bluuebunny/crossref_metadata_2025_split huggingface dataset:
RIGATonI: An R software for Rapid Identification of Genomic Alterations in Tumors affecting lymphocyte Infiltration
Authors: Vella Raven , Hoskins Emily L. , Yu Lianbo , Reeser Julie W. , Wing Michele R. , Samorodnitsky Eric , Stein Leah , Bruening Elizabeth G. , Paruchuri Anoosha , Churchman Michelle , Single Nancy , Chen Wei , Freud Aharon G. , Roychowdhury Sameek 
Published: March 2024

ABSTRACTTumor genomic alterations have been associated with altered tumor immune microenvironments and therapeutic outcomes. These studies raise a critical question: are there additional genomic variations altering the immune microenvironment in tumors that can provide insight into mechanisms of immune evasion? This question is the backbone of precision immuno-oncology. Current computational approaches to estimate immunity in bulk RNA sequencing (RNAseq) from tumors include gene set enrichment analysis and cellular deconvolution, but these techniques do not consider the spatial organization of lymphocytes or connect immune phenotypes with gene activity. Our new software package, Rapid Identification of Genomic Alterations in Tumors affecting lymphocyte Infiltration (RIGATonI), addresses these two gaps in separate modules: the Immunity Module and the Function Module. Using pathologist-reviewed histology slides and paired bulk RNAseq expression data, we trained a machine learning algorithm to detect high, medium, and low levels of immune infiltration (Immunity Module). We validated this technique using a subset of pathologist-reviewed slides not included in the training data, multiplex immunohistochemistry, flow cytometry, and digital staining of The Cancer Genome Atlas (TCGA). In addition to immune infiltrate classification, RIGATonI leverages another novel machine learning algorithm for the prediction of gain- and loss-of-function genomic alterations (Function Module). We validated this approach using clinically relevant and function-impacting genomic alterations from the OncoKB database. Combining these two modules, we analyzed all genomic alterations present in solid tumors in TCGA for their resulting protein function and immune phenotype. We visualized these results on a publicly available website. To illustrate RIGATonI’s potential to identify novel genomic variants with associated altered immune phenotypes, we describe increased anti-tumor immunity in renal cell carcinoma tumors harboring 14q deletions and confirmed these results with previously published single-cell RNA sequencing. Thus, we present our R package and online database, RIGATonI: an innovative software for precision immuno-oncology research.
Thalamic stimulation induced changes in network connectivity and excitability in epilepsy
Authors: Gregg Nicholas M. , Valencia Gabriela Ojeda , Pridalova Tereza , Huang Harvey , Kremen Vaclav , Lundstrom Brian N. , Van Gompel Jamie J. , Miller Kai J. , Worrell Gregory A. , Hermes Dora 
Published: March 2024

