drivers are largely confined to areas of structural remodelling and have a clear spatial and temporal relationship with focal drivers suggesting they are dependent on them. These novel mechanistic observations outline a plausible model for patient specific mechanisms maintaining AF.
Lesioned hemisphere-specific phenotypes of post-stroke fatigue emerge from motor and mood characteristics in chronic stroke
Authors: De Doncker William , Kuppuswamy Annapoorna 
Published: September 2023

AbstractPost-stroke fatigue commonly presents alongside several co-morbidities. The interaction between co-morbidities and their relationship to fatigue is not known. Here we focus on physical and mood comorbidities, alongside lesion characteristics. We predict the emergence of distinct fatigue phenotypes with distinguishable physical and mood characteristics.In this cross-sectional observational study, in 94 first time, non-depressed, moderate to minimally impaired chronic stroke survivors, the relationship between measures of motor function (Grip strength, Nine Hole Peg Test time), motor cortical excitability (Resting Motor Threshold), Hospital Anxiety and Depression Scale scores and Fatigue Severity Scale – 7 scores age, gender and side of stroke was established using Spearman’s rank correlation. Mood and motor variables were then entered into k-means clustering algorithm to identify number of unique clusters, if any. Post-hoc pairwise comparisons followed by corrections for multiple comparisons was performed to characterise differences between clusters in the variables included in k-means clustering.Clustering analysis revealed a 4-cluster model to be the winning model (average silhouette score of 0.311). There was no significant difference in FSS-7 scores between the 4 high-fatigue clusters. 2 clusters consisted of only left hemispheric strokes, and the remaining two were exclusively right hemisphere strokes. Factors that differentiated hemisphere-specific clusters was the level of depressive symptoms and anxiety. Motor characteristics distinguished the low-depressive left from right hemispheric clusters.The significant differences in side of stroke, and the differential relationship between mood and motor function in the 4 clusters reveals the heterogenous nature of post-stroke fatigue, which is amenable to categorisation. Such categorisation is critical for understanding the interactions between post-stroke fatigue and its presenting comorbid deficits, with significant implications for development of context/category specific interventions.
Comparing peptide identifications by FAIMS versus quadrupole gas-phase fractionation
Authors: Faivre Danielle A. , McGann Christopher D. , Merrihew Gennifer E. , Schweppe Devin K. , MacCoss Michael J. 
Published: September 2023

AbstractHigh-field asymmetric waveform ion mobility spectrometry (FAIMS) coupled to liquid chromatography-mass spectrometry (LC-MS) has been shown to increase peptide and protein detections compared to LC-MS/MS alone. However, FAIMS has not been compared to other methods of gas-phase fractionation, such as quadrupole gas-phase fractionation, which could increase our understanding of the mechanisms of improvement. The goal of this work was to assess whether FAIMS improves peptide identifications because 1) gas-phase fractionation enables the analysis of less abundant signals by excluding more abundant precursors from filling the ion trap, 2) the use of FAIMS reduces co-isolation of peptides during the MS/MS process resulting in a reduction of chimeric spectra, or 3) a combination of both. To investigate these hypotheses, pooled human brain tissue samples were measured in triplicate using FAIMS gas-phase fractionation, quadrupole gas-phase fractionation, or no gas-phase fractionation on two Thermo Eclipse Tribrid Mass Spectrometers. On both instruments, our data confirmed prior observations that FAIMS increased the number of peptides identified. We further demonstrated that the main benefit of FAIMS is due to the reduced co-isolation of persistent peptide precursor ions, which results in a decrease in chimeric spectra.
Long-term severe hypoxia adaptation induces non-canonical EMT and a novel Wilms Tumor 1 (WT1) isoform
Authors: Quenneville Jordan , Feghaly Albert , Tual Margaux , Major François , Gagnon Etienne 
Published: September 2023

ABSTRACTThe majority of cancer deaths are caused by solid tumors, where the four most prevalent cancers (breast, lung, colorectal and prostate) account for more than 60% of all cases (1). Tumor cell heterogeneity driven by variable cancer microenvironments, such as hypoxia, is a key determinant of therapeutic outcome. We developed a novel culture protocol, termed the Long-Term Hypoxia (LTHY) time course, to recapitulate the gradual development of severe hypoxia seenin vivo, to mimic conditions observed in primary tumors. Cells subjected to LTHY underwent a non-canonical epithelial to mesenchymal transition (EMT) based on miRNA and mRNA signatures as well as displayed EMT-like morphological changes. Concomitant to this, we report production of a novel truncated isoform of WT1 transcription factor (tWt1), a non-canonical EMT driver, with expression driven by a yet undescribed intronic promoter through hypoxia-responsive elements (HREs). We further demonstrated that tWt1 initiates translation from an intron-derived start codon, retains proper subcellular localization, DNA binding, and its human ortholog negatively predicts long-term patient survival. Our study demonstrates the importance of culture conditions that better mimic those observed in cancers, especially with regards to hypoxia, and identifies a novel isoform of WT1 which correlates with poor long-term survival in ovarian cancer.
Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response
Authors: Karasik Agnes , Lorenzi Hernan A. , DePass Andrew V. , Guydosh Nicholas R. 
Published: September 2023

