bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protease-controlled secretion and display of intercellular signals
Authors: Vlahos Alexander E. , Kang Jeewoo , Aldrete Carlos A. , Zhu Ronghui , Chong Lucy S. , Elowitz Michael B. , Gao Xiaojing J. 
Published: October 2021

AbstractTo program intercellular communication for biomedicine, it is crucial to regulate the secretion and surface display of signaling proteins. If such regulations are at the protein level, there are additional advantages, including compact delivery and direct interactions with endogenous signalling pathways. We created a modular, generalizable design calledRetainedEndoplasmic CleavableSecretion (RELEASE), with engineered proteins retained in the endoplasmic reticulum and displayed/secreted in response to specific proteases. The design allows functional regulation of multiple synthetic and natural proteins by synthetic protease circuits to realize diverse signal processing capabilities, including logic operation and threshold tuning. By linking RELEASE to additional novel sensing and processing circuits, we were able to achieve elevated protein secretion in response to “undruggable” oncogene KRAS mutants. RELEASE should enable the local, programmable delivery of intercellular cues for a broad variety of fields such as neurobiology, cancer immunotherapy and cell transplantation.
Crystal or Jelly? Effect of Color on the Perception of Translucent Materials with Photographs of Real-world Objects
Authors: Liao Chenxi , Sawayama Masataka , Xiao Bei 
Published: October 2021

AbstractTranslucent materials are ubiquitous in nature (e.g. teeth, food, wax), but our understanding of translucency perception is limited. Previous work in translucency perception has mainly used monochromatic rendered images as stimuli, which are restricted by their diversity and realism. Here, we measure translucency perception with photographs of real-world objects. Specifically, we use three behavior tasks: binary classification of “translucent” versus “opaque”, semantic attribute rating of perceptual qualities (see-throughness, glossiness, softness, glow and density), and material categorization. Two different groups of observers finish the three tasks with color or grayscale images. We find that observers’ agreements depend on the physical material properties of the objects such that translucent materials generate more inter-observer disagreements. Further, there are more disagreements among observers in the grayscale condition in comparison to that in color condition. We also discover that converting images to grayscale substantially affects the distributions of attribute ratings for some images. Furthermore, ratings of see-throughness, glossiness, and glow could predict individual observers’ binary classification of images in both grayscale and color conditions. Lastly, converting images to grayscale alters the perceived material categories for some images such that observers tend to misjudge images of food as non-food and vice versa. Our result demonstrates color is informative about material property estimation and recognition. Meanwhile, our analysis shows mid-level semantic estimation of material attributes might be closely related to high-level material recognition. We also discuss individual differences in our results and highlight the importance of such consideration in material perception.
Ultrasound-mediated delivery of novel tau-specific monoclonal antibody enhances brain uptake but not therapeutic efficacy
Authors: Bajracharya Rinie , Cruz Esteban , Götz Jürgen , Nisbet Rebecca M. 
Published: October 2021

AbstractTau-specific immunotherapy is an attractive therapeutic strategy for the treatment of Alzheimer’s disease and other tauopathies. However, targeting tau effectively remains a considerable challenge due to the restrictive nature of the blood-brain barrier (BBB), which excludes 99.9% of peripherally administered antibodies. We have previously shown that the delivery of tau-specific monoclonal antibody (mAb) with low-intensity scanning ultrasound in combination with intravenously injected microbubbles (SUS+MB) increases the passage of IgG antibodies into the brain. SUS+MB transiently opens tight junctions to allow paracellular transport, but also facilitates transcellular transport, particularly for larger cargoes. However, therapeutic efficacy after enhanced brain delivery has not been explored. To assess whether ultrasound-mediated delivery of tau-specific mAbs leads to an enhanced therapeutic response, K369I tau transgenic K3 mice were passively immunised once weekly for 12 weeks with a novel mAb, RNF5, in combination with SUS+MB. While none of the treatment arms improved behaviour or motor functions in these mice, we found that both RNF5 and SUS+MB treatments on their own reduced tau pathology, but, surprisingly, the combination of both (RNF5+SUS+MB) did not achieve an additive reduction in tau pathology. This was despite observing increased antibody penetration in the brain. Interestingly, a significant fraction of the antibody in the combination treatment was visualized in brain endothelial cells, suggesting that paracellular transport may not be the preferred uptake mechanism for RNF5. Taken altogether, more research is warranted to develop SUS+MB as a delivery modality for anti-tau antibodies.
Quantitative MRI reveals differences in striatal myelin in children with DLD
Authors: Krishnan Saloni , Cler Gabriel J. , Smith Harriet J. , Willis Hanna E. , Asaridou Salomi S. , Healy Máiréad P. , Papp Daniel , Watkins Kate E. 
Published: October 2021

