bluuebunny/crossref_metadata_2025_split huggingface dataset:
Informing antimicrobial stewardship with explainable AI
Authors: Cavallaro Massimo , Moran Ed , Collyer Benjamin , McCarthy Noel D. , Green Christopher , Keeling Matt J. 
Published: August 2022

AbstractThe accuracy and flexibility of artificial intelligence (AI) systems often comes at the cost of a decreased ability to offer an intuitive explanation of their predictions. This hinders trust and discourage adoption of AI in healthcare, exacerbated by concerns over liabilities and risks to patients’ health in case of misdiagnosis. Providing an explanation for a model’s prediction is possible due to recent advances in the field of interpretable machine learning. We considered a data set of hospital admissions linked to records of antibiotic prescriptions and susceptibilities of bacterial isolates. An appropriately trained gradient boosted decision tree algorithm, supplemented by a Shapley explanation model, predicts the likely antimicrobial drug resistance, with the odds of resistance informed by characteristics of the patient, admission data, and historical drug treatments and culture test results. Applying this AI-based system, we found that it substantially reduces the risk of mismatched treatment compared with the observed prescriptions. The Shapley values provide an intuitive association between observations/data and outcomes; the associations identified are broadly consistent with expectations based on prior knowledge from health specialists. The results, and the ability to attribute confidence and explanations, support the wider adoption of AI in healthcare.
Exploring structural connectomes in children with unilateral cerebral palsy using graph theory
Authors: Radwan Ahmed , Decraene Lisa , Dupont Patrick , Leenaerts Nicolas , Simon-Martinez Cristina , Klingels Katrijn , Ortibus Els , Feys Hilde , Sunaert Stefan , Blommaert Jeroen , Mailleux Lisa 
Published: August 2022

AbstractBackground and objectivesBrain damage during early development impacts the brain structural network and its coinciding functions. Here, we explored structural brain connectomes in children with unilateral cerebral palsy and its relation to sensory-motor function using a novel semi-automated graph theory analysis, investigating both hemispheres.MethodsIn 46 children with spastic unilateral cerebral palsy (mean age 10y7m±2y9m, 27 boys, 25 right-sided hemiplegia; Manual Ability Classification System I=15, II=16, III=15) we assessed upper limb somatosensory (two-point discrimination and stereognosis) and motor function (grip force, Assisting Hand Assessment and Jebsen-Taylor Hand Function Test). We collected multi-shell diffusion-weighted, T1-weighted and T2-FLAIR MRI and performed transcranial magnetic stimulation to identify the corticospinal tract (CST) wiring pattern. Structural connectomes were constructed using Desikan-Killiany parcellations with Virtual Brain Grafting and FreeSurfer, and Multi-Shell Multi-Tissue Constrained Spherical Deconvolution diffusion modelling with anatomically constrained tractography. Graph metrics (characteristic path length, global/local efficiency and clustering coefficient) were calculated for the whole brain, the ipsilesional/contralesional hemisphere, and the full/ipsilesional/contralesional sensory-motor network, and were compared between lesion types (periventricular white matter (PWM)=28, cortical and deep grey matter (CDGM)=18) and CST-wiring patterns (ipsilateral=14, bilateral=14, contralateral=12, unknown=6) using ANCOVA with age as covariate. We used elastic-net regularized regression to investigate how graph metrics, lesion volume, lesion type, CST-wiring pattern and age predicted sensory-motor function.ResultsIn both the whole brain and subnetworks, we observed a hyperconnectivity pattern in children with CDGM-lesions compared to PWM-lesions, with higher clustering coefficient (p=[<0.001-0.047], ), characteristic path length (p=0.003, ) and local efficiency (p=[0.001-0.02], ), as well as a faster decrease in global efficiency with age (p=[0.01-0.04], ). No differences were found between CST-wiring groups. In general, good predictions of sensory-motor function were obtained with elastic-net regression (R2=0.40-0.87). For motor function, the CST-wiring pattern was identified as the strongest predictor. For somatosensory function all independent variables contributed equally to the model.DiscussionWith this study, we demonstrated the feasibility and potential of structural connectomes using graph theory analysis in understanding disease severity and brain development in children with unilateral cerebral palsy. Hence, this exploratory study could support and direct future research.
Longitudinal analysis of serum neutralization of SARS-CoV-2 Omicron BA.2, BA.4 and BA.5 in patients receiving monoclonal antibodies
Authors: Bruel Timothée , Stéfic Karl , Nguyen Yann , Toniutti Donatella , Staropoli Isabelle , Porrot Françoise , Guivel-Benhassine Florence , Bolland William-Henry , Planas Delphine , Hadjadj Jérôme , Handala Lynda , Planchais Cyril , Prot Matthieu , Simon-Lorière Etienne , André Emmanuel , Baele Guy , Cuypers Lize , Mouthon Luc , Mouquet Hugo , Buchrieser Julian , Sève Aymeric , Prazuck Thierry , Maes Piet , Terrier Benjamin , Hocqueloux Laurent , Schwartz Olivier 
Published: August 2022

