bluuebunny/crossref_metadata_2025_split huggingface dataset:
phuEGO: A network-based method to reconstruct active signalling pathways from phosphoproteomics datasets
Authors: Giudice Girolamo , Chen Haoqi , Petsalaki Evangelia 
Published: August 2023

AbstractSignalling networks are critical for virtually all cell functions. Our current knowledge of cell signalling has been summarised in signalling pathway databases, which, while useful, are highly biassed towards well-studied processes, and don’t capture context specific network wiring or pathway cross-talk. Mass spectrometry-based phosphoproteomics data can provide a more unbiased view of active cell signalling processes in a given context, however, it suffers from low signal-to-noise ratio and poor reproducibility across experiments. Methods to extract active signalling signatures from such data struggle to produce unbiased and interpretable networks that can be used for hypothesis generation and designing downstream experiments.Here we present phuEGO, which combines three-layer network propagation with ego network decomposition to provide small networks comprising active functional signalling modules. PhuEGO boosts the signal-to-noise ratio from global phosphoproteomics datasets, enriches the resulting networks for functional phosphosites and allows the improved comparison and integration across datasets. We applied phuEGO to five phosphoproteomics data sets from cell lines collected upon infection with SARS CoV2. PhuEGO was better able to identify common active functions across datasets and to point to a subnetwork enriched for known COVID-19 targets. Overall, phuEGO provides a tool to the community for the improved functional interpretation of global phosphoproteomics datasets.
CASP15 cryoEM protein and RNA targets: refinement and analysis using experimental maps
Authors: Mulvaney Thomas , Kretsch Rachael C. , Elliott Luc , Beton Joe , Kryshtafovych Andriy , Rigden Daniel J. , Das Rhiju , Topf Maya 
Published: August 2023

AbstractCASP assessments primarily rely on comparing predicted coordinates with experimental reference structures. However, errors in the reference structures can potentially reduce the accuracy of the assessment. This issue is particularly prominent in cryoEM-determined structures, and therefore, in the assessment of CASP15 cryoEM targets, we directly utilized density maps to evaluate the predictions. A method for ranking the quality of protein chain predictions based on rigid fitting to experimental density was found to correlate well with the CASP assessment scores. Overall, the evaluation against the density map indicated that the models are of high accuracy although local assessment of predicted side chains in a 1.52 Å resolution map showed that side-chains are sometimes poorly positioned. The top 136 predictions associated with 9 protein target reference structures were selected for refinement, in addition to the top 40 predictions for 11 RNA targets. To this end, we have developed an automated hierarchical refinement pipeline in cryoEM maps. For both proteins and RNA, the refinement of CASP15 predictions resulted in structures that are close to the reference target structure, including some regions with better fit to the density. This refinement was successful despite large conformational changes and secondary structure element movements often being required, suggesting that predictions from CASP-assessed methods could serve as a good starting point for building atomic models in cryoEM maps for both proteins and RNA. Loop modeling continued to pose a challenge for predictors with even short loops failing to be accurately modeled or refined at times. The lack of consensus amongst models suggests that modeling holds the potential for identifying more flexible regions within the structure.
A collaboration between immune cells and the choroid plexus epithelium in brain inflammation
Authors: Xu Huixin , Lotfy Peter , Gelb Sivan , Pragana Aja , Hehnly Christine , Shipley Frederick B. , Zawadzki Miriam E. , Cui Jin , Deng Liwen , Taylor Milo , Webb Mya , Lidov Hart G. W. , Andermann Mark L. , Chiu Isaac M. , Ordovas-Montanes Jose , Lehtinen Maria K. 
Published: August 2023

ABSTRACTThe choroid plexus (ChP) is a vital brain barrier and source of cerebrospinal fluid (CSF). Here, we use chronic two-photon imaging in awake mice and single-cell transcriptomics to demonstrate that in addition to these roles, the ChP is a complex immune organ that regulates brain inflammation. In a mouse meningitis model, neutrophils and monocytes accumulated in ChP stroma and surged across the epithelial barrier into the CSF. Bi-directional recruitment of monocytes from the periphery and, unexpectedly, macrophages from the CSF to the ChP helped eliminate neutrophils and repair the barrier. Transcriptomic analyses detailed the molecular steps accompanying this process, including the discovery of epithelial cells that transiently specialized to nurture immune cells, coordinate their recruitment, survival, and differentiation, and ultimately, control the opening/closing of the ChP brain barrier. Collectively, we provide a new conceptual understanding and comprehensive roadmap of neuroinflammation at the ChP brain barrier.
MRI of OATP-expressing transplanted cells using clinical doses of gadolinium contrast agent
Authors: Bhattacharyya Tapas , Mallett Christiane L. , Hix Jeremy M.-L. , Shapiro Erik M. 
Published: August 2023