AbstractDevelopmental Language Disorder (DLD) is a common neurodevelopmental disorder characterised by receptive or expressive language difficulties or both. While theoretical frameworks and empirical studies support the idea that there may be neural correlates of DLD in frontostriatal loops, findings are inconsistent across studies. Here, we use a novel semiquantitative imaging protocol – multiparameter mapping (MPM) – to investigate microstructural neural differences in children with DLD. The MPM protocol allows us to reproducibly map specific indices of tissue microstructure. In 56 typically developing children and 33 children with DLD, we derived maps of: 1) longitudinal relaxation rate R1 (1/T1); 2) the transverse relaxation rate R2* (1/T2*); and 3) Magnetization Transfer Saturation (MTsat). R1 and MTsat predominantly index myelin, while R2* is sensitive to iron content. Children with DLD showed reductions in MTsat values in the caudate nucleus bilaterally, as well as in the left ventral sensorimotor cortex and Heschl’s gyrus. They also had globally lower R1 values. No group differences were noted in R2* maps. Differences in MTsat and R1 were coincident in the caudate nucleus bilaterally. These findings support our hypothesis of corticostriatal abnormalities in DLD and indicate abnormal levels of myelin in the dorsal striatum in children with DLD.
Performance Scaling for Structural MRI Surface Parcellations: A Machine Learning Analysis in the ABCD Study
Authors: Hahn Sage , Owens Max M. , Yuan DeKang , Juliano Anthony C , Potter Alexandra , Garavan Hugh , Allgaier Nicholas 
Published: October 2021

AbstractThe use of pre-defined parcellations on surface-based representations of the brain as a method for data reduction is common across neuroimaging studies. In particular, prediction-based studies typically employ parcellation-driven summaries of brain measures as input to predictive algorithms, but the choice of parcellation and its influence on performance is often ignored. Here we employed pre-processed structural magnetic resonance imaging data (sMRI) from the ABCD Study® to examine the relationship between 220 parcellations and out-of-sample predictive performance across 45 phenotypic measures in a large sample of 9-10-year-old children (N=9,432). Choice of Machine Learning (ML) pipeline and use of alternative multiple parcellation-based strategies were also assessed. Relative parcellation performance was dependent on the spatial resolution of the parcellation, with larger numbers of parcels (up to ∼4000) outperforming coarser parcellations, according to a power-law scaling of between 1/4 and 1/3. Performance was further influenced by the type of parcellation, ML pipeline, and general strategy, with existing literature-based parcellations, a support vector based pipeline, and ensembling across multiple parcellations, respectively, as the highest performing. These findings highlight the choice of parcellation as an important influence on downstream predictive performance, showing in some cases that switching to a higher resolution parcellation can yield a relatively large boost to performance.
Zapline-plus: a Zapline extension for automatic and adaptive removal of frequency-specific noise artifacts in M/EEG
Authors: Klug Marius , Kloosterman Niels A. 
Published: October 2021