AbstractThe emergence of novel Omicron lineages, such as BA.5, may impact the therapeutic efficacy of anti-SARS-CoV-2 neutralizing monoclonal antibodies (mAbs). Here, we evaluated the neutralization and ADCC activity of 6 therapeutic mAbs against Delta, BA.2, BA.4 and BA.5 isolates. The Omicron sub-variants escaped most of the antibodies but remained sensitive to Bebtelovimab and Cilgavimab. Consistent with their shared spike sequence, BA.4 and BA.5 displayed identical neutralization profiles. Sotrovimab was the most efficient at eliciting ADCC. We also analyzed 121 sera from 40 immunocompromised individuals up to 6 months after infusion of 1200 mg of Ronapreve (Imdevimab + Casirivimab), and 300 or 600 mg of Evusheld (Cilgavimab + Tixagevimab). Sera from Ronapreve-treated individuals did not neutralize Omicron subvariants. Evusheld-treated individuals neutralized BA.2 and BA.5, but titers were reduced by 41- and 130-fold, respectively, compared to Delta. A longitudinal evaluation of sera from Evusheld-treated patients revealed a slow decay of mAb levels and neutralization. The decline was more rapid against BA.5. Our data shed light on the antiviral activities of therapeutic mAbs and the duration of effectiveness of Evusheld pre-exposure prophylaxis.
Epidemiological profile and effectiveness of immediate postpartum contraception in Brazilian women
Authors: Steiner Marcelo Luis , Mendes Júlia Lorenzini , Giovanelli Silvana Aparecida , Carneiro Mônica , Strufaldi Rodolfo , da Silva Mariliza Henrique 
Published: August 2022

ABSTRACTWe analyzed the epidemiological profile of women who inserted copper intrauterine device (Cu-IUD), subdermal etonogestrel implant (ENG), tubal ligation (TL), depot medroxyprogesterone acetate (DMPA) or did not choose a contraceptive method (NCM) in the immediate postpartum. Also, we compared the contraceptive effectiveness of Cu-IUD and DPMA with non-MAC. Data from 20896 women were collected, of which 8183 (39%) opted for Cu-IUD, 559 (2.5%) DPMA, and 10989 (52.5%) for any method. When comparing these groups, women in the DPMA were younger (26.5±7.3, p<0.05), and NCM showed women with a lower number of pregnancies (2.2±1.3, p<0.05). Subjects in the TL group (4,6%) had the higher number of pregnancies (3,8±1.2, p<0.05), and ENG group, the highest number of miscarriages (1.6±1.3, p<0.05). Of those women who returned pregnant, 5.5% belonged to the DPMA group, 6% to the NCM group, and 2.3% to the Cu-IUD. Women who opted for Cu-IUD insertion were younger, had more pregnancies and vaginal delivery when compared to those who did not choose a method. Of those women who returned, the minority opted for Cu-IUD compared to those that opted for DPMA or no method.
Innovation and elaboration on the avian tree of life
Authors: Guillerme Thomas , Bright Jen A. , Cooney Christopher R. , Hughes Emma C. , Varley Zoë K. , Cooper Natalie , Beckerman Andrew P. , Thomas Gavin H. 
Published: August 2022

1AbstractWidely documented, megaevolutionary jumps in phenotypic diversity continue to perplex researchers because it remains unclear whether these dramatic changes can emerge from microevolutionary processes. Here we tackle this question using new approaches for modeling multivariate traits to evaluate the magnitude and distribution of elaboration and innovation in the evolution of bird beaks. We find that elaboration, evolution along the major axis of phenotypic change, is common at both macro- and megaevo-lutionary scales whereas innovation, evolution away from the major axis of phenotypic change, is more prominent at megaevolutionary scales. Indeed, the major axis of phenotypic change among species beak shapes at megaevolutionary scales is an emergent property of innovation across clades. Our analyses suggest that the reorientation of phenotypes via innovation is a ubiquitous route for divergence that can arise through gradual change alone, opening up new avenues for evolution to explore.
Pre-mRNA splicing order is predetermined and maintains splicing fidelity across multi-intronic transcripts
Authors: Choquet Karine , Koenigs Autum , Dülk Sarah-Luisa , Smalec Brendan M. , Rouskin Silvi , Churchman L. Stirling 
Published: August 2022

