bluuebunny/crossref_metadata_2025_split huggingface dataset:
MVD-Fuse: Detection of White Matter Degeneration via Multi-View Learning of Diffusion Microstructure
Authors: Fadnavis Shreyas , Polosecki Pablo , Garyfallidis Eleftherios , Castro Eduardo , Cecchi Guillermo 
Published: April 2021

AbstractDetecting neuro-degenerative disorders in early-stage and asymptomatic patients is challenging. Diffusion MRI (dMRI) has shown great success in generating biomarkers for cellular organization at the microscale level using complex biophysical models, but there has never been a consensus on a clinically usable standard model. Here, we propose a new framework (MVD-Fuse) to integrate measures of diverse diffusion models to detect alterations of white matter microstructure. The spatial maps generated by each measure are considered as a different diffusion representation (view), the fusion of these views being used to detect differences between clinically distinct groups. We investigate three different strategies for performing intermediate fusion: neural networks (NN), multiple kernel learning (MKL) and multi-view boosting (MVB). As a proof of concept, we applied MVD-Fuse to a classification of premanifest Huntington’s disease (pre-HD) individuals and healthy controls in the TRACK-ON cohort. Our results indicate that the MVD-Fuse boosts predictive power, especially with MKL (0.90 AUC vs 0.85 with the best single diffusion measure). Overall, our results suggest that an improved characterization of pathological brain microstructure can be obtained by combining various measures from multiple diffusion models.
Factors Affecting Guardians’ Decision Making on Clinic-based Purchase of Children’s Spectacles in Nigeria
Authors: Chan Ving Fai , Yong Ai Chee , Neill Ciaran O’ , Graham Christine , Congdon Nathan , Lohfeld Lynne , Stephan Tai , Ebri Anne Effiom 
Published: April 2021

AbstractBackgroundThis study aims to understand the key factors influencing guardians’ decisions when purchasing spectacles for their children in semi-urban and urban areas of Cross River State, Nigeria, where a spectacle cross-subsidisation scheme will be implemented.MethodsThis cross-sectional study was conducted among all consecutive guardians visiting the Calabar (urban), Ugep, Ikom and Ogoja (semi-urban) public eye clinics in Cross River State, southern Nigeria, from August 1 to October 31 2019, and whose children had significant refractive errors (myopia ≤-0.50D, hyperopia ≥1.50D, astigmatism >0.75D) and received spectacles. Guardians were interviewed using a questionnaire which included i) close-ended questions on reasons guardians choose to purchase spectacles for their children in eye clinics, ii) guardians’ perceptions of the quality and design of children’s current spectacle, iii) factors most heavily influencing their choice of spectacles for children, and iv) open-ended questions to seek guardians’ suggestions on how to improve the current spectacle range.ResultsAll 137 eligible guardians (n=92, 67.2% women) who visited the selected eye clinics participated in the study (response rate=100%), with 109 (79.6%) from semi-urban and 28 (20.4%) attending urban clinics. Guardians from both urban and semi-urban clinics prioritised frame design, quality, and material as the main factors affecting their decision when purchasing spectacles for their children. Female guardians and those with higher incomes were both 1.5 times more likely to emphasise frame quality when describing selection criteria for purchasing spectacles for their children than male guardians (p=0.01) or guardians earning less (p=0.03).ConclusionDesign, material, and frame quality are key factors influencing guardians when purchasing spectacles for their children in these setting and female guardians or those with higher income prioritise frame quality. This study could guide the planning and implementation of a novel cross-subsidisation scheme in Cross River State.
A multimodal 3D neuro-microphysiological system with neurite-trapping microelectrodes
Authors: Molina-Martínez Beatriz , Jentsch Laura-Victoria , Ersoy Fulya , van der Moolen Matthijs , Donato Stella , Ness Torbjørn V. , Heutink Peter , Jones Peter D. , Cesare Paolo 
Published: April 2021

