bluuebunny/crossref_metadata_2025 huggingface dataset:
Test-retest reproducibility of human brain multi-slice 1H FID-MRSI data at 9.4 T after optimization of lipid regularization, macromolecular model and spline baseline stiffness
Authors: Ziegs Theresia , Wright Andrew Martin , Henning Anke
Published: February 2022

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Purpose

This study analyzes the effects of retrospective lipid suppression, a simulated macromolecular prior knowledge and different spline baseline stiffness values on 9.4 T multi-slice proton FID-MRSI data spanning the whole cerebrum of human brain and its reproducibility of metabolite ratio (/tCr) maps for 10 brain metabolites.

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Methods

Measurements were performed twice on five volunteers using a non-accelerated FID MRSI 2D sequence at 9.4 T. The effects of retrospective lipid L2-regularization, macromolecular spectrum and different LCModel baseline flexibilities on SNR, FWHM, fitting residual, CRLB and the concentration ratio maps were investigated. Intra-subject, inter-session coefficient of variation of the mean metabolite ratios (/tCr) of each slice was calculated.

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Results

L2-regularization provided effective suppression of lipid-artifacts, but should be avoided if no artifacts are detected. Transversal, sagittal and coronal of many metabolite ratio maps correspond to anatomically expected concentration relations in gray and white matter for the majority of the cerebrum when using a flexible baseline in LCModel fit. Additionally, results from the second measurements of the same subjects show that slice positioning and data quality correlate significantly to the first measurement.

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Conclusion

Concentration ratio maps (/tCr) for 4 metabolites (tCho, NAA, Glu, mI) spanning the majority and six metabolites (NAAG, GABA, GSH, Tau, Gln, Asp) covering 32 mm in the upper part of the brain were acquired at 9.4 T using multi-slice FID MRSI with retrospective lipid suppression, a macromolecular spectrum and a flexible LCModel baseline.
Human orbitofrontal cortex signals decision outcomes to sensory cortex during flexible tactile learning
Authors: Wang Bin A. , Veismann Maike , Banerjee Abhishek , Pleger Burkhard
Published: February 2022

The ability to respond flexibly to an ever-changing environment relies on the orbitofrontal cortex (OFC). How the OFC associates sensory information with predicted outcomes to enable flexible sensory learning in humans remains elusive. Here, we combine a probabilistic tactile reversal learning task with functional magnetic resonance imaging (fMRI) to investigate how lateral OFC (lOFC) interacts with the primary somatosensory cortex (S1) to guide flexible tactile learning in humans. fMRI results reveal that lOFC and S1 exhibit distinct task-dependent engagement: while the lOFC responds transiently to unexpected outcomes immediately following reversals, S1 is persistently engaged during re-learning. Unlike the contralateral stimulus-responsive S1, activity in ipsilateral S1 mirrors the outcomes of behavior during re-learning, which is closely related to top-down signals from lOFC. These findings suggest that lOFC contributes to teaching signals to dynamically update representations in sensory areas, which implements computations critical for adaptive behavior.
A Prism Vote Framework for Individualized Risk Prediction of Traits in Genome-wide Sequencing Data of Multiple Populations
Authors: Xia Xiaoxuan , Sun Rui , Zhang Yexian , Wei Yingying , Li Qi , Chong Marc Ka Chun , Wu William Ka Kei , Zee Benny Chung-Ying , Tang Hua , Wang Maggie Haitian
Published: February 2022

Multi-population cohorts offer unprecedented opportunities for profiling disease risk in large samples, however, heterogeneous risk effects underlying complex traits across populations make integrative prediction challenging. In this study, we propose a novel Bayesian probability framework, the Prism Vote (PV), to construct risk predictions in heterogeneous genetic data. The PV views the trait of an individual as a composite risk from subpopulations, in which stratum-specific predictors can be formed in data of more homogeneous genetic structure. Since each individual is represented by a composition of subpopulation memberships, the framework enables individualized risk characterization. Simulations demonstrated that the PV framework applied with alternative prediction methods significantly improved prediction accuracy in mixed and admixed populations. The advantage of PV enlarges as the sample size, genetic heterogeneity, and population diversity increase. In two real genome-wide association data consists of multiple populations, we showed that the framework enhanced prediction accuracy of the linear mixed model by up to 12.1% in five-group cross validations. The proposed framework offers a new aspect to analyze individual’s disease risk and improve accuracy for predicting complex traits in genome data.
Taurine or N-acetylcysteine treatments prevent memory impairment and metabolite profile alterations in the hippocampus of high-fat diet-fed female mice
Authors: Garcia-Serrano Alba M. , Vieira Joao P.P. , Fleischhart Veronika , Duarte João M.N.
Published: February 2022

