bluuebunny/crossref_metadata_2025_split huggingface dataset:
The angiotensin type 2 receptor agonist C21 restores respiratory function in COVID19 - a double-blind, randomized, placebo-controlled Phase 2 trial
Authors: Tornling Göran , Batta Rohit , Porter Joanna , Bengtsson Thomas , Parmar Kartikeya , Kashiva Reema , Hallberg Anders , Cohrt Anne Katrine , Westergaard Kate , Dalsgaard Carl-Johan , Raud Johan 
Published: January 2021

ABSTRACTBackgroundAlthough several therapies have been evaluated for treatment of COVID-19, the morbidity and mortality in COVID-19 are still significant, and the need for safe and effective drugs remains high even after launch of vaccine programs.MethodsWe conducted a double-blind, randomized, placebo-controlled trial with the novel oral angiotensin II type 2 receptor agonist C21 in hospitalized COVID-19 patients with C-reactive protein 50-150 mg/L but not needing mechanical ventilation. Patients were randomly assigned to oral C21 (100 mg twice daily) or placebo for 7 days in addition to standard of care, including glucocorticoids and remdesivir.Results106 patients underwent randomization (51 in the C21 group and 55 in the placebo group). At day 14 after start of treatment, the proportion of patients still requiring supplemental oxygen was significantly reduced by 90% in the C21 group compared to the placebo group (p=0.003). Moreover, fewer patients required mechanical ventilation (one C21 patient and four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one and three deaths in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated.ConclusionsAs studied in hospitalized COVID-19 patients, C21 on top of standard of care led to a clinically beneficial improvement in respiratory function compared to placebo, paving the way for a pivotal randomised controlled trial.This study is registered atClinicalTrials.govwith identifierNCT04452435.
Local brain-age: A U-Net model
Authors: Popescu Sebastian G. , Glocker Ben , Sharp David J. , Cole James H. 
Published: January 2021

AbstractWe propose a new framework for estimating neuroimaging-derived “brain-age” at a local level within the brain, using deep learning. The local approach, contrary to existing global methods, provides spatial information on anatomical patterns of brain ageing. We trained a U-Net model using brain MRI scans from n=3463 healthy people (aged 18-90 years) to produce individualised 3D maps of brain-predicted age. When testing on n=692 healthy people, we found a median (across participant) mean absolute error (within participant) of 9.5 years. Performance was more accurate (MAE around 7 years) in the prefrontal cortex and periventricular areas. We also introduce a new voxelwise method to reduce the age-bias when predicting local brain-age “gaps”. To validate local brain-age predictions, we tested the model in people with mild cognitive impairment or dementia using data from OASIS3 (n=267). Different local brain-age patterns were evident between healthy controls and people with mild cognitive impairment or dementia, particularly in subcortical regions such as the accumbens, putamen, pallidum, hippocampus and amygdala. Comparing groups based on mean local brain-age over regions-of-interest resulted in large effects sizes, with Cohen’sdvalues >1.5, for example when comparing people with stable and progressive mild cognitive impairment. Our local brain-age framework has the potential to provide spatial information leading to a more mechanistic understanding of individual differences in patterns of brain ageing in health and disease.
Network modeling of dynamic brain interactions predicts emergence of neural information that supports human cognitive behavior
Authors: Mill Ravi D. , Hamilton Julia L. , Winfield Emily C. , Lalta Nicole , Chen Richard H. , Cole Michael W. 
Published: January 2021