AbstractThree-dimensional cell technologies as pre-clinical models are emerging tools for mimicking the structural and functional complexity of the nervous system. The accurate exploration of phenotypes in engineered 3D neuronal cultures, however, demands morphological, molecular and especially functional measurements. Particularly crucial is measurement of electrical activity of individual neurons with millisecond resolution. Current techniques rely on customized electrophysiological recording set-ups, characterized by limited throughput and poor integration with other readout modalities. Here we describe a novel approach, using multiwell glass microfluidic microelectrode arrays, allowing non-invasive electrical recording from engineered 3D neural tissues. We demonstrate parallelized studies with reference compounds, calcium imaging and optogenetic stimulation. Additionally, we show how microplate compatibility allows automated handling and high-content analysis of human induced pluripotent stem cell–derived neurons. This microphysiological platform opens up new avenues for high-throughput studies on the functional, morphological and molecular details of neurological diseases and their potential treatment by therapeutic compounds.
Oncogenic PKA signaling stabilizes MYC oncoproteins via an aurora kinase A-dependent mechanism
Authors: Chan Gary K. L. , Maisel Samantha , Hwang Yeonjoo C. , Wolber Rebecca R. B. , Vu Phuong , Patra Krushna C. , Bouhaddou Mehdi , Kenerson Heidi L. , Yeung Raymond S. , Swaney Danielle L. , Krogan Nevan J. , Turnham Rigney E. , Scott John D. , Riehle Kimberly J. , Bardeesy Nabeel , Gordan John D. 
Published: April 2021

AbstractGenetic alterations that activate protein kinase A (PKA) signaling are found across many tumor types, but their downstream oncogenic mechanisms are poorly understood. We used global phosphoproteomics and kinome activity profiling to map the conserved signaling outputs driven by diverse genetic changes that activate PKA in human cancer, including melanoma and fibrolamellar carcinoma (FLC). We define two consensus networks of effectors downstream of PKA in cancer models. One is centered on RAS/MAPK components, and a second involves Aurora Kinase A (AURKA). We find that AURKA stabilizes c-MYC and n-MYC protein levels and expression programs in PKA-dependent tumor models, in part via a positive feedback loop mediated by the oncogenic kinase PIM2. This process can be suppressed by conformation-disrupting AURKA inhibitors such as CD-532. Our findings elucidate two independent mechanisms of PKA-driven tumor cell growth and offer insight into drug targets for study in FLC and other PKA-dependent malignancies.
Comparative analysis of molecular representations in prediction of drug combination effects
Authors: Zagidullin B. , Wang Z. , Guan Y. , Pitkänen E. , Tang J. 
Published: April 2021

AbstractApplication of machine and deep learning methods in drug discovery and cancer research has gained a considerable amount of attention in the past years. As the field grows, it becomes crucial to systematically evaluate the performance of novel computational solutions in relation to established techniques. To this end we compare rule-based and data-driven molecular representations in prediction of drug combination sensitivity and drug synergy scores using standardized results of 14 throughput screening studies, comprising 64 200 unique combinations of 4 153 molecules tested in 112 cancer cell lines. We evaluate the clustering performance of molecular representations and quantify their similarity by adapting the Centered Kernel Alignment metric. Our work demonstrates that to identify an optimal molecular representation type it is necessary to supplement quantitative benchmark results with qualitative considerations, such as model interpretability and robustness, which may vary between and throughout preclinical drug development projects.Abstract Figure
Using embedded alginate microparticles to tune the properties ofin situforming poly(N-isopropylacrylamide)-graft-chondroitin sulfate bioadhesive hydrogels for replacement and repair of the nucleus pulposus of the intervertebral disc
Authors: Christiani Thomas , Mys Karen , Dyer Karl , Kadlowec Jennifer , Iftode Cristina , Vernengo Andrea Jennifer 
Published: April 2021