AbstractHepatic organic anion transporting polypeptides (OATPs) transport off-the-shelf, FDA-approved, hepatospecific Gd-based MRI contrast agents into cells that express the transporters enhancing signal on clinical T1-weighted MRI. Studies have used MRI to identify OATP-overexpressing tumors and metastases in mice following the delivery of Gd-EOB-DTPA at 27-67-fold higher than clinical doses. With safety and regulatory concern over Gd-based contrast agents, translation of this imaging paradigm to humans for regenerative medicine cell therapy will require substantially lower doses of agent.Here we complemented static T1-weighted MRI and/or T1-mapping with dynamic contrast enhanced (DCE)-MRI and show that even low intracellular accumulation of contrast agent results in a sustained signal enhancement in OATP-overexpressing tumors while control, non-expressing tumors have rapid wash-in and wash-out dynamics which could be distinguished by performing area-under-the-curve (AUC) analyses.
A rapid genome‐wide analysis of isolated giant viruses using MinION sequencing
Authors: Hikida Hiroyuki , Okazaki Yusuke , Zhang Ruixuan , Nguyen Thi Tuyen , Ogata Hiroyuki 
Published: August 2023

AbstractFollowing the discovery of Acanthamoeba polyphaga mimivirus, diverse giant viruses have been isolated. However, only a small fraction of these isolates have been completely sequenced, limiting our understanding of the genomic diversity of giant viruses. MinION is a portable and low‐cost long‐read sequencer that can be readily used in a laboratory. Although MinION provides highly error‐prone reads that require correction through additional short‐read sequencing, recent studies assembled high‐quality microbial genomes only using MinION sequencing. Here, we evaluated the accuracy of MinION‐only genome assemblies for giant viruses by re‐sequencing a prototype marseillevirus. Assembled genomes presented over 99.98% identity to the reference genome with a few gaps, demonstrating a high accuracy of the MinION‐only assembly. As a proof of concept, we de novo assembled five newly isolated viruses. Average nucleotide identities to their closest known relatives suggest that the isolates represent new species of marseillevirus, pithovirus and mimivirus. The assembly of subsampled reads demonstrated that their taxonomy and genomic composition could be analysed at the 50× sequencing coverage. We also identified a pithovirus gene whose homologues were detected only in metagenome‐derived relatives. Collectively, we propose that MinION‐only assembly is an effective approach to rapidly perform a genome‐wide analysis of isolated giant viruses.
Refractory response to entrectinib for ROS‐1 rearranged NSCLC with concurrent de novo TP53 mutation showing good response to CNS lesion, but poor duration of response: A case report
Authors: Ito Kentaro , Nishio Miho , Fujiwara Kentaro , Nishii Yoichi , Ushiro Kengo , Yasui Hiroki , Hataji Osamu 
Published: August 2023

AbstractEntrectinib, a ROS‐1 inhibitor, has been shown to be effective for patients with ROS‐1 fused NSCLC, and has been established as the standard of care for this population. Entrectinib has been shown to achieve a better response to brain metastasis due to the characteristic of the drug having a weak interaction with P‐glycoprotein and, even in prospective studies, the intracranial response is higher. Patients have been known to acquire resistance to molecularly targeted drugs such as EGF‐TKIs or ALK‐TKIs during targeted therapy. Similarly, the mechanisms of resistance to entrectinib have been reported, but information about the effects of TP53 mutation with entrectinib are still limited. Here, we experienced a case of a patient with ROS‐1 fusion and concurrent TP53 mutation who was treated with entrectinib, resulting in a response to brain metastasis but rapid resistance to entrectinib. Our case demonstrates both the intracranial activity of entrectinib and the potential for resistance to entrectinib due to TP53 mutation.
Gambling, tobacco use, and health among individuals in substance use disorder treatment
Authors: Pagano Anna , Le Thao , Fong Timothy , Reid Rory , Delucchi Kevin , Guydish Joseph 
Published: August 2023

