bluuebunny/crossref_metadata_2025_split huggingface dataset:
Federated analysis in COINSTAC reveals functional network connectivity and spectral links to smoking and alcohol consumption in nearly 2,000 adolescent brains
Authors: Gazula Harshvardhan , Rootes-Murdy Kelly , Holla Bharath , Basodi Sunitha , Zhang Zuo , Verner Eric , Kelly Ross , Murthy Pratima , Chakrabarti Amit , Basu Debasish , Nanjayya Subodh Bhagyalakshmi , Singh Rajkumar Lenin , Singh Roshan Lourembam , Kalyanram Kartik , Kartik Kamakshi , Kalyanaraman Kumaran , Ghattu Krishnaveni , Kuriyan Rebecca , Kurpad Sunita Simon , Barker Gareth J , Bharath Rose Dawn , Desrivieres Sylvane , Purushottam Meera , Orfanos Dimitri Papadopoulos , Sharma Eesha , Hickman Matthew , Toledano Mireille , Vaidya Nilakshi , Banaschewski Tobias , Bokde Arun L.W. , Flor Herta , Grigis Antoine , Garavan Hugh , Gowland Penny , Heinz Andreas , Brühl Rüdiger , Martinot Jean-Luc , Paillère Martinot Marie-Laure , Artiges Eric , Nees Frauke , Paus Tomáš , Poustka Luise , Fröhner Juliane H. , Robinson Lauren , Smolka Michael N. , Walter Henrik , Winterer Jeanne , Whelan Robert ,   IMAGEN Consortium, Turner Jessica A. , Sarwate Anand D. , Plis Sergey M. , Benegal Vivek , Schumann Gunter , Calhoun Vince D. 
Published: February 2022

AbstractWith the growth of decentralized/federated analysis approaches in neuroimaging, the opportunities to study brain disorders using data from multiple sites has grown multi-fold. One such initiative is the Neuromark, a fully automated spatially constrained independent component analysis (ICA) that is used to link brain network abnormalities among different datasets, studies, and disorders while leveraging subject-specific networks. In this study, we implement the neuromark pipeline in COINSTAC, an open-source neuroimaging framework for collaborative/decentralized analysis. Decentralized analysis of nearly 2000 resting-state functional magnetic resonance imaging datasets collected at different sites across two cohorts and co-located in different countries was performed to study the resting brain functional network connectivity changes in adolescents who smoke and consume alcohol. Results showed hypoconnectivity across the majority of networks including sensory, default mode, and subcortical domains, more for alcohol than smoking, and decreased low frequency power. These findings suggest that global reduced synchronization is associated with both tobacco and alcohol use. This work demonstrates the utility and incentives associated with large-scale decentralized collaborations spanning multiple sites.
Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice
Authors: Szegö Eva M , Malz Laura , Bernhardt Nadine , Rösen-Wolff Angela , Falkenburger Björn H. , Luksch Hella 
Published: February 2022

AbstractThe innate immune system can protect against certain aspects of neurodegenerative diseases, but also contribute to disease progression. Stimulator of interferon genes (STING) is activated after detection of cytoplasmic dsDNA by cGAS (cyclic GMP-AMP synthase) as part of the defense against viral pathogens, activating type I interferon and NF-kB/inflammasome signaling. In order to specifically test the relevance of this pathway for the degeneration of dopaminergic neurons in Parkinson’s disease, we studied a mouse model with heterozygous expression of the constitutively active STING variant N153S.In adult mice expressing N153S STING, the number of dopaminergic neurons was smaller than in controls, as was the density of dopaminergic axon terminals and the concentration of dopamine in the striatum. We also observed alpha-synuclein pathology and a lower density of synaptic puncta. Neuroinflammation was quantified by staining astroglia and microglia, by measuring mRNAs, proteins and nuclear translocation of transcription factors. Neuroinflammatory markers were already elevated in juvenile mice, thus preceding the degeneration of dopaminergic neurons. Inflammation and neurodegeneration were blunted in mice deficient for signaling by type I interferons or inflammasomes, but not suppressed completely.Collectively, these findings demonstrate that chronic activation of the STING innate immunity pathway is sufficient to cause degeneration of dopaminergic neurons. This pathway could be targeted therapeutically.
Corticospinal excitability is influenced by the recent history of electrical digital stimulation: implications for the relative magnitude of short-latency afferent inhibition
Authors: Bonnesen Marie Trolle , Fuglsang Søren Asp , Siebner Hartwig Roman , Christiansen Lasse 
Published: February 2022