AbstractLow back pain (LBP) is a major public health issue associated with degeneration of the intervertebral disc (IVD). The early stages of degeneration are characterized by the dehydration of the central, gelatinous portion of the IVD, the nucleus pulposus (NP). One possible treatment approach is to replace the NP in the early stages of IVD degeneration with a hydrogel that restores healthy biomechanics while supporting tissue regeneration. The present study evaluates a novel thermosensitive hydrogel based on poly(N-isopropylacrylamide-graft-chondroitin sulfate) (PNIPAAM-g-CS) for NP replacement. The hypothesis was tested that the addition of freeze-dried, calcium crosslinked alginate microparticles (MPs) to aqueous solutions of PNIPAAm-g-CS would enable tuning of the rheological properties of the injectable solution, as well as the bioadhesive and mechanical properties of the thermally precipitated composite gel. Further, we hypothesized that the composite would support encapsulated cell viability and differentiation. Structure-material property relationships were evaluated by varying MP concentration and diameter. The addition of high concentrations (50 mg/mL) of small MPs (20 ± 6 µm) resulted in the greatest improvement in injectability, compressive mechanical properties, and bioadhesive strength of PNIPAAm-g-CS. This combination of PNIPAAM-g-CS and alginate MPs supported the survival, proliferation, and differentiation of adipose derived mesenchymal stem cells (ADMSCs) towards an NP-like phenotype in the presence of soluble GDF-6. When implantedex vivointo the intradiscal cavity of degenerated porcine IVDs, the formulation restored the compressive and neutral zone (NZ) stiffnesses to intact values and resisted expulsion under lateral bending. Overall, results indicate the potential of the hydrogel composite to serve as a scaffold for supporting NP regeneration. This work uniquely demonstrates that encapsulation of re-hydrating polysaccharide-based MPs may be an effective method for improving key functional properties ofin situforming hydrogels for orthopaedic tissue engineering applications.
Mindfulness Training Alters Resting-State EEG Dynamics in Novice Practitioners via Mindful Breathing and Body-scan
Authors: Hydra Ng Hei-Yin , Wu Changwei W. , Huang Feng-Ying , Cheng Yu-Ting , Guu Shiao-Fei , Huang Chih-Mao , Hsu Chia-Fen , Chao Yi-Ping , Jung Tzyy-Ping , Chuang Chun-Hsiang 
Published: April 2021

AbstractMindfulness-based stress reduction (MBSR) has been proven to improve mental health and quality of life. This study examined how mindfulness training and various types of mindfulness practices altered brain activity. Specifically, the spectral powers of scalp electroencephalography (EEG) of the MBSR group who underwent an 8-week mindfulness training—including mindful breathing and body-scan—were evaluated and compared with those of the waitlist controls. Empirical results indicated that the long-term mindfulness intervention effect significantly elevated the resting-state beta powers and reduced resting-state delta powers in both practices; such changes were not observed in the waitlist control. Compared with mindful breathing, body-scanning resulted in an overall decline in EEG spectral powers at both delta and gamma bands among trained participants. Together with our preliminary data of expert mediators, the aforementioned spectral changes were salient after intervention, but mitigated along with expertise. Additionally, after receiving training, the MBSR group’s mindfulness and emotion regulation levels improved significantly, which were correlated with the EEG spectral changes in the theta, alpha, and low-beta bands. This study elaborated the neurophysiological correlates of mindfulness practices, suggesting that MBSR might function as a unique internal processing that involves increased vigilant capability and induces alterations similar to other cognitive training.
Dynamic reconfiguration of macaque brain networks during free-viewing of natural scenes
Authors: Ortiz-Rios Michael , Balezeau Fabien , Haag Marcus , Schmid Michael C. , Kaiser Marcus 
Published: April 2021