AbstractBackground and ObjectivesGambling is highly comorbid with disordered use of tobacco and other drugs, and may increase relapse risk among substance use disorder (SUD) patients. We investigated associations between gambling and tobacco use behaviors among SUD patients to inform clinical care.MethodsPatients (N = 651, 170 female) from 25 residential SUD treatment programs in California completed surveys about tobacco use, health, and gambling. Using multivariate regression, we examined associations between gambling, tobacco use behaviors, and mental and physical health.ResultsPast‐year gamblers were more likely than non‐gamblers to be current smokers (adjusted odds ratio [AOR] = 1.44, 95% confidence interval [CI] = 1.03, 2.01). Smokers who gambled had higher mean Heaviness of Smoking Index (HSI) scores (mean difference = +0.32, 95% CI = 0.04, 0.60), and more often reported smokeless tobacco use (AOR = 1.73, 95% CI = 1.16, 2.58), compared to non‐gambling smokers. Past‐year problem gamblers were more likely than all others (non‐gamblers and non‐problem gamblers) to be current smokers (AOR = 1.44, 95% CI = 1.08, 1.90) and to report high psychosocial stress (AOR = 1.87, 95% CI = 1.34, 2.61). Smokers with problem gambling also had higher HSI scores (mean difference = +0.54, 95% CI = 0.14, 0.95) compared to smokers without problem gambling.Discussion and ConclusionsGambling and problem gambling were associated with tobacco use and heavier smoking. SUD patients with gambling comorbidity may be heavier smokers and may need concurrent treatment for tobacco use and problem gambling.Scientific SignificanceThis study provides novel data regarding gambling and tobacco use behaviors among SUD patients.
The beneficial effect of early and prolonged kangaroo mother care on long‐term neuro‐developmental outcomes in low birth neonates – A cohort study
Authors: Bisanalli Shridevi , Balachander Bharathi , Shashidhar A. , Raman Vijaya , Josit Pavitra , Rao Suman PN 
Published: August 2023

AbstractAimKangaroo mother care (KMC) has immense short‐term benefits, but data on long‐term outcomes are scarce. Hence, this study aimed to compare the neurodevelopmental outcomes at 12 months of corrected age (CA) in infants <2000 g receiving early and prolonged KMC to a control group.MethodsThis was a cohort study that was conducted from January 2017 to November 2018. All neonates<2000 g were eligible for the study. Neonates that received early initiation (<72 h of life) and prolonged KMC comprised the intervention group and were compared to neonates without the intervention. Bayley Scales of Infant and Toddler Development, Third edition (BSID‐III) was done at 12 months of CA, and this was analysed using t‐test and multi‐linear regression analysis.ResultsThere were 75 neonates in the intervention and 69 in the control group. Baseline characteristics were comparable. We found higher composite scores for cognition (110.38 ± 9.89 vs. 105.44 ± 8.77, p value = 0.023), language (107.51 ± 10.72 vs. 101.05 ± 12.06, p value = 0.014) and adaptive behaviour (87.97 ± 9.97 vs. 80 ± 9.1, p value<0.001) in the early and prolonged KMC group in comparison to the control group.ConclusionInfants with early and prolonged KMC have better neurodevelopmental outcomes in terms of cognition, language and adaptive behaviour at 12 months of CA.
Against loneliness we unite: A solidarity‐based account of loneliness
Authors: Lederman Zohar 
Published: August 2023

AbstractLoneliness is ubiquitous and is bad for our health, making it a bioethical concern. It is perhaps true now more than ever before. Recent publications in bioethics have discussed loneliness in the context of responsibility, solidarity, and autonomy, especially relational autonomy. In this paper, I elaborate on the relation between solidarity and loneliness, proposing an account of loneliness as lack of solidarity. Some cases of loneliness, I argue, may be defined and explained by not having someone to identify with you in some relevant aspect or without someone to assist you. I specifically use the work of George Orwell to make my case.
A multisource analysis of child streetism in Nigerian urban centres
Authors: Ogunkan David V. 
Published: August 2023