AbstractBackgroundElectrical stimulation of the hand can suppress the motor evoked potential (MEP) elicited by transcranial magnetic stimulation (TMS) of the primary motor hand area (M1-HAND) when the afferent stimulus arrives in M1-HAND at the time of TMS. The magnitude of short-latency afferent inhibition (SAI) is expressed as the ratio between the conditioned and unconditioned MEP and is widely used to probe sensorimotor interactions in human physiological studies.Objective/HypothesisWe hypothesized that corticospinal excitability and SAI are influenced by the recent history of peripheral electrical stimulation.MethodsIn twenty healthy participants, we recorded MEPs from the right first dorsal interosseus muscle. MEPs were evoked by single-pulse TMS of the left M1-HAND alone (unconditioned TMS) or by TMS preceded by electrical stimulation of the right index finger (“homotopic” conditioning) or little finger (“heterotopic” conditioning). The three conditions were pseudo-randomly intermixed or delivered in blocks in which a single condition was repeated five or ten times. MEP amplitudes and SAI magnitudes were compared using linear mixed effect models.ResultsAll stimulation protocols consistently produced SAI, which was stronger after homotopic stimulation. Randomly intermingling the three stimulation conditions reduced the relative magnitude of homotopic and heterotopic SAI as opposed to blocked stimulation. The apparent attenuation of SAI was caused by a suppression of the unconditioned but not the conditioned MEP amplitude during the randomly intermixed condition.Conclusion(s)The recent history of afferent stimulation modulates corticospinal excitability. This “history effect” impacts on the relative magnitude of SAI depending on how conditioned and unconditioned responses are intermixed and needs to be taken into consideration when probing afferent inhibition and corticospinal excitability.
Generalized Hypergeometric Distributions Generated by Birth-Death Process in Bioinformatics
Authors: Kuznetsov Vladimir A. , Grageda Andre , Farbod Davood 
Published: February 2022

AbstractModern high-throughput biological systems detection methods generate empirical frequency distributions (EFD) which exhibit complex forms and have long right-side tails. Such EFD are often observed in normal and pathological processes, of which the probabilistic properties are essential, but the underlying probability mechanisms are poorly understood. To better understand the probability mechanisms driving biological complexity and the pathological role of extreme values, we propose that the observed skewed discrete distributions are generated by non-linear transition rates of birth and death processes (BDPs). We introduce a (3d+1)-parameter Generalized Gaussian Hypergeometric Probability ((3d+1)-GHP) model with the probabilities defined by a stationary solution of generalized BDP (g-BDP) and represented by generalized hypergeometric series with regularly varying function properties. We study the Regularly Varying 3d-Parameter Generalized Gaussian Hypergeometric Probability (3d-RGHP) function’s regular variation properties, asymptotically constant slow varying component, unimodality and upward/ downward convexity which allows us to specify a family of 3d-RGHP models and study their analytical and numerical characteristics. The frequency distribution of unique muta-tions occurring in the human genome of patients with melanoma have been analyzed as an example application of our theory in bioinformatics. The results show that the parameterized model not only fits the ‘heavy tail’ well, but also the entire EFD taken on the complete experimental outcome space. Our model provides a rigorous and flexible mathematical framework for analysis and application of skewed distributions generated by BDPs which often occur in bioinformatics and big data science.
Gamma Oscillations and Emotional Memory
Authors: Luther Lisa , de Voogd Lycia D. , Hagenaars Muriel A. , Jensen Ole 
Published: February 2022