Obesity impacts brain metabolism and function, and constitutes a risk factor for dementia development. Long-term exposure to obesogenic diets leads to taurine accumulation in the hippocampus of rodents. Taurine has putative beneficial effects on cell homeostasis, and is reported to improve cognition. Therefore, hippocampal taurine accumulation in obese and diabetic models might constitute a counteracting response to metabolic stress. This study tested the hypothesis that treatment with taurine or with N-acetylcysteine (NAC), which provides cysteine for the synthesis of taurine and the antioxidant glutathione, prevent obesity-associated hippocampal alterations and memory impairment. Female mice were fed either a regular diet or a high-fat diet (HFD). For the same period, some mice had access to 3%(w/v) taurine or 3%(w/v) NAC in the drinking water. After 2 months, magnetic resonance spectroscopy was used to measure metabolite profiles. Then, memory was assessed in novel object and novel location recognition tests. HFD feeding caused memory impairment in both tests, and reduced concentration of lactate, phosphocreatine-to-creatine ratio, and the neuronal marker N-acetylaspartate in the hippocampus. Both taurine and NAC prevented HFD-induced memory impairment and N-acetylaspartate reduction. NAC, but not taurine, prevented the HFD-induced reduction of lactate and phosphocreatine-to-creatine ratio. Analysis of the metabolite profile further revealed prominent NAC/taurine-induced increase of glutamate and GABA levels in the hippocampus. We conclude that NAC and taurine prevent of neuronal dysfunction, while only NAC prevents energy metabolism dysregulation in HFD-induced obesity in female mice.
No evidence that post-training D2R dopaminergic drug administration affects fear generalization in male rats
Authors: Schroyens Natalie , Vercammen Laura , Özcan Burcu , Ossorio Salazar Victoria Aurora , Zaman Jonas , De Bundel Dimitri , Beckers Tom , Luyten Laura
Published: February 2022

The neurotransmitter dopamine plays an important role in the processing of emotional memories, and prior research suggests that dopaminergic manipulations immediately after fear learning can affect the retention and generalization of acquired fear. The current study focuses specifically on the role of dopamine D2 receptors (D2Rs) in adult, male Wistar rats. In a series of five experiments, D2R (ant)agonists were injected systemically immediately after differential cued fear conditioning (CS+ followed by shock, CS− without shock). All five experiments involved the administration of the D2R agonist quinpirole at different doses versus saline (n = 12, 16 or 44 rats/group). Additionally, one of the studies administered the D2R antagonist raclopride (n = 12). One day later, freezing during the CS+ and CS− was assessed. We found no indications for an effect of quinpirole or raclopride on fear generalization during this drug-free test. Importantly, and contradicting prior research in mice, the evidence for the absence of an effect of quinpirole (1 mg/kg) on fear generalization was substantial according to Bayesian analyses and was observed in a highly powered experiment (N = 87). We did find acute behavioral effects in line with the literature, for both quinpirole and raclopride in a locomotor activity test.
Rabbit Hindlimb Kinematics and Ground Contact Pressure During the Stance Phase of Hopping Gait
Authors: Hall Patrick T. , Stubbs Caleb , Anderson David E. , Greenacre Cheryl B. , Crouch Dustin L.
Published: February 2022

Though the rabbit is a common animal model in musculoskeletal research, there is very limited data reported on healthy rabbit biomechanics. Our objective was to quantify the normative hindlimb biomechanics of six New Zealand White rabbits (3 male, 3 female) during the stance phase of hopping gait. We measured biomechanics by synchronously recording sagittal plane motion and ground contact pressure using a video camera and pressure mat, respectively. Both foot angle (i.e., angle between foot and ground) and ankle angle curves were unimodal. The peak ankle dorsiflexion angle was 65.9°±12.7° and occurred at 39% stance, while the peak ankle plantarflexion angle was 136.9°±7.8° at toe-off. Minimum and maximum foot angles were 16.6°±6.4° at 12% stance and 125.4°±4.0° at toe-off, respectively. During stance, the knee joint center gradually progressed 4.7 cm downward and 18.1 cm forward, on average. The maximum vertical ground reaction force and contact area, both averaged across rabbits, were 42.5 ± 11.4 %BW and 7.5 ± 1.8 cm2, respectively. Our study confirmed that rabbits exhibit a plantigrade gait pattern, similar to humans. Future studies can reference our data to quantify the extent to which orthopedic interventions affect rabbit biomechanics.
An in vitro model of fibrosis using crosslinked native extracellular matrix-derived hydrogels to modulate biomechanics without changing composition
Authors: Nizamoglu M. , de Hilster R.H.J , Zhao F. , Sharma P.K. , Borghuis T. , Harmsen M.C. , Burgess J.K.
Published: February 2022