AbstractBackgroundThe clinical effects of deep brain stimulation for neurological conditions manifest across multiple timescales, spanning seconds to months, and involve direct electrical modulation, neuroplasticity, and network reorganization. In epilepsy, the delayed effects of deep brain stimulation on seizures limit optimization. Single pulse electrical stimulation and the resulting pulse evoked potentials offer a measure network effective connectivity and excitability. This study leverages single pulse and high frequency thalamic stimulation during stereotactic electroencephalography to assess seizure network engagement, modulate network activity, and track changes in excitability and epileptiform abnormalities.MethodsTen individuals with drug resistant epilepsy undergoing clinical stereotactic electroencephalography were enrolled in this retrospective cohort study. Each underwent a trial of high frequency (145 Hz) thalamic stimulation. Pulse evoked potentials were acquired before and after high frequency stimulation. Baseline evoked potential root-mean-square amplitude assessed seizure network engagement, and modulation of amplitude (post high frequency stimulation versus baseline; Cohen’sdeffect size) assessed change in network excitability. Interictal epileptiform discharge rates were measured by an automated classifier at baseline and during high frequency stimulation. Statistical significance was determined using paired-sample t-tests (p<0.05 significance level). This study was approved by the Mayo Clinic Institutional Review Board, with informed consent obtained from all participants.ResultsThalamic stimulation delivered for >1.5 hours significantly reduced pulse evoked potential amplitudes in connected areas compared to baseline, with the degree of modulation correlated with baseline connectivity strength. Shorter stimulation durations did not induce reliable changes. High frequency stimulation immediately suppressed interictal epileptiform discharge rates in seizure networks with strong baseline thalamocortical connectivity. Pulse evoked potentials delineated the anatomical distribution of network engagement, revealing distinct patterns across thalamic subfields.ConclusionPulse evoked potentials and thalamic stimulation during stereotactic electroencephalography provide novel network biomarkers to evaluate target engagement and modulation of large-scale networks across acute and subacute timescales. This approach demonstrates potential for efficient, data-driven neuromodulation optimization, and a new paradigm for personalized deep brain stimulation in epilepsy.
Intracalvariosseous injection bypasses the blood-brain barrier as a novel drug delivery approach for pre-clinical and clinical trials in stroke
Authors: Liu Wenqian , Wang Nanxing , Yang Mo , Zhang Meiyang , Liu Xiangrong , Shi Kaibin , Liu Weiming , Ou Yunwei , Liu Liping , Yang Zhonghua , Liu Yanfang , Zhou Mengyuan , Liao Xiaoling , Qu Hui , Shi Fu-Dong , Pan Yuesong , Wang Chaoyu , Feng Xuezheng , Zhao Xingquan , Zhang Mingjun , Wang Yongjun , Wang Yilong 
Published: March 2024

AbstractCentral nervous system (CNS) accessibility constitutes a major hurdle for drug development to treat neurological diseases. Existing drug delivery methods rely integrity of the blood-brain barrier (BBB) for CNS penetration. Here we showed that the microchannels between the skull marrow and the dura mater could be harnessed for drug delivery by intracalvariosseous (ICO) injection. Drugs administered via ICO injection were found to reach cranial bone marrow-dura-perivascular space, and the injection procedure did not cause osteomyelitis or BBB damage. To validate this approach, we examined the efficacy of two neuroprotective agents, NA-1 and Y-3, via ICO injection in rat model of stroke and found that ICO injection increased drug accumulation in the brain compared to intravenous injection, reduced infarct area and alleviated neurological deficits. We subsequently conducted a clinical trial to assess the safety of ICO in acute ischemic stroke patients (ClinicalTrials.govidentifierNCT05849805), showing that ICO injection was feasible and safe in humans and its therapeutic effects may be observed. Collectively, our study identifies that the microchannels between the skull bone marrow and the dura mater act as a new channel for CNS drug delivery to achieve high intracranial drug exposure in a short period of time. The safety of ICO injection makes it a promising route of drug administration for CNS diseases.
Blood pressure management in 1,000 patients with CureApp HT digital therapeutics for hypertension
Authors: Nomura Akihiro , Takagi Yusuke , Tanigawa Tomoyuki , Takamura Masayuki , Node Koichi , Kario Kazuomi 
Published: March 2024

SummaryBackgroundEssential hypertension patients who utilized a new digital therapeutics (DTx) application for hypertension for up to 6 months achieved notable decreases in ambulatory, home, and office blood pressures, per the HERB-DH1 randomized controlled trial. Nevertheless, the extent of its effectiveness in clinical settings is not yet fully understood. This study seeks to evaluate blood pressure changes among the initial 1,000 hypertensive patients prescribed the DTx app in a practice-based real-world data (RWD) cohort.MethodsDeidentified data from the CureApp HT clinical information database was examined. The primary outcome measure evaluated the difference in morning systolic blood pressure (SBP) at home between week 12 and baseline. Variations in morning home SBP from week 24 (measured from baseline) and app engagement rates from weeks 12 and 24 (measured from baseline) were significant secondary outcomes. We also used analysis of covariance to compare home morning SBPs between the RWD cohort and the historical HERB-DH1 control group.FindingsThe practice-based RWD cohort had a mean age of 54·8 ± 11·6 years, and 48·9% of them were female. Their baseline morning home SBP was 132·8 ± 12·9 mmHg, and 91·7% of them used the app. At week 12, their morning home SBP decreased by −4·9 mmHg (confidence interval (CI), −5·6 to −4·2), and at week 24, it dropped by −6·1 mmHg (CI, −7·3 to −5·0). These declines were much greater than those seen in the HERB-DH1 control group. Subgroup analysis showed pragmatic SBP reductions with DTx in patients aged 265 years or on medication at baseline, a cohort previously excluded from the HERB-DH1 trial.InterpretationThe initial 1,000 hypertensive patients prescribed the DTx app showed significant decreases in morning home SBP. These results may suggest importance of the DTx app’s engagement and effectiveness that could extend to older adult patients and those on medication.FundingCureApp, Inc.
A Novel Perspective on Genes Driving Metastatic Pancreatic Cancer Revealed by Single-cell RNA Sequencing
Authors: Sayad Saed , Hiatt Mark , Mustafa Hazem 
Published: March 2024