AbstractMotivationChild streetism, a concept that describes the desperate situations of children working, living, or surviving on the street, is a complex phenomenon and one of the challenges posed by urban poverty worldwide.PurposeThe increased study of street children in Nigerian urban centres over the last 10 years has seen the accumulation of evidence underpin new policies to address this worldwide problem. This article summarizes the determinants of child streetism, the risks associated with it (violence, street gangsterism, drugs and substance abuse), and the intervention policies and programmes for street children in Nigeria.Methods and approachThe article is based on a textual narrative synthesis analysis of the relevant literature published between 2012 and 2023.FindingsAnalysis of the literature shows that street children engage in harmful and risky behaviours and are caught in a cycle of abuse and poverty. Interventions to help street children are generally hampered by a lack of understanding of the causes, impacts, situations, and general characteristics. The literature suggests that the most successful interventions typically capitalize on people's strengths, incorporate elements of participation, self‐help, and mutual support, and take the least stigmatizing approach.Policy implicationsChild streetism is an expression of a complicated web of determinants that require structural solutions. Any policy addressing the problem of child streetism must consider the phenomenon as a product of several complex and interrelated factors. Of these, uncontrolled urbanization, poor urban planning and management, and poverty are the most obvious.
Impact of aortic valve stenosis on myocardial deformation in different left ventricular levels: A three‐dimensional speckle tracking echocardiography study
Authors: Hjertaas Johannes Just , Einarsen Eigir , Gerdts Eva , Kokorina Marina , Moen Christian Arvei , Urheim Stig , Saeed Sahrai , Matre Knut 
Published: August 2023

AbstractBackgroundGlobal systolic left ventricular (LV) myocardial function progressively declines as degenerative aortic valve stenosis (AS) progresses. Whether this results in uniformly distributed deformation changes from base to apex has not been investigated.MethodsEighty‐five AS patients underwent three‐dimensional (3D) echocardiography in this cross‐sectional study. Patients were grouped by peak jet velocity into mild (n = 32), moderate (n = 31), and severe (n = 22) AS. 3D speckle tracking derived strain, rotation, twist, and torsion were obtained to assess global LV function and myocardial function at the apical, mid, and basal levels.ResultsGlobal longitudinal strain (GLS) was lower in patients with severe AS (‐16.1 ± 2.4% in mild, ‐15.5 ± 2.5% in moderate, and ‐13.5 ± 3.0% in severe AS [all p < .01]). Peak basal and mid longitudinal strain (LS), basal rotation and twist from apical to basal level followed the same pattern, while peak apical LS was higher in moderate AS compared to severe AS (all p < .05). In multivariate analyses, lower GLS was particularly associated with male sex, higher body mass index and peak aortic jet velocity, lower basal LS with higher filling pressure (E/e’) and LV mass, lower mid LS with higher RWT and presence of AS symptoms, and lower apical LS with male sex and higher systolic blood pressure, respectively (all p < .05).ConclusionUsing 3D speckle tracking echocardiography reveals regional and global changes in LV mechanics in AS related to the severity of AS, LV remodeling and presence of cardiovascular risk factors.
CPEB4–CLOCK crosstalk during temporal lobe epilepsy
Authors: de Diego‐Garcia Laura , Brennan Gary P. , Auer Theresa , Menendez‐Mendez Aida , Parras Alberto , Martin‐Gil Alba , Mitra Meghma , Ollà Ivana , Villalba‐Benito Leticia , Gil Beatriz , Alves Mariana , Lau Kelvin , Delanty Norman , Beausang Alan , Cryan Jane , Brett Francesca M. , Farrell Michael A. , O'Brien Donncha F. , Mendez Raúl , Carracedo‐Rodríguez Gonzalo , Henshall David C. , Lucas José J. , Engel Tobias 
Published: August 2023