SummaryViral infection triggers several dsRNA sensors that lead to changes in gene expression in the cell. One of these sensors activates an endonuclease, RNase L, that cleaves single stranded RNA. However, how the resultant widespread RNA fragmentation affects gene expression is not fully understood. Here we show that this fragmentation induces the Ribotoxic Stress Response via ZAKα, potentially through ribosome collisions. The p38 and JNK pathways that are activated as part of this response promote outcomes that inhibit the virus, such as programmed cell death. We also show that RNase L limits the translation of stress-responsive genes, including antiviralIFITmRNAs andGADD34that encodes an antagonist of the Integrated Stress Response. Intriguingly, we found the activity of the generic endonuclease, RNase A, recapitulates many of the same molecular phenotypes as activated RNase L, demonstrating how widespread RNA cleavage can evoke an antiviral program.HighlightsActivated RNase L acts with dsRNA-sensing pathways to promote cell signalingRNA fragmentation induces transcription through ZAKα signalingActivation of RNase L modulates levels of eIF2α phosphorylationTranslation of theGADD34andIFITmRNAs is inhibited by active RNase L
Natural genetic variation quantitatively regulates heart rate and dimension
Authors: Gierten Jakob , Welz Bettina , Fitzgerald Tomas , Thumberger Thomas , Hummel Oliver , Leger Adrien , Weber Philipp , Hassel David , Hübner Norbert , Birney Ewan , Wittbrodt Joachim 
Published: September 2023

AbstractThe polygenic contribution to heart development and function along the health-disease continuum remains unresolved. To gain insight into the genetic basis of quantitative cardiac phenotypes, we utilize highly inbred Japanese rice fish models,Oryzias latipes, andOryzias sakaizumii. Employing automated quantification of embryonic heart rates as core metric, we profiled phenotype variability across five inbred strains. We observed maximal phenotypic contrast between individuals of the HO5 and the HdrR strain. HO5 showed elevated heart rates associated with embryonic ventricular hypoplasia and impaired adult cardiac function. This contrast served as the basis for genome-wide mapping. In a segregation population of 1192 HO5 x HdrR F2 embryos, we mapped 59 loci (173 genes) associated with heart rate. Experimental validation of the top 12 candidate genes in loss-of-function models revealed their causal and distinct impact on heart rate, development, ventricle size, and arrhythmia. Our study uncovers new diagnostic and therapeutic targets for developmental and electrophysiological cardiac diseases and provides a novel scalable approach to investigate the intricate genetic architecture of the vertebrate heart.One-Sentence SummaryKey loci for vertebrate heart function mapped and validated, highlighting diagnostic and potential therapeutic targets for cardiac disorders.
Therapeutic mitigation of measles-like immune amnesia and exacerbated disease after prior respiratory virus infections in ferrets
Authors: Cox Robert M , Wolf Josef D , Lieberman Nicole A , Lieber Carolin M , Kang Hae-Ji , Sticher Zachary M , Yoon Jeong-Joong , Andrews Meghan K , Govindarajan Mugunthan , Krueger Rebecca E , Sobolik Elizabeth B. , Natchus Michael G , Gewirtz Andrew T , deSwart Rik , Kolykhalov Alexander A , Hekmatyar Khan , Sakamoto Kaori , Greninger Alexander L , Plemper Richard K 
Published: September 2023

SummaryAfter years of the COVID-19 pandemic, over 40 million children worldwide are at risk of measles due to delayed vaccination1and temporary SARS-CoV-2 viral dominance2. Acute measles has a case-fatality rate of ∼1%, but most morbidity and mortality arise post-measles due to destruction of pre-existing immune memory by lymphotropic measles virus (MeV)3,4, a paramyxovirus of theMorbillivirusgenus. MeV-induced immune amnesia is not mitigated by post-exposure vaccination and the impact of unrelated respiratory virus disease history on measles severity has not been defined. We used a lethal canine distemper virus (CDV)-ferret model as surrogate for human morbillivirus disease5and employed the orally efficacious broad-spectrum paramyxovirus polymerase inhibitor GHP-883096to establish measles treatment paradigms. Applying a receptor tropism-intact recombinant CDV with low lethality, we providein vivoconfirmation of the morbillivirus immune amnesia hypothesis and reveal an 8-day advantage of antiviral treatment versus therapeutic vaccination in preserving immune memory. Infection of ferrets with non-lethal influenza A virus (IAV) A/CA/07/2009 (H1N1) or respiratory syncytial virus (RSV) four weeks prior to CDV caused exacerbated CDV disease that rapidly advanced to fatal hemorrhagic pneumonia associated with lung onslaught by commensal bacteria. RNAseq of BAL samples and lung tissue identified CDV-induced expression of trefoil factor (TFF) peptides, which was absent in animals pre-infected with IAV, thus highlighting that immune priming by unrelated respiratory viruses influences morbillivirus infection outcome. Non-invasive pulmonary ferret MRI revealed that severe outcomes of consecutive IAV/CDV infections were prevented by oral GHP-88309 treatment even when initiated after peak clinical signs of CDV. These findings validate the morbillivirus immune amnesia hypothesis, define treatment paradigms for measles, identify prior disease history as risk factor for exacerbated morbillivirus disease, and demonstrate that treating morbillivirus infection with direct-acting oral antivirals provides therapeutic benefit regardless of whether the time window to mitigate primary clinical signs of infection has closed.