Extracellular matrix (ECM) is a dynamic network of proteins, proteoglycans and glycosaminoglycans, providing structure to the tissue and biochemical and biomechanical instructions to the resident cells. In fibrosis, the composition and the organization of the ECM are altered, and these changes influence cellular behaviour. Biochemical (i. e. protein composition) and biomechanical changes in ECM take place simultaneously in vivo. Investigating these changes individually in vitro to examine their (patho)physiological effects has been difficult. In this study, we generated an in vitro model to reflect the altered mechanics of a fibrotic microenvironment through applying fibre crosslinking via ruthenium/sodium persulfate crosslinking on native lung ECM-derived hydrogels. Crosslinking of the hydrogels without changing the biochemical composition of the ECM resulted in increased stiffness and decreased viscoelastic stress relaxation. The altered stress relaxation behaviour was explained using a generalized Maxwell model. Fibre analysis of the hydrogels showed that crosslinked hydrogels had a higher percentage of matrix with a high density and a shorter average fibre length. Fibroblasts seeded on ruthenium-crosslinked lung ECM-derived hydrogels showed myofibroblastic differentiation with a loss of spindle-like morphology together with greater α-smooth muscle actin (α-SMA) expression, increased nuclear area and circularity without any decrease in the viability, compared with the fibroblasts seeded on the native lung-derived ECM hydrogels. In summary, ruthenium crosslinking of native ECM-derived hydrogels provides an exciting opportunity to alter the biomechanical properties of the ECM-derived hydrogels while maintaining the protein composition of the ECM to study the influence of mechanics during fibrotic lung diseases.
Within-individual consistency and between-individual variation in the shapes of eggs laid by tree swallows (Tachycineta bicolor)
Authors: Taff Conor C. , Ryan Thomas A. , Uehling Jennifer J. , Injaian Allison S. , Vitousek Maren N.
Published: February 2022

Bird eggs come in a wide variety of shapes and recent large-scale studies across species have renewed interest in understanding the factors that generate and maintain this diversity. However, these advances largely overlook the fact that egg shape also varies dramatically within species: between populations, between individuals, and between eggs produced by the same individual. We measured the shape and size of 1382 eggs produced by 205 tree swallows (Tachycineta bicolor) in 259 nests with many females having eggs measured in two or three years. We found that intra-specific variation in the asymmetry and ellipticity of tree swallow eggs spanned the range of typical egg shapes from 69% of species reported in a recent comparative study. Variation in shape and size was largely explained by individual identity, as the repeatability of egg shape and size was remarkably high both for eggs produced within a clutch and for clutches produced in successive years. All characteristics of mother and daughter eggs were positively correlated, although with a sample size of only 15 pairs these relationships were not significant. Female mass and structural size were correlated with the size of eggs produced, but not with their shape. Older females produced eggs that were larger, more asymmetrical, and less elliptical; this pattern was driven by a combination of both longitudinal changes in egg characteristics as females aged and by differential overwinter survival of females with particular egg characteristics. We found no evidence that any aspect of shape or size that we measured was related to nestling measurements or fate. Finally, we found that the patterns of covariation in aspects of egg size and shape between-individuals differed from that observed within-individuals, suggesting that the mechanisms driving egg shape variation might differ across these levels. A complete understanding of avian egg shapes will need to incorporate variation at multiple scales and we discuss the interpretation of our results in light of recent large-scale comparative studies that focus only on mean species egg shapes.
Residual DNA in enzymes may pose a challenge for DIY RNA sequencing protocols: how to deal
Authors: Krivoy Andrey , Botsmanov Yegor , Cheranev Valery , Shmitko Anna , Belova Vera , Moskalenko Viktoriya , Afasizhev Robert , Shut Anastasia , Korostin Dmitriy , Rebrikov Denis
Published: February 2022