AbstractBackgroundPancreatic ductal adenocarcinoma (PDAC) is formidable in its advanced, metastatic stage. Aggressive spread of malignant cells from the pancreas to distant organs like the liver and lungs is often detected late, complicating treatment by markedly limiting therapeutic options and worsening prognosis by drastically diminishing survival. Understanding the molecular intricacies driving metastasis is crucial for developing targeted therapies for this deadly disease with otherwise narrow recourse.MethodWe obtained single-cell transcriptomes (GSE154778) from the website of the United States National Institutes of Health. The single-cell RNA profiles of 10 PDAC primary tumors and six metastatic lesions, dissociated from one another, were obtained using the 10x Genomics Chromium platform. Our analysis focused on identifying genes, pathways, and gene ontology terms with distinct expression patterns between metastatic and primary single cells.ResultsThrough single-cell RNA-sequencing (RNA-seq), we discerned significant alterations in gene expression profiles between primary tumors and metastatic lesions in PDAC, particularly emphasizing the dysregulation of ribosomal protein (RP) gene family as potential drivers of aggressive cancer behavior. Moreover, the enrichment of pathways related to metabolism, hypoxia response, and microbial influences underscores the intricate interplay between cellular adaptations and the tumor microenvironment in facilitating metastasis. Conversely, the downregulation of signaling pathways and extracellular matrix remodeling suggests a loss of regulatory control and enhanced invasive potential in metastatic cells.ConclusionsIn our comparison of primary and metastatic PDAC using single-cell RNA-seq, we have identified numerous differentially expressed genes, pathways, and gene ontology terms. The most significant finding may be that the ribosomal protein (RP) gene family is shared by 48 of the top 50 overexpressed pathways (comprising 5,848 genes), meaning that altering any member of this family as a potential driver could affect 48 pathways simultaneously. This revelation that metastatic cells may be regressed to a non-metastatic state by downregulating the RP gene family presents a promising pathway since this family is druggable.
B cell maturation restored ancestral germlines to control Omicron BA.2.86
Authors: Paciello Ida , Pierleoni Giulio , Pantano Elisa , Antonelli Giada , Pileri Piero , Maccari Giuseppe , Cardamone Dario , Realini Giulia , Perrone Federica , Neto Martin Mayora , Pozzessere Simone , Fabbiani Massimiliano , Panza Francesca , Rancan Ilaria , Tumbarello Mario , Montagnani Francesca , Medini Duccio , Maes Piet , Temperton Nigel , Simon-Loriere Etienne , Schwartz Olivier , Rappuoli Rino , Andreano Emanuele 
Published: March 2024

ABSTRACTThe unceasing interplay between SARS-CoV-2 and the human immune system has led to a continuous maturation of the virus and B cell response providing an opportunity to track their evolution in real time. We longitudinally analyzed the functional activity of almost 1,000 neutralizing human monoclonal antibodies (nAbs) isolated from vaccinated people, and from individuals with hybrid and super hybrid immunity (SH), developed after three mRNA vaccine doses and two breakthrough infections. The most potent neutralization and Fc functions against highly mutated variants, including BA.2.86, were found in the SH cohort. Despite different priming, epitope mapping revealed a convergent maturation of the functional antibody response. Neutralization was mainly driven by Class 1/2 nAbs while Fc functions were induced by Class 3/4 antibodies. Remarkably, broad neutralization was mediated by restored IGHV3-53/3-66 B cell germlines which, after heterogenous exposure to SARS-CoV-2 S proteins, increased their level of somatic hypermutations. Our study shows the resilience of the human immune system which restored previously expanded germlines and activated naïve B cells to broaden the antibody repertoire of antibodies to control future SARS-CoV-2 variants.
Viral delivery of recombinases to activate heritable genetic switches in plants
Authors: Chamness James C. , Cody Jon P. , Cruz Anna J. , Voytas Daniel F. 
Published: March 2024