AbstractRemoving power line noise and other frequency-specific artifacts from electrophysiological data without affecting neural signals remains a challenging task. Recently, an approach was introduced that combines spectral and spatial filtering to effectively remove line noise: Zapline (de Cheveigné, 2020). This algorithm, however, requires manual selection of the noise frequency and the number of spatial components to remove during spatial filtering. Moreover, it assumes that noise frequency and spatial topography are stable over time, which is often not warranted. To overcome these issues, we introduce Zapline-plus, which allows adaptive and automatic removal of frequency-specific noise artifacts from M/EEG and LFP data. To achieve this, our extension first segments the data into periods (chunks) in which the noise is spatially stable. Then, for each chunk, it searches for peaks in the power spectrum, and finally applies Zapline. The exact noise frequency around the found target frequency is also determined separately for every chunk to allow fluctuations of the peak noise frequency over time. The number of to-be-removed components by Zapline is automatically determined using an outlier detection algorithm. Finally, the frequency spectrum after cleaning is analyzed for suboptimal cleaning and parameters are adapted accordingly if necessary before re-running the process. The software creates a detailed plot for monitoring the cleaning. We showcase the efficacy of the different features of our algorithm by applying it to four openly available data sets, two EEG sets containing both stationary and mobile task conditions, and two MEG sets containing strong line noise.
Characterization of red fluorescent reporters for dual-color in vivo three-photon microscopy
Authors: Thornton Michael A. , Futia Gregory L. , Stockton Michael E. , Ozbay Baris N. , Kilborn Karl , Restrepo Diego , Gibson Emily A. , Hughes Ethan G. 
Published: October 2021

SignificanceThree-photon (3P) microscopy significantly increases the depth and resolution of in vivo imaging due to decreased scattering and nonlinear optical sectioning. Simultaneous excitation of multiple fluorescent proteins is essential to study multicellular interactions and dynamics in the intact brain.AimWe characterized the excitation laser pulses at a range of wavelengths for 3P microscopy, and then explored the application of tdTomato or mScarlet and EGFP for dual-color single-excitation structural 3P imaging deep in the living mouse brain.ApproachWe used frequency-resolved optical gating to measure the spectral intensity, phase, and retrieved pulse widths at a range of wavelengths. Then, we performed in vivo single wavelength-excitation 3P imaging in the 1225 - 1360 nm range deep in the mouse cerebral cortex to evaluate the performance of tdTomato or mScarlet in combination with EGFP.ResultsWe find that tdTomato and mScarlet, expressed in oligodendrocytes and neurons respectively, have high signal-to-background in the 1300–1360 nm range, consistent with enhanced 3P cross sections.ConclusionsThese results suggest that a single excitation wavelength source is advantageous for multiple applications of dual-color brain imaging and highlight the importance of empirical characterization of individual fluorophores for 3P microscopy.
High-throughput Evaluation of Epilepsy-associated KCNQ2 Variants Reveals Functional and Pharmacological Heterogeneity
Authors: Vanoye Carlos G. , Desai Reshma R. , Ji Zhigang , Adusumilli Sneha , Jairam Nirvani , Ghabra Nora , Joshi Nishtha , Fitch Eryn , Helbig Katherine , McKnight Dianalee , Lindy Amanda , Zou Fanggeng , Helbig Ingo , Cooper Edward , George Alfred L. 
Published: October 2021

ABSTRACTHundreds of KCNQ2 variants have been identified by genetic testing of children with early onset epilepsy and/or developmental disability. Voltage-clamp recording from heterologous cells has proved useful for establishing deleterious functional effects of KCNQ2 variants, but procedures adapting these assays for standardized, higher throughput data collection and reporting are lacking. In this study, we employed automated patch clamp recording to assess in parallel the functional and pharmacological properties of 79 missense and 2 in-frame deletion variants of KCNQ2. Among the variants we studied were a training set of 18 pathogenic variants previously studied by voltage-clamp recording, 24 mostly rare population variants, and 39 disease-associated variants with unclear functional effects. Variant KCNQ2 subunits were transiently expressed in a cell line stably expressing KCNQ3 to reconstitute the physiologically relevant channel complex. Variants with severe loss-of-function were also co-expressed 1:1 with WT KCNQ2 in the KCNQ3 cell line to mimic the heterozygous genotype and assess dominant-negative behavior. In total, we analyzed electrophysiological data recorded from 9,480 cells. The functional properties of WT KCNQ2/KCNQ3 channels and pharmacological responses to known blockers and activators determined by automated patch clamp recording were highly concordant with previous findings. Similarly, functional properties of 18 known pathogenic variants largely matched previously published results and the validated automated patch clamp assay. Many of the 39 previously unstudied disease-associated KCNQ2 variants exhibited prominent loss-of-function and dominant-negative effects, providing strong evidence in support of pathogenicity. All variants, exhibit response to retigabine (10 µM), although there were differences in maximal responses. Variants within the ion selectivity filter exhibited the weakest responses whereas retigabine had the strongest effect on gain-of-function variants in the voltage-sensor domain. Our study established a high throughput method to detect deleterious functional consequences of KCNQ2 variants. We demonstrated that dominant-negative loss-of-function is a common mechanism associated with missense KCNQ2 variants but this does not occur with rare population variation in this gene. Importantly, we observed genotype-dependent differences in the response of KCNQ2 variants to retigabine.
Displacement of PKA catalytic subunit from AKAP signaling islands drives pathology in Cushing’s syndrome
Authors: Omar Mitchell H. , Byrne Dominic P. , Jones Kiana N. , Lakey Tyler M. , Collins Kerrie B. , Lee Kyung-Soon , Daly Leonard A. , Forbush Katherine A. , Lau Ho-Tak , Golkowski Martin , McKnight G. Stanley , Breault David T. , Lefrançois-Martinez Anne-Marie , Martinez Antoine , Eyers Claire E. , Baird Geoffrey S. , Ong Shao-En , Smith F. Donelson , Eyers Patrick A. , Scott John D. 
Published: October 2021