High-throughput RNA sequencing (RNA-seq) is widely employed for gene expression profiling. This report on do-it-yourself RNA-Seq library preparation pitfalls, highlighting their correct identification and successful overcoming, may be helpful to research groups commencing a DIY RNA-Seq workflow and facing similar problems.
A novel hidden Markov approach to studying dynamic functional connectivity states in human neuroimaging
Authors: Hussain Sana , Langley Jason , Seitz Aaron R. , Hu Xiaoping P. , Peters Megan A. K.
Published: February 2022

Introduction

Hidden Markov models are a popular choice to extract and examine recurring patterns of activity or functional connectivity in neuroimaging data, both in terms of spatial patterns and their temporal progression. Although many diverse hidden Markov models have been applied to neuroimaging data, most have defined states based on activity levels (intensity-based states) rather than patterns of functional connectivity between brain areas (connectivity-based states), which is problematic if we want to understand connectivity dynamics: intensity-based states are unlikely to provide comprehensive information about dynamic connectivity patterns.

Methods

We addressed this problem by introducing a new hidden Markov model that defines states based on full functional connectivity profiles among brain regions. We empirically explored the behavior of this new model in comparison to existing approaches based on intensity-based or summed functional connectivity states using the HCP unrelated 100 functional magnetic resonance imaging “resting state” dataset.

Results

Our ‘full functional connectivity’ model discovered connectivity states with more distinguishable (i.e., unique and separable from each other) patterns than previous approaches, and recovered simulated connectivity-based states more faithfully than the other models tested.

Discussion

Thus, if our goal is to extract and interpret connectivity states in neuroimaging data, our new model outperforms previous methods which miss crucial information about the evolution of functional connectivity in the brain.

Impact statement

Hidden Markov models can be used to investigate brain states noninvasively. Previous models “recover” connectivity from intensity-based hidden states, or from connectivity ‘summed’ across nodes. Here we introduce a novel connectivity-based hidden Markov model and show how it can reveal true connectivity hidden states under minimal assumptions.
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

With 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

The 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

Background

Electrical 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/Hypothesis

We hypothesized that corticospinal excitability and SAI are influenced by the recent history of peripheral electrical stimulation.

Methods

In 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.

Results

All 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

Modern 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

Increased 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

Pigmentation 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

Ultrasound 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

Elderly 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

Tumor 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

Drug 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 Summary

Sequential 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

Poor 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

The 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.
Coordinated Cortical Thickness Alterations across Psychiatric Conditions: A Transdiagnostic ENIGMA Study
Authors: Hettwer MD , Larivière S , Park BY , van den Heuvel OA , Schmaal L , Andreassen OA , Ching CRK , Hoogman M , Buitelaar J , Veltman DJ , Stein DJ , Franke B , van Erp TGM ,   ENIGMA ADHD Working Group,   ENIGMA Autism Working Group,   ENIGMA Bipolar Disorder Working Group,   ENIGMA Major Depression Working Group,   ENIGMA OCD Working Group,   ENIGMA Schizophrenia Working Group, Jahanshad N , Thompson PM , Thomopoulos SI , Bethlehem RAI , Bernhardt BC , Eickhoff SB , Valk SL
Published: February 2022

Introduction

Mental disorders are increasingly conceptualized as overlapping spectra with underlying polygenicity, neurodevelopmental etiology, and clinical comorbidity. They share multi-level neurobiological alterations, including network-like brain structural alterations. However, whether alteration patterns covary across mental disorders in a biologically meaningful way is currently unknown.

Methods

We accessed summary statistics on cortical thickness alterations from 12,024 patients with six mental disorders and 18,969 controls from the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium. First, we studied cortical thickness co-alteration networks as a form of pathological structural covariance. We identified regions exhibiting high inter-regional covariance across disorders (‘hubs’), and regions that strongly connect to these hubs facilitating network spreading of disease effects (‘epicenters’). Next, we applied manifold learning to reveal organizational gradients guiding transdiagnostic patterns of illness effects. Last, we tested whether these gradients capture differential cortical susceptibility with respect to normative cortical thickness covariance, cytoarchitectonic, transcriptomic, and meta-analytical task-based profiles.