AbstractViral vectors provide an increasingly versatile platform for transformation-free reagent delivery to plants. RNA viral vectors can be used to induce gene silencing, overexpress proteins, or introduce gene editing reagents, but they are often constrained by carrying capacity or restricted tropism in germline cells. Site-specific recombinases that catalyze precise genetic rearrangements are powerful tools for genome engineering that vary in size and, potentially, efficacy in plants. In this work, we show that viral vectors based onTobacco rattle virus(TRV) deliver and stably express four recombinases ranging in size from ∼0.6kb to ∼1.5kb, and achieve simultaneous marker removal and reporter activation through targeted excision in transgenicNicotiana benthamianatarget lines. TRV vectors with Cre, FLP, CinH, and Integrase13 efficiently mediated recombination in infected somatic tissue, and also led to heritable modifications at high frequency. An excision-activated Ruby reporter enabled simple and high-resolution tracing of infected cell lineages, without the need for molecular genotyping. Together, our experiments broaden the scope of viral recombinase delivery, and offer insights into infection dynamics that may be useful in the development of future viral vectors.
Influenza virus shedding and symptoms: Dynamics and implications from a multi-season household transmission study
Authors: Morris Sinead E. , Nguyen Huong Q. , Grijalva Carlos G. , Hanson Kayla E. , Zhu Yuwei , Biddle Jessica E. , Meece Jennifer K. , Halasa Natasha B. , Chappell James D. , Mellis Alexandra M. , Reed Carrie , Biggerstaff Matthew , Belongia Edward A. , Talbot H. Keipp , Rolfes Melissa A. 
Published: March 2024

AbstractIsolation of symptomatic infectious persons can reduce influenza transmission. However, virus shedding that occurs without symptoms will be unaffected by such measures. Identifying effective isolation strategies for influenza requires understanding the interplay between individual virus shedding and symptom presentation. From 2017–2020, we conducted a case-ascertained household transmission study using influenza real-time reverse transcription quantitative PCR (RT-qPCR) testing of nasal swabs and daily symptom diary reporting for up to 7 days after enrollment (≤14 days after index onset). We assumed real-time RT-qPCR cycle threshold (Ct) values were indicators of quantitative virus shedding and used symptom diaries to create a score that tracked influenza-like-illness (ILI) symptoms (fever, cough, or sore throat). We fit phenomenological nonlinear mixed-effects models stratified by age and vaccination status and estimated two quantities influencing isolation effectiveness: shedding before symptom onset and shedding that might occur once isolation ends. We considered different isolation end points (including 24 hours after fever resolution or 4 days after symptom onset) and assumptions about the infectiousness of Ct shedding trajectories. Of the 116 household contacts with ≥2 positive tests for longitudinal analyses, 105 (91%) experienced ≥1 ILI symptom. On average, children <5 years experienced greater peak shedding, longer durations of shedding, and elevated ILI symptom scores compared with other age groups. Most individuals (63/105) shed <10% of their total shed virus before symptom onset, and shedding after isolation varied substantially across individuals, isolation end points, and infectiousness assumptions. Our results can inform strategies to reduce transmission from symptomatic individuals infected with influenza.Significance StatementIndividuals infected with influenza are encouraged to avoid contact with others for a period following symptom onset. This action should reduce the likelihood of onward transmission if infectious virus shedding is associated with symptom presentation. We modeled influenza virus shedding and symptom dynamics in participants of a multi-season household transmission study. On average, children <5 years shed more virus for longer durations and experienced elevated influenza-like-illness symptoms compared with older age groups. Most shedding took place after symptom onset, and estimated shedding that might remain after a period of avoiding contact with others depended on how the end of this period was defined. Our results can help inform strategies to reduce transmission from symptomatic individuals infected with influenza.
The descriptive epidemiology of type 2 diabetes in the United Kingdom from 2004 to 2021
Authors: Currie Craig J. , Currie Jessica G. , Holden Sarah E. , Morgan Christopher Ll. , Heywood Benjamin R. , Peters John R. ,   the Livingstone Development Team
Published: March 2024