AbstractCombinatorially, intron excision within a given nascent transcript could proceed down any of thousands of paths, each of which would expose different dynamic landscapes of cis-elements and contribute to alternative splicing. In this study, we found that post-transcriptional multi-intron splicing order in human cells is largely predetermined, with most genes spliced in one or a few predominant orders. Strikingly, these orders were conserved across cell types and stages of motor neuron differentiation. Introns flanking alternatively spliced exons were frequently excised last, after their neighboring introns. Perturbations to the spliceosomal U2 snRNA altered the preferred splicing order of many genes, and these alterations were associated with the retention of other introns in the same transcript. In one gene, early removal of specific introns was sufficient to induce delayed excision of three proximal introns, and this delay was caused by two distinct cis-regulatory mechanisms. Together, our results demonstrate that multi-intron splicing order in human cells is predetermined, is influenced by a component of the spliceosome, and ensures splicing fidelity across long pre-mRNAs.
Variations in Atlantic water influx and sea-ice cover drive taxonomic and functional shifts in Arctic marine bacterial communities
Authors: Priest Taylor , Appen Wilken-Jon von , Oldenburg Ellen , Popa Ovidiu , Torres-Valdés Sinhué , Bienhold Christina , Metfies Katja , Fuchs Bernhard M. , Amann Rudolf , Boetius Antje , Wietz Matthias 
Published: August 2022

ABSTRACTThe Arctic Ocean is experiencing unprecedented changes as a result of climate warming, necessitating detailed analyses on the ecology and dynamics of biological communities to understand current and future ecosystem shifts. Here we show the pronounced impact that variations in Atlantic water influx and sea-ice cover have on bacterial communities in the East Greenland Current (Fram Strait) using two, 2-year high-resolution amplicon datasets and an annual cycle of long-read metagenomes. Densely ice-covered polar waters harboured a temporally stable, resident microbiome. In contrast, low-ice cover and Atlantic water influx shifted community dominance to seasonally fluctuating populations enriched in genes for phytoplankton-derived organic matter degradation. We identified signature populations associated with distinct oceanographic conditions and predicted their ecological niches. Our study indicates progressing “Biological Atlantification” in the Arctic Ocean, where the niche space of Arctic bacterial populations will diminish, while communities that taxonomically and functionally resemble those in temperate oceans will become more widespread.
Latent human herpesvirus 6 is reactivated in chimeric antigen receptor T cells
Authors: Lareau Caleb A. , Yin Yajie , Maurer Katie , Sandor Katalin D. , Yagnik Garima , Peña José , Crawford Jeremy Chase , Spanjaart Anne M. , Gutierrez Jacob C. , Haradhvala Nicholas J. , Abay Tsion , Stickels Robert R. , Verboon Jeffrey M. , Liu Vincent , Southard Jackson , Song Ren , Li Wenjing , Shrestha Aastha , Parida Laxmi , Getz Gad , Maus Marcela V. , Li Shuqiang , Moore Alison , Amado Rafael G. , Talleur Aimee C. , Thomas Paul G. , Dehghani Houman , Pertel Thomas , Kundaje Anshul , Gottschalk Stephen , Roth Theodore L. , Kersten Marie J. , Wu Catherine J. , Majzner Robbie G. , Satpathy Ansuman T. 
Published: August 2022

AbstractCell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells are still being understood. For example, we currently lack a comprehensive understanding of the mechanisms of neurotoxicity observed in patients receiving T cell therapies, including recent reports of encephalitis caused by human herpesvirus 6 (HHV-6) reactivation1. Here, via petabase-scale viral RNA data mining, we examine the landscape of human latent viral reactivation and demonstrate that HHV-6B can become reactivated in human CD4+ T cells in standardin vitrocultures. Using single-cell sequencing, we identify a rare population of HHV-6 ‘super-expressors’ (~1 in 300-10,000 cells) that possess high viral transcriptional activity in chimeric antigen receptor (CAR) T cell culture before spreading to infect other cellsin vitro. Through the analysis of single-cell sequencing data from patients receiving cell therapy products that are FDA-approved2or used in clinical studies3,4, we identify the presence of CAR+, HHV-6 super-expressor T cellsin vivo. Together, our study implicates cell therapy products as a source of lytic HHV-6 reported in clinical trials1,5–7and has broad implications for the design, production, and monitoring of cell therapies.
Metabolic demands of the posteromedial default mode network are shaped by dorsal attention and frontoparietal control networks
Authors: Godbersen GM , Klug S , Wadsak W , Pichler V , Raitanen J , Rieckmann A , Stiernman L , Cocchi L , Breakspear M , Hacker M , Lanzenberger R , Hahn A 
Published: August 2022