AbstractMutations in the catalytic subunit of protein kinase A (PKAc) drive the stress hormone disorder adrenal Cushing’s syndrome. Here we define mechanisms of action for the PKAc-L205R and W196R variants. Both Cushing’s mutants are excluded from A kinase anchoring protein (AKAP) signaling islands and consequently diffuse throughout the cell. Kinase-dead experiments show that PKA activity is required for cortisol hypersecretion. However, kinase activation is not sufficient, as only cAMP analog drugs that displace native PKAc from AKAPs enhance cortisol release. Rescue experiments that incorporate mutant PKAc into AKAP signaling islands abolish cortisol overproduction, indicating that kinase anchoring restores normal endocrine function. Phosphoproteomics show that PKAc-L205R and W196R engage different mitogenic signaling pathways. ERK activity is elevated in adrenal-specific PKAc-W196R knock-in mice. Conversely, PKAc-L205R attenuates Hippo signaling, thereby upregulating the YAP/TAZ transcriptional co-activators. Thus, aberrant localization of each Cushing’s variant promotes the transmission of a distinct downstream pathogenic signal.
High survival following bleaching highlights the resilience of a highly disturbed region of the Great Barrier Reef
Authors: Page Cathie A , Giuliano Christine , Bay Line K , Randall Carly J 
Published: October 2021

AbstractNatural bleaching events provide an opportunity to examine how local scale environmental variation influences bleaching severity and recovery. During the 2020 marine heatwave, we documented widespread and severe coral bleaching (75 – 98% of coral cover) throughout the Keppel Islands in the Southern inshore Great Barrier Reef. Acropora, Pocillopora and Porites were the most severely affected genera, while Montipora was comparatively less susceptible. Site-specific heat-exposure metrics were not correlated with Acropora bleaching severity, but recovery was faster at sites that experienced lower heat exposure. Despite severe bleaching and exposure to accumulated heat that often results in coral mortality (degree heating weeks ∼ 4 – 8), cover remained stable. Approximately 94% of fate-tracked Acropora millepora colonies survived, perhaps owing to reduced irradiance stress from high turbidity, heterotrophic feeding, and large tidal flows that can increase mass transfer. Severe bleaching followed by rapid recovery, and the continuing dominance of Acropora populations in the Keppel Islands is indicative of high resilience. These coral communities have survived an 0.8 °C increase in average temperatures over the last 150 years. However, recovery following the 2020 bleaching was driven by the easing of thermal stress, which may challenge their recovery potential under further warming.Open Research StatementData are not yet provided but are being compiled. Upon acceptance data will be archived on GitHub.
Genetic and genomic architecture of species-specific cuticular hydrocarbon variation in parasitoid wasps
Authors: Buellesbach Jan , Holze Henrietta , Schrader Lukas , Liebig Jürgen , Schmitt Thomas , Gadau Juergen , Niehuis Oliver 
Published: October 2021