Results

Co-alteration network hubs were linked to normative connectome hubs and anchored to prefrontal and temporal disease epicenters. The principal gradient derived from manifold learning captured maximally different embedding of prefrontal and temporal epicenters within co-alteration networks, followed a normative cortical thickness gradient, and established a transcriptomic link to cortico-cerebello-thalamic circuits. Moreover, gradients segregated functional networks involved in basic sensory, attentional/perceptual, and domain-general cognitive processes, and distinguished between regional cytoarchitectonic profiles.

Conclusion

Together, our findings indicate that disease impact occurs in a synchronized fashion and along multiple levels of hierarchical cortical organization. Such axes can help to disentangle the different neurobiological pathways underlying mental illness.
Fading of brain network fingerprint in Parkinson’s disease predicts motor clinical impairment
Authors: Troisi Lopez E , Minino R , Liparoti M , Polverino A , Romano A , De Micco R , Lucidi F , Tessitore A , Amico E , Sorrentino G , Jirsa V , Sorrentino P
Published: February 2022

The clinical connectome fingerprint (CCF) was recently introduced as a way to assess brain dynamics and used to predict the cognitive decline in preclinical Alzheimer’s disease. In this paper we explore the performance of CCF in 47 Parkinson’s disease (PD) patients and 47 healthy controls, under the hypothesis that patients would show reduced identifiability as compared to controls, and that such reduction could be used to predict motor impairment. Using source-reconstructed magnetoencephalography signals, we built functional connectomes and observed reduced identifiability in patients compared to healthy individuals in the beta band. Furthermore, we found that the reduction in identifiability was proportional to the motor impairment, assessed through the Unified Parkinson’s Disease Rating Scale, and, interestingly, able to predict it (at the subject level). Along with previous evidence, this paper shows that CCF captures disrupted dynamics in neurodegenerative diseases and is particularly effective in predicting motor clinical impairment in PD.
Transparency and reporting characteristics of COVID-19 randomized controlled trials
Authors: Kapp Philipp , Esmail Laura , Ghosn Lina , Ravaud Philippe , Boutron Isabelle
Published: February 2022

Randomized controlled trials (RCTs) are essential to support clinical decision making. We assessed the transparency, completeness and consistency of reporting of 244 reports (120 peer-reviewed journal publications; 124 preprints) of RCTs assessing pharmacological interventions for the treatment of COVID-19 published the first 17 months of the pandemic (up to May 31, 2021). Transparency was poor. Only 55% of trials were prospectively registered; 39% made their full protocols available and 29% provided access to their statistical analysis plan. Only 6% completely reported the most important information. Primary outcome(s) reported in trial registries and published reports were inconsistent in 47% of trials. Of the 124 RCTs published as preprint, 76 were secondarily published in a peer-reviewed journal. There was no major improvement after the peer-review process.

Lack of transparency, completeness and consistency of reporting is an important barrier to trust, interpretation and synthesis in COVID-19 clinical trials.
Increase in coercive measures in psychiatric hospitals in Germany during the COVID-19 Pandemic
Authors: Flammer Erich , Eisele Frank , Hirsch Sophie , Steinert Tilman
Published: February 2022

Objective

To examine whether the pandemic in 2020 caused changes in psychiatric hospital cases, the percentage of patients exposed to coercive interventions, and aggressive incidents.

Methods

We used the case registry for coercive measures of the State of Baden-Wuerttemberg, comprising case-related data on mechanical restraint, seclusion, physical restraint, and forced medication in each of the State’s 31 licensed hospitals treating adults, to compare data from 2019 and 2020.

Results

The number of cases in adult psychiatry decreased by 7.6% from 105,782 to 97,761. The percentage of involuntary cases increased from 12.3 to 14.1%, and the absolute number of coercive measures increased by 4.7% from 26,269 to 27,514. The percentage of cases exposed to any kind of coercive measure increased by 24.6% from 6.5 to 8.1%, and the median cumulative duration per affected case increased by 13.1% from 12.2 to 13.8 hrs, where seclusion increased more than mechanical restraint. The percentage of patients with aggressive incidents, collected in 10 hospitals, remained unchanged.

Conclusions

While voluntary cases decreased considerably during the pandemic, involuntary cases increased slightly. However, the increased percentage of patients exposed to coercion is not only due to a decreased percentage of voluntary patients, as the duration of coercive measures per case also increased. The changes that indicate a deterioration in treatment quality were probably caused by the multitude of measures to manage the pandemic. The focus of attention has shifted from prevention of coercion to prevention of infection.