AbstractIncreased visual gamma band activity is known to relate to memory and encoding in cognitive tasks and has been shown to be present during arousing compared to neutral stimulus processing. Here, we set out to investigate whether gamma activity is stronger for later remembered compared to later forgotten emotional pictures. Thirty-two healthy participants underwent a passive viewing task in which they viewed 208 (104 arousing (52 pleasant and 52 unpleasant) and 104 neutral) pictures from the International Affective Picture System (IAPS) database while we simultaneously recorded their electroencephalogram (EEG). Immediately after, they performed a recognition task including the 208 target pictures they saw before and 104 new pictures (52 arousing (26 pleasant and 26 unpleasant) and 52 neutral) as lures. We found that arousing pictures (unpleasant ones in particular) were better remembered compared to neutral pictures. Importantly, gamma activity was enhanced for remembered compared to forgotten pictures and this effect was stronger for arousing pictures. We conclude that previous findings regarding enhanced gamma as a signature of subsequent memory generalizes to emotional memory. Our findings therefore shed new light on the role of visual gamma band activity in arousal and memory formation.
Melanism in a wild sifaka population: Darker where cold and fragmented
Authors: Tapanes Elizabeth , Kamilar Jason M. , Nukala Maanas A. , Irwin Mitchell T. , Bradley Brenda J. 
Published: February 2022

AbstractPigmentation is one of the most striking examples of diversity in the natural world. Mainly, pelage (hair/fur) pigmentation provides a substrate for selection (i.e., crypsis, signaling, thermoregulation) and is capable of rapid change. Thus, this trait may be the one potential early signal of adaptation (or maladaptation) in wild primate populations. However, most of our hypotheses on the forces responsible for primate pelage pigmentation are based solely on macro-evolutionary studies. Here, we characterize pelage color and pattern variation within a population of wild primates, diademed sifakas (Propithecus diadema), exhibiting striking diversity in coloration (melanic to tri-colored). Our approach jointly assesses climate and pelage variation across the region. We score pelage using a semi-quantitative methodology. We then test if pelage variation is associated with climatic or demographic factors (i.e., sex-class, age-class) across the Tsinjoarivo forest, Madagascar. We find darker bodies and less complex faces occur in colder and more fragmented forests. We explore three hypotheses that may explain this phenotypic pattern: isolation by distance, an environmental gradient, or unique local adaptation. Importantly, each scenario signals the need for enhanced conservation of diademed sifakas in the Tsinjoarivo forest. More studies on primate pigmentation in wild populations will be needed to contextualize if this pattern is exceptional or typical. It is likely that in other primate populations pigmentation may also foretell of adaptation or environmental mismatch.
Deep Learning-based Microbubble Localization for Ultrasound Localization Microscopy
Authors: Chen Xi , Lowerison Matthew R. , Dong Zhijie , Han Aiguo , Song Pengfei 
Published: February 2022

AbstractUltrasound localization microscopy (ULM) is an emerging vascular imaging technique that overcomes the resolution-penetration compromise of ultrasound imaging. Accurate and robust microbubble (MB) localization is essential for successful ULM. In this study, we present a deep learning (DL)- based localization technique that uses both Field-II simulation and in vivo chicken embryo chorioallantoic membrane (CAM) data for training. Both radiofrequency (RF) and in-phase quadrature (IQ) data were tested in this study. The simulation experiment shows that the proposed DL-based localization was able to reduce both missing MB localization rate and MB localization error. In general, RF data showed better performance than IQ. For the in vivo CAM study with high MB concentration, DL-based localization was able to reduce the vessel MB saturation time by more than 50% as compared to conventional localization. Additionally, we propose a DL-based framework for real-time visualization of the high-resolution microvasculature. The findings of the paper support the use of DL for more robust and faster MB localization, especially under high MB concentrations. The results indicate that further improvement could be achieved by incorporating temporal information of the MB data.
DNA methylation-based age acceleration observed in IDH wild-type glioblastoma is associated with better outcome - including in elderly patients
Authors: Bady Pierre , Marosi Christine , Weller Michael , Grønberg Bjørn H. , Schultz Henrik , Taphoorn Martin J. B. , Gijtenbeek Johanna M. M. , van den Bent Martin J. , Deimling Andreas von , Stupp Roger , Malmström Annika , Hegi Monika E. 
Published: February 2022