AbstractHow cognitive task behavior is generated by brain network interactions is a central question in neuroscience. Answering this question calls for the development of novel analysis tools that can firstly capture neural signatures of task information with high spatial and temporal precision (the “where and when”), and then allow for empirical testing of alternative network models of brain function that link information to behavior (the “how”). We outline a novel network modeling approach suited to this purpose that is applied to non-invasive functional neuroimaging data in humans. We first dynamically decoded the spatiotemporal signatures of task information in the human brain by combining MRI-individualized source electroencephalography with multivariate pattern analysis. A newly developed network modeling approach - dynamic activity flow modeling - then simulated the flow of task-evoked activity over more causally interpretable (relative to standard functional connectivity approaches) resting-state functional connections (dynamic, lagged, direct and directional). We demonstrate the utility of this modeling approach by applying it to elucidate network processes underlying sensory-motor information flow in the brain, revealing accurate predictions of empirical response information dynamics underlying behavior. Extending the model towards simulating network lesions suggested a role for the cognitive control networks (CCNs) as primary drivers of response information flow, transitioning from early dorsal attention network-dominated sensory-to-response transformation to later collaborative CCN engagement during response selection. These results demonstrate the utility of the dynamic activity flow modeling approach in identifying the generative network processes underlying neurocognitive phenomena.
Early life experience sets hard limits on motor learning as evidenced from artificial arm use
Authors: Maimon-Mor Roni O. , Schone Hunter R. , Slater David Henderson , Faisal A. Aldo , Makin Tamar R. 
Published: January 2021

AbstractThe study or artificial arms provides a unique opportunity to address long-standing questions on sensorimotor plasticity and development. Learning to use an artificial arm arguably depends on fundamental building blocks of body representation and would therefore be impacted by early-life experience. We tested artificial arm motor-control in two adult populations with upper-limb deficiency: congenital one-handers – who were born with a partial arm, and amputees – who lost their biological arm in adulthood. Brain plasticity research teaches us that the earlier we train to acquire new skills (or use a new technology) the better we benefit from this practice as adults. Instead, we found that although one-hander started using an artificial arm as toddlers, they produced increased error noise and directional errors when reaching to visual targets, relative to amputees who performed similarly to controls. However, the earlier a one-hander was fitted with an artificial arm the better their motor control was. We suggest that visuomotor integration, underlying the observed deficits, is highly dependent on either biological or artificial arm experience at a very young age. Subsequently, opportunities for sensorimotor plasticity become more limited.
Training neural networks to recognize speech increased their correspondence to the human auditory pathway but did not yield a shared hierarchy of acoustic features
Authors: Thompson Jessica A.F. , Bengio Yoshua , Formisano Elia , Schönwiesner Marc 
Published: January 2021

AbstractThe correspondence between the activity of artificial neurons in convolutional neural networks (CNNs) trained to recognize objects in images and neural activity collected throughout the primate visual system has been well documented. Shallower layers of CNNs are typically more similar to early visual areas and deeper layers tend to be more similar to later visual areas, providing evidence for a shared representational hierarchy. This phenomenon has not been thoroughly studied in the auditory domain. Here, we compared the representations of CNNs trained to recognize speech (triphone recognition) to 7-Tesla fMRI activity collected throughout the human auditory pathway, including subcortical and cortical regions, while participants listened to speech. We found no evidence for a shared representational hierarchy of acoustic speech features. Instead, all auditory regions of interest were most similar to a single layer of the CNNs: the first fully-connected layer. This layer sits at the boundary between the relatively task-general intermediate layers and the highly task-specific final layers. This suggests that alternative architectural designs and/or training objectives may be needed to achieve fine-grained layer-wise correspondence with the human auditory pathway.HighlightsTrained CNNs more similar to auditory fMRI activity than untrainedNo evidence of a shared representational hierarchy for acoustic featuresAll ROIs were most similar to the first fully-connected layerCNN performance on speech recognition task positively associated with fmri similarity
Voltage-sensitive sodium channel (Vssc) mutations associated with pyrethroid insecticide resistance inAedes aegypti(L.) from Jeddah, Kingdom of Saudi Arabia – baseline information for aWolbachiarelease program
Authors: Endersby-Harshman Nancy M. , Ali AboElgasim , Alhumrani Basim , Alkuriji Mohammed Abdullah , Al-Fageeh Mohammed B. , Al-Malik Abdulaziz , Alsuabeyl Mohammed S. , Elfekih Samia , Hoffmann Ary A. 
Published: January 2021