AbstractNatural vision involves the activation of a wide range of higher-level regions processing objects, motion, faces and actions. Here, we pursue a data-driven approach to explore how higher-level visual processes relate to the underlying structural and functional connectivity. Using a free-viewing paradigm in four awake rhesus macaque monkeys, we investigate how different visual scenes change functional connectivity. Additionally, we explore how such functional connectivity, as measured through fMRI, is related to the structural connectivity, as measured through diffusion weighted imaging. At first, we evaluate the consistency of the elicited free-viewing pattern using standard analytical techniques. We also evaluate the underlying structural connectivity via diffusion data by tracking white matter bundle projections from the visual cortex. We then reconstruct free-viewing and structural networks and quantify their properties. Centrality measures over the entire fMRI time-series revealed a consistent functional network engaged during free-viewing that included widespread hub regions across frontal (FEF, 46v), parietal (LIP, Tpt), and occipitotemporal cortex (MT, V4 and TE) among others. Interestingly, a small number of highly-weighted and long-length inter-hemispheric connections indicated the presence of long-range integrative properties during free-viewing. We hypothesized that during free-viewing, networks had the capacity to change their local and distal connections depending on the on-going changes in visual scenes. To capture these network dynamics, we depart from the static modular architecture of the structural networks and demonstrate that hubs in free-viewing networks reorganize according to the presence of objects, motion, and faces in the movie scenes indicating poly-functional properties. Lastly, we compare each NHP subject network and observe high consistency between individuals across the same network type with closer correspondence between structural networks (e.g., diffusion based and those partially assembled from tract-tracing). In summary, our network analyses revealed ongoing changes in large-scale functional organization present during free-viewing in the macaque monkey and highlight the advantages of multi-contrast imaging in awake monkeys for investigating dynamical processes in visual cognition. To further promote the use of naturalistic free-viewing paradigms and increase the development of macaque neuroimaging resources, we share our datasets in the PRIME-DE consortium.
Neural Sources Underlying Visual Word Form Processing as Revealed by Steady State Visual Evoked Potentials (SSVEP)
Authors: Wang Fang , Kaneshiro Blair , Strauber C. Benjamin , Hasak Lindsey , Nguyen Quynh Trang H. , Yakovleva Alexandra , Vildavski Vladimir Y. , Norcia Anthony M. , McCandliss Bruce D. 
Published: April 2021

AbstractEEG has been central to investigations of the time course of various neural functions underpinning visual word recognition. Recently the steady-state visual evoked potential (SSVEP) paradigm has been increasingly adopted for word recognition studies due to its high signal-to-noise ratio. Such studies, however, have been typically framed around a single source in the left ventral occipitotemporal cortex (vOT). Here, we combine SSVEP recorded from 16 adult native English speakers with a data-driven spatial filtering approach—Reliable Components Analysis (RCA)—to elucidate distinct functional sources with overlapping yet separable time courses and topographies that emerge when contrasting words with pseudofont visual controls. The first component topography was maximal over left vOT regions with an early latency (approximately 180 msec). A second component was maximal over more dorsal parietal regions with a longer latency (approximately 260 msec). Both components consistently emerged across a range of parameter manipulations including changes in the spatial overlap between successive stimuli, and changes in both base and deviation frequency. We then contrasted word-in-nonword and word-in-pseudoword to test the hierarchical processing mechanisms underlying visual word recognition. Results suggest that these hierarchical contrasts fail to evoke a unitary component that might be reasonably associated with lexical access.
Rigidifying ade novoenzyme increases activity and induces a negative activation heat capacity
Authors: Hindson SA , Bunzel HA , Frank B , Svistunenko DA , Williams C , van der Kamp MW , Mulholland AJ , Pudney CR , Anderson JLR 
Published: April 2021

ABSTRACTConformational sampling profoundly impacts the overall activity and temperature dependence of enzymes. Peroxidases have emerged as versatile platforms for high value biocatalysis owing to their broad palette of potential biotransformations. Here, we explore the role of conformational sampling in mediating ade novoperoxidase’s activity. We demonstrate that 2,2,2-triflouoroethanol (TFE) affects the equilibrium of enzyme conformational states, tending towards a more globally rigid structure. This is correlated with increases both stability and activity. Notably, these effects are concomitant with the emergence of curvature in the temperature-activity profile, trading off activity gains at ambient temperature with losses at high temperatures. We apply macromolecular rate theory (MMRT) to understand enzyme temperature dependence data. These data point to an increase in protein rigidity associated with a difference in the distribution of protein dynamics between the ground and transition state. We compare the thermodynamics of thede novoenzyme activity to those of a natural peroxidase, horseradish peroxidase. We find that the native enzyme resembles the rigidifiedde novoenzyme in terms of the thermodynamics of enzyme catalysis and the putative distribution of protein dynamics between the ground and transition state. The addition of TFE apparently causes C45 to behave more like the natural enzyme. Our data suggest robust, generic strategies for improving biocatalytic activity by manipulating protein rigidity; for functionalde novoprotein catalysts in particular, this can provide more enzyme-like catalysts without further rational engineering, computational redesign or directed evolution.
Contrasting processing tomato cultivars unlink yield and pollen viability under heat stress
Authors: Miller Golan , Beery Avital , Singh Prashant Kumar , Wang Fengde , Zelingher Rotem , Motenko Etel , Lieberman-Lazarovich Michal 
Published: April 2021