AbstractElderly patients represent a growing proportion of individuals with glioblastoma, who however, are often excluded from clinical trials owing to poor expected prognosis. Little is known about molecular features that would justify different treatment modalities, not related to frailty and co-morbidities.We investigated the DNA methylome (450k) for age related associations using 4 different glioblastoma datasets (mean age, years: DKFZ, 60; TCGA, 62; Nordic, 71; EORTC-26981/NCIC-CE.3 & Lausanne-Pilot, 54), including two are cohorts from clinical trials. We excluded patient samples not compatible with glioblastoma grade 4 WHO-CNS-5 classification 2021. The combined methylome was interrogated for differences based on age, DNA methylation (DNAm) age acceleration (DNAm age “Horvath-clock” minus patient age), methylation-based classification (Heidelberg), entropy, and functional methylation of DNA damage response (DDR) genes.Age dependent methylation included 19 CpGs (p-value≤0.1, Bonferroni corrected), comprising ELOVL2 that is part of a 13-gene forensic age predictor. Three CpGs met our criteria of functional methylation defined as correlation of methylation with expression (r≤-0.3) of the corresponding gene. Most of the age related CpGs (n=16) were also associated with age acceleration that itself was associated with a large number of CpGs (n=50551). Over 70% age acceleration-associated CpGs (n=36348) overlapped with those associated with the methylation based tumor classification (n=170759). Functional methylation of few DDR genes was associated with age acceleration (n=8), tumor classification (n=12), or both (n=4), the latter including MGMT. DNAm age acceleration was significantly associated with better outcome in the trial cohorts of the EORTC/NCIC & Lausanne Pilot, and Nordic (treating elderly patients). Multivariate analysis included treatment (RT, RT/TMZ→TMZ; TMZ, RT), MGMT promoter methylation status, and interaction with treatment.In conclusion, DNA methylation features of age acceleration are an integrative part of the methylation-based tumor classification (RTK I, RTK II, MES), while age seems hardly reflected in the glioblastoma DNA methylome.
The Growth Laws of Brain Metastases
Authors: Ocaña-Tienda Beatriz , Pérez-Beteta Julián , Jiménez-Sánchez Juan , García David Molina , de Mendivil Ana Ortiz , Asenjo Beatriz , Albillo David , Pérez-Romasanta Luís A. , Valiente Manuel , Zhu Lucía , García-Gómez Pedro , González-Del Portillo Elisabet , Llorente Manuel , Carballo Natalia , Arana Estanislao , Pérez-García Víctor M. 
Published: February 2022

AbstractTumor growth is the result of the interplay of complex biological processes in huge numbers of individual cells living in changing environments. Effective simple mathematical laws have been shown to describe tumor growth in vitro, or simple animal models with bounded-growth dynamics accurately. However, results for the growth of human cancers in patients are scarce. Our study mined a large dataset of 1133 brain metastases (BMs) with longitudinal imaging follow-up to find growth laws for untreated BMs and recurrent treated BMs. Untreated BMs showed high growth exponents, most likely related to the underlying evolutionary dynamics, with experimental tumors in mice resembling accurately the disease. Recurrent BMs growth exponents were smaller, most probably due to a reduction in tumor heterogeneity after treatment, which may limit the tumor evolutionary capabilities. In silico simulations using a stochastic discrete mesoscopic model with basic evolutionary dynamics led to results in line with the observed data.
Repurposing azacitidine and carboplatin to prime for anti-PDL1 re-challenge of immunotherapy-resistant melanoma
Authors: van der Westhuizen Andre , Lyle Megan , Graves Moira C. , Zhu Xiaoqiang , Wong Jason W. H. , Cornall Kerrie , Ren Shu , Pugliese Leanna , Levy Richard , Majid Adeeb , Vilain Ricardo E. , Bowden Nikola A. 
Published: February 2022