AbstractBackgroundDengue suppression often relies on control of the mosquito vector,Aedes aegypti, through applications of insecticides of which the pyrethroid group has played a dominant role. Insecticide resistance is prevalent inAe. aegyptiaround the world and the resulting reduction of insecticide efficacy is likely to exacerbate the impact of dengue. Dengue has been a public health problem in Saudi Arabia, particularly in Jeddah, since its discovery there in the 1990s and insecticide use for vector control is widespread throughout the city. An alternative approach to insecticide use, based on blocking dengue transmission in mosquitoes by the endosymbiontWolbachia, is being trialled in Jeddah following the success of this approach in Australia and Malaysia. Knowledge of insecticide resistance status of mosquito populations in Jeddah is a prerequisite for establishing aWolbachia-based dengue control program as releases ofWolbachiamosquitoes succeed when resistance status of the release population is similar to that of the wild population.MethodsWHO resistance bioassays of mosquitoes with deltamethrin, permethrin and DDT were used in conjunction with TaqMan®SNP Genotyping Assays to characterise mutation profiles ofAe. aegyptifrom Jeddah.ResultsScreening of the voltage sensitive sodium channel (Vssc), the pyrethroid target-site, revealed mutations at codons 989, 1016 and 1534 inAe. aegyptifrom two districts of Jeddah. The triple mutant homozygote (1016G/1534C/989P) was confirmed from Al Safa and Al Rawabi. Bioassays with pyrethroids (Type I and II) and DDT showed that mosquitoes were resistant to each of these compounds based on WHO definitions. An association betweenVsscmutations and resistance was established for the Type II pyrethroid, deltamethrin, with one genotype (989P/1016G/1534F) conferring a survival advantage over two others (989S/1016V/1534C and the triple heterozygote). An indication of synergism of Type I pyrethroid activity with piperonyl butoxide suggests that detoxification by cytochrome P450s accounts for some of the pyrethroid resistance response inAe. aegyptipopulations from Jeddah.ConclusionsThe results provide a baseline for monitoring and management of resistance as well as knowledge ofVsscgenotype frequencies required inWolbachiarelease populations to ensure homogeneity with the target field population.
Decoding silence in free recall
Authors: Fumarola Francesco , He Zhengqi , Kuśmierz Łukasz , Toyoizumi Taro 
Published: January 2021

AbstractIn experiments on free recall from lists of items, not all memory retrievals are necessarily reported. Previous studies investigated unreported retrievals by attempting to induce their externalization. We show that, without any intervention, their statistics may be directly estimated through a model-free analysis of inter-response times – the silent intervals between recalls. A delay attributable to unreported recalls emerges in three situations: if the final item was already recalled (“silent recency effect”); if the item that, within the list, follows the latest recalled item was already recalled (“silent contiguity effect”); and in sequential recalls within highly performing trials (“sequential slowdown”). We then turn to reproducing all these effects by a minimal model where the discarding of memories (“bouncing”) occurs either if they are repetitious or, in strategically organized trials, if they are not sequential. Based on our findings, we propose various approaches to further probing the submerged dynamics of memory retrieval.
CloudReg: Automatic Terabyte-Scale Cross-Modal Brain Volume Registration
Authors: Chandrashekhar Vikram , Tward Daniel J , Crowley Devin , Crow Ailey K , Wright Matthew A , Hsueh Brian Y , Gore Felicity , Machado Timothy A , Branch Audrey , Rosenblum Jared S , Deisseroth Karl , Vogelstein Joshua T 
Published: January 2021

AbstractQuantifying terabyte-scale multi-modal human and animal imaging data requires scalable analysis tools. We developed CloudReg, an open-source, automatic, terabyte-scale, cloud-based image analysis pipeline that pre-processes and registers cross-modal volumetric datasets with artifacts via spatially-varying polynomial intensity transform. CloudReg accurately registers the following datasets to their respective atlases:in vivohuman andex vivomacaque brain magnetic resonance imaging,ex vivomouse brain micro-computed tomography, and cleared murine brain light-sheet microscopy.
Dynamics of global gene expression and chromatin accessibility of the peripheral nervous system in animal models of persistent pain
Authors: Stephens Kimberly E. , Zhou Weiqiang , Renfro Zachary , Ji Zhicheng , Ji Hongkai , Guan Yun , Taverna Sean D. 
Published: January 2021