ABSTRACTCuticular hydrocarbons (CHCs) serve two fundamental functions in insects: protection against desiccation and chemical signaling. CHC profiles can consist of dozens of different compounds and are considered a prime example for a complex trait. How the interaction of genes shapes CHC profiles, which are essential for insect survival, adaptation, and reproductive success, is still poorly understood. Here we investigate the genetic and genomic basis of CHC biosynthesis and variation in parasitoid wasps of the genusNasonia. Taking advantage of the wasps’ haplo-diploid sex determination and cross-species fertility, we mapped 91 quantitative trait loci (QTL) explaining variation of a total of 43 CHCs in F2hybrid males from interspecific crosses between threeNasoniaspecies. To identify candidate genes, we localized orthologs of CHC biosynthesis-related genes in theNasoniagenomes. By doing so, we discovered multiple genomic regions where the location of QTL coincides with the location of CHC biosynthesis-related candidate genes. Most conspicuously, on a region on chromosome 1 close to the centromere, multiple CHC biosynthesis-related candidate genes co-localize with several QTL explaining variation in methyl-branched alkanes. The genetic underpinnings behind this compound class are not well understood so far, despite their high potential for encoding chemical information as well as their prevalence in bothNasoniaCHC profiles and many other Hymenoptera. Our study considerably extends our knowledge on the so far little-known genetic and genomic architecture governing biosynthesis and variation of this fundamental compound class, establishing a model for methyl-branched alkane genetics in the Hymenoptera in general.
Inverse Potts model improves accuracy of phylogenetic profiling
Authors: Fukunaga Tsukasa , Iwasaki Wataru 
Published: October 2021

AbstractPhylogenetic profiling is a powerful computational method for revealing the functions of function-unknown genes. Although conventional similarity evaluation measures in phylogenetic profiling showed high prediction accuracy, they have two estimation biases: an evolutionary bias and a spurious correlation bias. Existing studies have focused on the evolutionary bias, but the spurious correlation bias has not been analyzed. To eliminate the spurious correlation bias, we applied an evaluation measure based on the inverse Potts model (IPM) to phylogenetic profiling. We also proposed an evaluation measure to remove both the evolutionary and spurious correlation biases using the IPM. In an empirical dataset analysis, we demonstrated that these IPM-based evaluation measures improved the prediction performance of phylogenetic profiling. In addition, we found that the integration of several evaluation measures, including the IPM-based evaluation measures, had superior performance to a single evaluation measure. The source code is freely available at https://github.com/fukunagatsu/Ipm.
High-throughput imaging of Caenorhabditis elegans aging using collective activity monitoring
Authors: Fouad Anthony D , Churgin Matthew A , Hayden Julia , Xu Joyce , Park Jeong-Inn , Liu Alice , Teng Christopher , Sun Hongjing , Parrado Mateo , Bowlin Peter , De La Torre Miguel , Crombie Timothy A. , Sedore Christine A. , Coleman-Hulbert Anna L. , Johnson Erik , Philips Patrick , Andersen Erik C. , Fang-Yen Christopher 
Published: October 2021

ABSTRACTThe genetic manipulability and short lifespan of C. elegans make it an important model for aging research. Widely applied methods for measurements of worm aging based on manual observation are labor intensive and low-throughput. Here, we describe the Worm Collective Activity Monitoring Platform (WormCamp), a system for assaying aging in C. elegans by monitoring activity of populations of worms in standard 24-well plates. We show that metrics based on the rate of decline in collective activity can be used to estimate the average lifespan and locomotor healthspan in the population. Using the WormCamp, we assay a panel of highly divergent natural isolates of C. elegans and show that both lifespan and locomotor healthspan display substantial heritability. To facilitate analysis of large numbers of worms, we developed a robotic imaging system capable of simultaneous automated monitoring of activity, lifespan, and locomotor healthspan in up to 2,304 populations containing a total of ~90,000 animals. We applied the automated system to conduct a large-scale RNA interference screen for genes that affect lifespan and locomotor healthspan. The WormCamp system is complementary to other current automated methods for assessing C. elegans aging and is well suited for efficiently screening large numbers of conditions.