AbstractDrug repurposing offers the opportunity for approved chemotherapy agents to be used to re-establish sensitivity to immune checkpoint blockade (ICB) therapy. Here we investigated the clinical and translational aspects of an early phase II study of azacitidine and carboplatin priming for anti-PDL1 immunotherapy (Avelumab) in patients with advanced ICB-resistant melanoma. 20 participants with ICB resistant metastatic melanoma received 2 × 4-week cycles of azacitidine and carboplatin followed by ICB re-challenge with anti-PD-L1 avelumab. The overall response rate (ORR) determined after 2 × 4-week cycles of azacitidine and carboplatin priming was 10% (2/20) with 2 partial responses (PR). The ORR determined after priming followed by 6 cycles of avelumab (week 22) was 10%, with 2/20 participants achieving iPR. The clinical benefit rate (CBR) for azacitidine and carboplatin priming was 65% (13/20) and after priming followed by 6 cycles of avelumab CBR was 35% (n = 7/20). The median PFS was 18.0 weeks (95% CI: 14.87 – 21.13 weeks) and the median OS was 47.86 weeks (95% CI: 9.67 – 86.06 weeks). Translational correlation analysis of tumour biopsies at baseline, after priming and after 6 cycles of avelmuab confirmed HLA-A generally increased after priming with azacitidine and carboplatin, particularly if it was absent at the start of treatment. Average methylation of CpGs across the HLA-A locus showed a consistent decrease in methylation after priming and T-cells, in particular CD8+, showed the greatest increase in infiltration. Priming with azacitidine and carboplatin can induce disease stabilization and re-sensitisation to ICB for metastatic melanoma.One Sentence SummarySequential azacitidine and carboplatin stabilises disease burden and re-establishes sensitivity to checkpoint immune blockade immunotherapy.
Placental microRNAs associate with early childhood growth characteristics
Authors: Kennedy Elizabeth M. , Hermetz Karen , Burt Amber , Pei Dong , Koestler Devin C , Hao Ke , Chen Jia , Gilbert-Diamond Diane , Ramakrishnan Usha , Karagas Margaret R. , Marsit Carmen J 
Published: February 2022

ABSTRACTPoor placental function is a common cause of intrauterine growth restriction, which in turn is associated with increased risks of perinatal morbidity, mortality and long-term adverse health outcomes. Our prior work suggests that birthweight and childhood obesity-associated genetic variants functionally impact placental function and that placental microRNA are associated with birthweight. To address the influence of the placenta beyond birth, we assessed the relationship between placental microRNAs and early childhood growth. Using the SITAR package, we generated two parameters that describe individual weight trajectories of children (0-5 years) in the New Hampshire Birth Cohort Study (NHBCS). Using negative binomial generalized linear models, we identified placental microRNAs that associate with growth parameters (FDR<0.05), while accounting for sex, gestational age at birth, and maternal parity. Genes targeted by the six growth trajectory-associated microRNAs are enriched (FDR<0.02) in growth factor signaling (TGF/beta: miR-1290; EGF/R: miR-155, Let-7c; FGF/R: miR-155; IGF/R: Let-7c, miR-155, miR-1290), cyclic AMP signaling (miR-1246), calmodulin signaling (miR-216a, miR-1246), and NOTCH signaling (miR-629). These pathways function in placental proliferation, differentiation and function. Our results support the hypothesis that fetal environment, specifically placental cellular dynamics and function guided by microRNA expression, can have impacts beyond birth, into early childhood.
Psychological, endocrine and polygenic predictors of emotional well-being during the COVID-19 pandemic in a longitudinal birth cohort
Authors: Nguyen Thao , Zillich Lea , Cetin Metin , Hall Alisha S.M. , Foo Jerome C. , Sirignano Lea , Frank Josef , Send Tabea S. , Gilles Maria , Rietschel Marcella , Deuschle Michael , Witt Stephanie H. , Streit Fabian 
Published: February 2022

AbstractThe COVID-19 pandemic severely affected the lives of families, and the well-being of children and their parent. Prenatal stress, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and genetic factors might influence individuals’ well-being in the presence of a major stressor such as the COVID-19 pandemic.The present work is part of an ongoing birth cohort study and aims to investigate maternal perceived stress, early childhood HPA axis activity, and polygenic risk scores (PRSs) as predictors of emotional well-being during the COVID-19 pandemic. All participants are part of the ongoing birth cohort study POSEIDON. Emotional well-being of children (n=263) and mothers (n=241) was assessed during the COVID-19 pandemic using the CRISIS questionnaire in two waves between June 2020 and February 2021. Associations of well-being with previously assessed maternal perceived stress, children’s salivary and morning urine cortisol at 45 months, PRSs for depression, schizophrenia, loneliness were investigated.A positive association between the children’s and mothers’ emotional well-being was found. Lower emotional well-being was observed in both children and mothers during the pandemic compared to before. Children’s emotional well-being improved over the course of the pandemic. Prenatally assessed maternal perceived stress was associated with a decrease in children’s but not in the mothers’ well-being. Cortisol measures and PRSs were not significantly associated with emotional wellbeing.The present study confirms that emotional well-being of children and mothers are linked, and were negatively affected by the COVID-19 pandemic, with differences in development over time.