AbstractEfforts to understand genetic variability involved in an individual’s susceptibility to chronic pain support a role for upstream regulation by epigenetic mechanisms. To examine the transcriptomic and epigenetic basis of chronic pain that resides in the peripheral nervous system, we used RNA-seq and ATAC-seq of the rat dorsal root ganglion (DRG) to identify novel molecular pathways associated with pain hypersensitivity in two well-studied persistent pain models induced by Chronic Constriction Injury (CCI) of the sciatic nerve and intra-plantar injection of Complete Freund’s Adjuvant (CFA) in rats. Our RNA-seq studies identify a variety of biological process related to synapse organization, membrane potential, transmembrane transport, and ion binding. Interestingly, genes that encode transcriptional regulators were disproportionately downregulated in both models. Our ATAC-seq data provide a comprehensive map of chromatin accessibility changes in the DRG. A total of 1123 regions showed changes in chromatin accessibility in one or both models when compared to the naïve and 31 shared differentially accessible regions (DAR)s. Functional annotation of the DARs identified disparate molecular functions enriched for each pain model which suggests that chromatin structure may be altered differently following sciatic nerve injury and hind paw inflammation. Motif analysis identified 17 DNA sequences known to bind transcription factors in the CCI DARs and 33 in the CFA DARs. Two motifs were significantly enriched in both models. Our improved understanding of the changes in chromatin accessibility that occur in chronic pain states may identify regulatory genomic elements that play essential roles in modulating gene expression in the DRG.SummaryShared transcriptomic and epigenetic changes in two animal models improves our understanding of how chromatin structural changes alter DRG gene expression under persistent pain conditions.
Age dependency and lateralization in the three branches of the human superior longitudinal fasciculus
Authors: Amemiya Kaoru , Naito Eiichi , Takemura Hiromasa 
Published: January 2021

AbstractThe superior longitudinal fascicle/fasciculus (SLF) is a major white matter tract connecting the frontal and parietal cortices in humans. Although the SLF has often been analyzed as a single entity, several studies have reported that the SLF is segregated into three distinct branches (SLF I, II, and III). They have also reported the right lateralization of the SLF III volume and discussed its relationship with lateralized cortical functions in the fronto-parietal network. However, to date, the homogeneity or heterogeneity of the age dependency and lateralization properties of SLF branches have not been fully clarified. Through this study, we aimed to clarify the age dependency and lateralization of SLF I-III by analyzing diffusion-weighted MRI (dMRI) and quantitative R1 (qR1) map datasets collected from a wide range of age groups, mostly comprising right-handed children, adolescents, adults, and seniors (6 to 81 years old). The age dependency in dMRI measurement (fractional anisotropy, FA) was heterogeneous among the three SLF branches, suggesting that these branches are regulated by distinct developmental and aging processes. Lateralization analysis on SLF branches revealed that the right SLF III was larger than the left SLF III in adults, replicating previous reports. FA measurement also suggested that, in addition to SLF III, SLF II was lateralized to the right hemisphere in adolescents and adults. We further found a left lateralization of SLF I in qR1 data, a microstructural measurement sensitive to myelin levels, in adults. These findings suggest that the SLF sub-bundles are distinct entities in terms of age dependency and lateralization.
The worm affair: Genetic diversity in two species of symbionts that co-occur in tubeworms from the Mediterranean Sea
Authors: Zvi-Kedem Tal , Shemesh Eli , Tchernov Dan , Rubin-Blum Maxim 
Published: January 2021