AbstractAlthough BOLD signal decreases in the default mode network (DMN) are commonly observed during attention-demanding tasks, their neurobiological underpinnings are not fully understood. Previous work has shown decreases but also increases in glucose metabolism that match with or dissociate from these BOLD signal decreases, respectively. To resolve this discrepancy, we analyzed functional PET/MRI data from 50 healthy subjects during the performance of the visuo-spatial processing game Tetris® and combined this with previously published data sets of working memory as well as visual and motor stimulation. Our findings show that the glucose metabolism of the posteromedial DMN is dependent on the metabolic demands of the correspondingly engaged task-positive brain networks. Specifically, the dorsal attention (involved in Tetris®) and frontoparietal networks (engaged during working memory) shape the glucose metabolism of the posteromedial DMN in opposing directions. External attention-demanding tasks lead to a downregulation of the posteromedial DMN with consistent decreases in the BOLD signal and glucose metabolism, whereas working memory is subject to metabolically expensive mechanisms of BOLD signal suppression. We suggest that the former finding is mediated by decreased glutamate signaling, while the latter results from active GABAergic inhibition, regulating the competition between self-generated and task-driven internal demands. The results demonstrate that the DMN relates to cognitive processing in a flexible manner and does not always act as a cohesive task-negative network in isolation.
Small non-coding vault RNA1-2 modulates expression of cell membrane proteins through nascent RNA silencing
Authors: Alagia Adele , Terenova Jana , Ketley Ruth F. , Di Fazio Arianna , Chelysheva Irina , Gullerova Monika 
Published: August 2022

AbstractGene expression can be regulated by transcriptional or post-transcriptional gene silencing. Recently, we described nuclear nascent RNA silencing (NRS) that is mediated by Dicer dependent tRNA-derived small RNA molecules. In addition to tRNA, RNA polymerase III also transcribes Vault RNA, a component of the ribonucleoprotein complex Vault.Here, we show that Dicer dependent small vault RNA1-2 (svtRNA1-2) associate with Argonaute 2 (Ago2). Whilst endogenous vtRNA1-2 is present mostly in cytoplasm, svtRNA1-2 localises predominantly in nucleus. Furthermore, in Ago2 and Dicer knockdown cells, a subset of genes which are upregulated at the nascent level were predicted to be targeted by svtRNA1-2 in the intronic region. Genomic deletion of vtRNA1-2 results in impaired cellular proliferation and the upregulation of genes associated with cell membrane physiology and cell adhesion. Silencing activity of svtRNA1-2 molecules is dependent on seed-plus-complementary-paired hybridisation features and the presence of a 5-nucleotide loop protrusion on target RNAs.Our data reveal a role for Dicer dependent svtRNA1-2, possessing unique molecular features, in modulation of expression of membrane associated proteins at the nascent RNA level.
Antisense oligonucleotide therapy for the common Stargardt disease type 1-causing variant in ABCA4
Authors: Kaltak Melita , de Bruijn Petra , Piccolo Davide , Lee Sang-Eun , Dulla Kalyan , Hoogenboezem Thomas , Beumer Wouter , Webster Andrew R. , Collin Rob W.J. , Cheetham Michael E. , Platenburg Gerard , Swildens Jim 
Published: August 2022

ABSTRACTThe c.5461-10T>C p.[Thr1821Aspfs*6,Thr1821Valfs*13] variant has been identified as the most common severe Stargardt disease type 1 (STGD1)-associated variant in ABCA4. STGD1 is the most recurrent hereditary form of maculopathy and so far, no treatment is available for STGD1. In STGD1 patients homozygous for this variant, the onset of the disease typically is in childhood and patients are legally blind by early adulthood. The variant leads to exon skipping and generates out-of-frame ABCA4 transcripts that prevent the translation of functional ABCA4 protein.We applied antisense oligonucleotides (AONs) to restore the wild-type RNA splicing in ABCA4 c.5461-10T>C. The effect of AONs was investigated in vitro using an ABCA4 midigene model and 3D human retinal organoids (ROs) homozygous for the ABCA4 c.5461-10T>C variant. The mRNA in untreated ROs contained only disease-associated isoforms, whereas the organoids treated with the lead AON sequence showed 53% splicing correction and restoration of ABCA4 protein.Collectively, these data identified the lead candidate QR-1011 as a potent splice-correcting AON to be further developed as therapeutic intervention for patients harboring the severe ABCA4 c.5461-10T>C variant.
Most protein domains exist as variants with distinct functions across cells, tissues, and diseases
Authors: Vitting-Seerup Kristoffer 
Published: August 2022