AbstractObjectivePosttranscriptional mechanisms are increasingly recognized as important contributors to the formation of hyperexcitable networks in epilepsy. Messenger RNA (mRNA) polyadenylation is a key regulatory mechanism governing protein expression by enhancing mRNA stability and translation. Previous studies have shown large‐scale changes in mRNA polyadenylation in the hippocampus of mice during epilepsy development. The cytoplasmic polyadenylation element‐binding protein CPEB4 was found to drive epilepsy‐induced poly(A) tail changes, and mice lacking CPEB4 develop a more severe seizure and epilepsy phenotype. The mechanisms controlling CPEB4 function and the downstream pathways that influence the recurrence of spontaneous seizures in epilepsy remain poorly understood.MethodsStatus epilepticus was induced in wild‐type and CPEB4‐deficient male mice via an intra‐amygdala microinjection of kainic acid. CLOCK binding to the CPEB4 promoter was analyzed via chromatin immunoprecipitation assay and melatonin levels via high‐performance liquid chromatography in plasma.ResultsHere, we show increased binding of CLOCK to recognition sites in the CPEB4 promoter region during status epilepticus in mice and increased Cpeb4 mRNA levels in N2A cells overexpressing CLOCK. Bioinformatic analysis of CPEB4‐dependent genes undergoing changes in their poly(A) tail during epilepsy found that genes involved in the regulation of circadian rhythms are particularly enriched. Clock transcripts displayed a longer poly(A) tail length in the hippocampus of mice post‐status epilepticus and during epilepsy. Moreover, CLOCK expression was increased in the hippocampus in mice post‐status epilepticus and during epilepsy, and in resected hippocampus and cortex of patients with drug‐resistant temporal lobe epilepsy. Furthermore, CPEB4 is required for CLOCK expression after status epilepticus, with lower levels in CPEB4‐deficient compared to wild‐type mice. Last, CPEB4‐deficient mice showed altered circadian function, including altered melatonin blood levels and altered clustering of spontaneous seizures during the day.SignificanceOur results reveal a new positive transcriptional–translational feedback loop involving CPEB4 and CLOCK, which may contribute to the regulation of the sleep–wake cycle during epilepsy.
Fenfluramine in the treatment of Dravet syndrome: Results of a third randomized, placebo‐controlled clinical trial
Authors: Sullivan Joseph , Lagae Lieven , Cross J. Helen , Devinsky Orrin , Guerrini Renzo , Knupp Kelly G. , Laux Linda , Nikanorova Marina , Polster Tilman , Talwar Dinesh , Ceulemans Berten , Nabbout Rima , Farfel Gail M. , Galer Bradley S. , Gammaitoni Arnold R. , Lock Michael , Agarwal Anupam , Scheffer Ingrid E. ,   the FAiRE DS Study Group
Published: August 2023

AbstractObjectiveThis study was undertaken to assess the safety and efficacy of fenfluramine in the treatment of convulsive seizures in patients with Dravet syndrome.MethodsThis multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, phase 3 clinical trial enrolled patients with Dravet syndrome, aged 2–18 years with poorly controlled convulsive seizures, provided they were not also receiving stiripentol. Eligible patients who had ≥6 convulsive seizures during the 6‐week baseline period were randomized to placebo, fenfluramine .2 mg/kg/day, or fenfluramine .7 mg/kg/day (1:1:1 ratio) administered orally (maximum dose = 26 mg/day). Doses were titrated over 2 weeks and maintained for an additional 12 weeks. The primary endpoint was a comparison of the monthly convulsive seizure frequency (MCSF) during baseline and during the combined titration–maintenance period in patients given fenfluramine .7 mg/kg/day versus patients given placebo.ResultsA total of 169 patients were screened, and 143 were randomized to treatment. Mean age was 9.3 ± 4.7 years (±SD), 51% were male, and median baseline MCSF in the three groups ranged 12.7–18.0 per 28 days. Patients treated with fenfluramine .7 mg/kg/day demonstrated a 64.8% (95% confidence interval = 51.8%–74.2%) greater reduction in MCSF compared with placebo (p < .0001). Following fenfluramine .7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% in the placebo group (p < .0001). The median longest seizure‐free interval was 30 days in the fenfluramine .7 mg/kg/day group compared with 10 days in the placebo group (p < .0001). The most common adverse events (>15% in any group) were decreased appetite, somnolence, pyrexia, and decreased blood glucose. All occurred in higher frequency in fenfluramine groups than placebo. No evidence of valvular heart disease or pulmonary artery hypertension was detected.SignificanceThe results of this third phase 3 clinical trial provide further evidence of the magnitude and durability of the antiseizure response of fenfluramine in children with Dravet syndrome.
Effect of stress‐relieved heat treatment on very high cycle fatigue performance of additive manufactured Ti‐6Al‐4V alloy
Authors: Tusher Md Mehide Hasan , Ince Ayhan 
Published: August 2023

AbstractLaser powder bed fusion (L‐PBF) technique is utilized in various industries to create intricate designs. The durability of L‐PBF components should be evaluated when subjected to different load cycles to widen their applicability in other fields. While previous studies have mostly concentrated on static and low cycle loads, high cycle and very high cycle loadings are crucial in many applications. This study examines the impact of stress‐relieved (SR) heat treatment on very high cycle fatigue (VHCF) performance of L‐PBF Ti‐6Al‐4V alloy. The SR heat treatment enhanced the VHCF response of the alloy by lowering defect levels and their size along with changing the microstructure, thus demonstrating their increased versatility for wider industrial applications.