SummaryThe symbioses between the vestimentiferan tubeworms and their chemosynthetic partners (Gammaproteobacteria, Chromatiales,Sedimenticolaceae) hallmark the success of these organisms in hydrothermal vent and hydrocarbon seep deep-sea habitats. The fidelity of these associations varies, as both the hosts and the symbionts can be loose in partner choice. Some tubeworms may host distinct symbiont phylotypes, which often co-occur in a single host individual. To better understand the genetic basis for the ‘promiscuity’ of tubeworm symbioses, we curated and investigated metagenome-assembled genomes of two symbiont phylotypes (species, based on the average nucleotide identity <95%) inLamellibrachia anaximandri, a vestimentiferan endemic to the Mediterranean Sea, in individuals collected from Palinuro hydrothermal vents (Italy) and hydrocarbon seeps (Eratosthenes seamount and Palmahim disturbance). Using comparative genomics, we show that mainly mobilome and defense mechanism-related features distinguish the symbiont genotypes. While many central metabolic functions are conserved in the tubeworm symbionts, nitrate respiration (Nar, Nap and Nas proteins) is modular, yet this modularity is not linked to speciation, but rather to local adaptation. Our results hint that variation in a single moonlighting protein may be responsible for the host-symbiont fidelity.
Impaired differential learning of fear versus safety signs in obsessive-compulsive disorder
Authors: Elsner Björn , Reuter Benedikt , Said Mahboba , Linnman Clas , Kathmann Norbert , Beucke Jan-Carl 
Published: January 2021

AbstractPavlovian learning mechanisms are of great importance both for models of psychiatric disorders and treatment approaches, but understudied in obsessive-compulsive disorder (OCD). Using an established Pavlovian fear conditioning and reversal procedure, we studied skin conductance responses (SCRs) in 41 patients with OCD and in 32 matched healthy control participants. Within both groups, fear acquisition and reversal effects were evident. When comparing groups, patients showed impaired differential learning of threatening and safe stimuli, consistent with previous research. In contrast to prior findings, differential learning impairments were restricted to fear acquisition, and not observed in the reversal stage of the experiment. As previous and present fear reversal experiments in OCD differed in the use of color coding to facilitate stimulus discrimination, the studies converge to suggest that differential learning of threatening versus safe stimuli is impaired in OCD, but manifests itself differently depending on the difficulty of the association to be learned. When supported by the addition of color, patients with OCD previously appeared to acquire an association early but failed to reverse it according to changed contingencies. In absence of such color coding of stimuli, our data suggest that patients with OCD already show differential learning impairments during fear acquisition, which may relate to findings of altered coping with uncertainty previously observed in OCD. Impaired differential learning of threatening versus safe stimuli should be studied further in OCD, in order to determine whether impairments in differential learning predict CBT treatment outcomes in patients, and whether they are etiologically relevant for OCD.
Suberin plasticity to developmental and exogenous cues is regulated by a set of MYB transcription factors
Authors: Shukla Vinay , Han Jian-Pu , Cléard Fabienne , Legendre Linnka Lefebvre- , Gully Kay , Flis Paulina , Berhin Alice , Andersen Tonni Grube , Salt David E , Nawrath Christiane , Barberon Marie 
Published: January 2021

AbstractSuberin is a hydrophobic biopolymer that can be deposited at the periphery of cells, forming protective barriers against biotic and abiotic stress. In roots, suberin forms lamellae at the periphery of endodermal cells where it plays crucial roles in the control of water and mineral transport. Suberin formation is highly regulated by developmental and environmental cues. However, the mechanisms controlling its spatiotemporal regulation are poorly understood. Here, we show that endodermal suberin is regulated independently by developmental and exogenous signals to fine tune suberin deposition in roots. We found a set of four MYB transcription factors (MYB41, MYB53, MYB92 and MYB93), that are regulated by these two signals, and are sufficient to promote endodermal suberin. Mutation of these four transcription factors simultaneously through genome editing, lead to a dramatic reduction of suberin formation in response to both developmental and environmental signals. Most suberin mutants analyzed at physiological levels are also affected in another endodermal barrier made of lignin (Casparian strips), through a compensatory mechanism. Through the functional analysis of these four MYBs we generated plants allowing unbiased investigations of endodermal suberin function without accounting for confounding effects due to Casparian strip defects, and could unravel specific roles of suberin in nutrient homeostasis.