AbstractBackgroundProtein domains are the active subunits that provide proteins with specific functions through precise three-dimensional structures. Such domains facilitate most protein functions, including molecular interactions and signal transduction. Currently, these protein domains are described and analyzed as invariable molecular building blocks with fixed functions.ResultsI show that most human protein domains exist as multiple distinct variants that I term “domain isotypes”. Different domain isotypes are used in a cell, tissue, and disease-specific manner and have surprisingly different 3D structures. Accordingly, I find that domain isotypes, compared to each other, modulate or abolish the functionality of protein domains.ConclusionsMy results challenge the current view of protein domains as invariable building blocks and have significant implications for both wet- and dry-lab workflows. The extensive use of protein domain isotypes within protein isoforms adds to the growing body of evidence suggesting that the sciences should move from the current gene-centric research paradigm toward an isoform-centric research paradigm.
Sphingosine kinases promote Ebola virus infection and can be targeted to inhibit filoviruses, coronaviruses, and arenaviruses using late endocytic trafficking to enter cells
Authors: Stewart Corina M. , Bo Yuxia , Fu Kathy , Chan Mable , Kozak Robert , Apperley Kim Yang-Ping , Laroche Geneviève , Beauchemin André , Kobinger Gary , Kobasa Darwyn , Côté Marceline 
Published: August 2022

AbstractEntry of enveloped viruses in host cells requires the fusion of the viral and host cell membranes, a process that is facilitated by viral fusion proteins protruding from the viral envelope. For fusion, viral fusion proteins need to be triggered by host factors and for some viruses, such as Ebola virus (EBOV) and Lassa fever virus, this event occurs inside endosomes and/or lysosomes. Consequently, these ‘late-penetrating viruses’ must be internalized and delivered to entry-conducive intracellular vesicles. Because endocytosis and vesicular trafficking are tightly regulated cellular processes, late penetrating viruses also depend on specific host factors, such as signaling molecules, for efficient viral delivery to the site of fusion, suggesting that these could be targeted for antiviral therapy. In this study, we investigated a role for sphingosine kinases (SKs) in viral entry and found that chemical inhibition of sphingosine kinase 1 (SK1) and/or SK2 and knockdown of SK1 or SK2, inhibited entry of EBOV into host cells. Mechanistically, inhibition of SK1 and/or SK2 prevented EBOV from reaching late-endosomes and lysosomes that are positive for the EBOV receptor, Niemann Pick C1 (NPC1). Furthermore, we present evidence that suggests the trafficking defect caused by SK1/2 inhibition occurs independently of S1P signaling through cell-surface S1PRs. Lastly, we found that chemical inhibition of SKs prevents entry of other late-penetrating viruses, including arenaviruses and coronaviruses, in addition to inhibiting infection by replication competent EBOV and SARS-CoV-2 in Huh7.5 cells. In sum, our results highlight an important role played by SKs in endocytic trafficking which can be targeted to inhibit entry of late-penetrating viruses. SK inhibitors could serve as a starting point for the development of broad-spectrum antiviral therapeutics.
Negative cooperativity underlies dynamic assembly of the Par complex regulators Cdc42 and Par-3
Authors: Vargas Elizabeth , Prehoda Kenneth E. 
Published: August 2022

AbstractThe Par complex polarizes diverse animal cells through the concerted action of multiple regulators. Binding to Par-3 couples the complex to cortical flows that construct the Par membrane domain. Once localized properly, the complex is thought to transition from Par-3 to the Rho GTPase Cdc42 to activate the complex. While this transition is a critical step in Par-mediated polarity, little is known about how it occurs. Through a biochemical reconstitution approach utilizing purified, intact Par complex and qualitative binding assays, we found that Par-3 and Cdc42 exhibit strong negative cooperativity for the Par complex. We show that the interactions between the second and third PDZ protein interaction domains of Par-3 and the aPKC Kinase-PBM (PDZ binding motif) mediate the displacement of Cdc42 from the Par complex. Our results indicate that Par-3, Cdc42, Par-6, and aPKC are the minimal components that are sufficient for this transition to occur and that no external factors are required. Our findings provide the mechanistic framework for understanding a critical step in the regulation of Par complex polarization and activity.