AbstractThe occurring climate change is causing temperature increment in crop production areas worldwide, generating conditions of heat stress that negatively affect crop productivity. Tomato (Solanum lycopersicum), a major vegetable crop, is highly susceptible to conditions of heat stress. When tomato plants are exposed to ambient day/night temperatures that exceed 32°C/20°C respectively during the reproductive phase, fruit set and fruit weight are reduced, leading to a significant decrease in yield. Processing tomato cultivars are cultivated in open fields, where environmental conditions are not controlled, therefore plants are exposed to multiple abiotic stresses, including heat stress. Understanding the physiological response of modern processing tomato cultivars to heat stress may facilitate the development of thermotolerant cultivars. Here, we compared two tomato processing cultivars, H4107 and H9780, that we found to be constantly differing in yield performance. Using field and temperature-controlled greenhouse experiments, we show that the observed difference in yield is attributed to the occurrence of heat stress conditions. In addition, fruit-set and seed production were significantly improved in the thermotolerant cultivar H4107, compared with H9780. Despite the general acceptance of pollen viability as a measure of thermotolerance, there was no difference in the percentage of viable pollen between H4107 and H9780 under either of the conditions tested. Therefore, processing tomato cultivars may present a particular case, in which other factors are central for heat stress tolerance. Our results also demonstrate the value of combining controlled with uncontrolled experimental settings, in order to identify heat stress related responses and facilitate the development of thermotolerant processing tomato cultivars.
How many markers are needed to robustly determine a cell’s type?
Authors: Fischer Stephan , Gillis Jesse 
Published: April 2021

SummaryOur understanding of cell types has advanced considerably with the publication of single cell atlases. Marker genes play an essential role for experimental validation and computational analyses such as physiological characterization through pathway enrichment, annotation, and deconvolution. However, a framework for quantifying marker replicability and picking replicable markers is currently lacking. Here, using high quality data from the Brain Initiative Cell Census Network (BICCN), we systematically investigate marker replicability for 85 neuronal cell types. We show that, due to dataset-specific noise, we need to combine 5 datasets to obtain robust differentially expressed (DE) genes, particularly for rare populations and lowly expressed genes. We estimate that 10 to 200 meta-analytic markers provide optimal performance in downstream computational tasks. Replicable marker lists condense single cell atlases into interpretable and generalizable information about cell types, opening avenues for downstream applications, including cell type annotation, selection of gene panels and bulk data deconvolution.
Constitutively activeSARM1variants found in ALS patients induce neuropathy
Authors: Bloom A. Joseph , Mao Xianrong , Strickland Amy , Sasaki Yo , Milbrandt Jeffrey , DiAntonio Aaron 
Published: April 2021

AbstractIn response to injury, neurons activate a program of organized axon self-destruction initiated by the NAD+hydrolase SARM1. In healthy neurons SARM1 is autoinhibited, but single amino acid changes can abolish autoinhibition leading to constitutively-active SARM1 enzymes that promote degeneration when expressed in cultured neurons. To investigate whether naturally-occurring human variants might similarly disrupt SARM1 autoinhibition and potentially contribute to risk for neurodegenerative disease, we assayed the enzymatic activity of 29 rareSARM1alleles identified among 8,507 amyotrophic lateral sclerosis (ALS) patients. Ten missense variants or small in-frame deletions exhibit constitutive NADase activity, including more than half of those that are unique to the ALS patients or that occur in multiple patients. Expression of these constitutively active ALS-associated SARM1 alleles in cultured dorsal root ganglion (DRG) neurons is pro-degenerative and cytotoxic. Intrathecal injection of an AAV expressing the commonSARM1reference allele is innocuous to mice, but a construct harboringSARM1V184G, the constitutively active variant found most frequently in the ALS patients, causes axon loss, motor dysfunction, and sustained neuroinflammation. These results implicate rare hypermorphicSARM1alleles as candidate genetic risk factors for ALS and other neurodegenerative conditions.