AbstractPurposeTo provide contemporary estimates of the incidence and prevalence of type 2 diabetes in the UK.MethodsData from UK primary care (CPRD) were analyzed using an automated, analytical platform that produces validated, rapid analytics–Livingstone.ResultsWe selected 1,125,028 people with type 2 diabetes (44.7% female). The crude incidence was stable. In 2004 the incidence rate was 4.18 cases per 1,000 people, reducing to 4.13/1,000 in 2021. There was a shift in age-specific incidence to earlier age-groups. The crude prevalence showed a marked increase, rising from 2.95% to 5.41%, levelling off slightly in later years. Increases in prevalence were observed in all groups. Northern Ireland consistently had the lowest prevalence, and Wales had a notably higher prevalence, increasing from 3.71% in 2004 to 6.37%. The mean age at diagnosis decreased in females by 5.5 years to 58.5 years, and by 2.5 years in men, to 58.8 years.ConclusionsThe incidence of type 2 diabetes was largely stable over 20 years but there were changes over time in age-specific groups resulting from a shift to earlier onset or earlier diagnosis. The shift to earlier diagnosis was far more pronounced in women than in men. Prevalence increased markedly, but the rate of increase appeared to be leveling-off a little. There were notable differences in the epidemiology of type 2 diabetes between the four constituent countries of the UK. The number of younger people diagnosed with type 2 diabetes remains a concern.GuarantorCraig Currie is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Identification of RACK1A as a component of the auxin-ethylene crosstalk regulating apical hook development inArabidopsis thaliana
Authors: Ma Qian , Liu Sijia , Raggi Sara , Doyle Siamsa M. , Pařízková Barbora , Barange Deepak Kumar , Wilkinson Edward G. , Garcia Isidro Crespo , Bygdell Joakim , Wingsle Gunnar , Boer Dirk Roeland , Strader Lucia C. , Almqvist Fredrik , Novák Ondřej , Robert Stéphanie 
Published: March 2024

AbstractApical hook development is an ideal model for studying differential growth in plants, and is controlled by complex hormonal crosstalk, with auxin and ethylene being the major players. Here, we identified a bioactive small molecule that decelerates apical hook opening inArabidopsis thaliana. Our genetic studies suggest that this molecule enhances or maintains the auxin maximum found in the inner hook side and requires certain auxin and ethylene signaling components to modulate apical hook opening. Using biochemical approaches, we then revealed the WD40 repeat scaffold protein RECEPTOR FOR ACTIVATED C KINASE 1A (RACK1A) as a direct target of this compound. We present data in support of RACK1A playing a positive role in apical hook opening by negatively regulating the differential auxin response gradient across the hook via specific auxin and ethylene signaling mechanisms and thereby adjusting differential cell growth, an essential process for organ structure and function in plants. We have thus identified a role for RACK1A and auxin-ethylene crosstalk in negatively regulating differential cell growth to promote apical hook opening.Significance StatementDifferential growth, or the growth of cells at different rates across tissues, is essential for providing shape and structure during plant development. The apical hook is a transient structure formed by differential cell growth across the hypocotyl tip in dark-grown seedlings, which protects the underlying tissues, and which opens during seedling development. We identified a small molecule that decelerates hook opening and discovered that it targets the protein RECEPTOR FOR ACTIVATED C KINASE 1A (RACK1A). We then showed that RACK1A promotes apical hook opening at the level of crosstalk between the plant hormones auxin and ethylene, by adjusting differential cell growth. Our work paves the way to a better understanding of how plants regulate and adapt their growth during development.