bluuebunny/crossref_metadata_2025_split huggingface dataset:
Scarf: A toolkit for memory efficient analysis of large-scale single-cell genomics data
Authors: Dhapola Parashar , Rodhe Johan , Olofzon Rasmus , Bonald Thomas , Erlandsson Eva , Soneji Shamit , Karlsson Göran 
Published: May 2021

ABSTRACTThe increasing capacity to perform large-scale single-cell genomic experiments continues to outpace the computational requirements to efficiently handle growing datasets. Herein we present Scarf, a modularly designed Python package that seamlessly interoperates with other single-cell toolkits and allows for memory-efficient single-cell analysis of millions of cells on a laptop or low-cost devices like single board computers. We demonstrate Scarf’s memory and compute-time efficiency by applying it to the largest existing single-cell RNA-Seq and ATAC-Seq datasets. Scarf wraps memory-efficient implementations of a graph-based t-stochastic neighbour embedding and hierarchical clustering algorithm. Moreover, Scarf performs accurate reference-anchored mapping of datasets while maintaining memory efficiency. By implementing a novel data downsampling algorithm, Scarf additionally can generate representative sampling of cells from a given dataset wherein rare cell populations and lineage differentiation trajectories are conserved. Together, Scarf provides a framework wherein any researcher can perform advanced processing, downsampling, reanalysis, and integration of atlas-scale datasets on standard laptop computers.
Effects of gestational age at birth on perinatal structural brain development in healthy term-born babies
Authors: Gale-Grant Oliver , Fenn-Moltu Sunniva , França Lucas , Dimitrova Ralica , Christaens Daan , Cordero-Grande Lucilio , Chew Andrew , Falconer Shona , Harper Nicholas , Price Anthony N , Hutter Jana , Hughes Emer , O’Muircheartaigh Jonathan , Rutherford Mary , Counsell Serena J , Rueckert Daniel , Nosarti Chiara , Hajnal Joseph V , McAlonan Grainne , Arichi Tomoki , Edwards A David , Batalle Dafnis 
Published: May 2021

AbstractMultiple studies have demonstrated less favourable childhood outcomes in infants born in early term (37-38 weeks gestation) compared to those born at full term (40-41 weeks gestation). While this could be due to higher perinatal morbidity, gestational age at birth may also have a direct effect on the brain and subsequent neurodevelopment in term-born babies. Here we characterise structural brain correlates of gestational age at birth in healthy term-born neonates and their relationship to later neurodevelopmental outcome. We used T2 and diffusion weighted Magnetic Resonance Images acquired in the neonatal period from a cohort (n=454) of healthy babies born at term age (>37 weeks gestation) and scanned between 1 and 41 days after birth. Images were analysed using tensor based morphometry (TBM) and tract based spatial statistics (TBSS). Neurodevelopment was subsequently assessed at age 18 months using the Bayley-III Scales of Infant and Toddler Development, and the effects of gestational age at birth and related neuroimaging findings on outcome were analysed with linear regression. Infants born earlier had areas of higher relative ventricular volume, and lower relative brain volume in the basal ganglia, cerebellum and brainstem. Earlier birth was also associated with lower fractional anisotropy, higher mean, axial and radial diffusivity in major white matter tracts. Gestational age at birth was positively associated with all Bayley-III subscales at age 18 months. Linear regression models predicting outcome from gestational age at birth were significantly improved by adding neuroimaging features associated with gestational age at birth. This work adds to the growing body of evidence of the impact of early term birth and highlights the importance of considering the effect of gestational age at birth in future neuroimaging studies including term-born babies.
Neural correlates of audio-visual integration of socially meaningful information in macaque monkeys
Authors: Froesel Mathilda , Gacoin Maëva , Clavagnier Simon , Hauser Marc , Goudard Quentin , Hamed Suliann Ben 
Published: May 2021

AbstractSocial interactions rely on the ability to interpret semantic and emotional information, often from multiple sensory modalities. In human and nonhuman primates, both the auditory and visual modalities are used to generate and interpret communicative signals. In individuals with autism, not only are there deficits in social communication, but in the integration of audio-visual information. At present, we know little about the neural mechanisms that subserve the interpretation of complex social events, including the audio-visual integration that is often required with accompanying communicative signals. Based on heart rate estimates and fMRI in two macaque monkeys (Macaca mulatta), we show that individuals systematically associate affiliative facial expressions or social scenes with corresponding affiliative vocalizations, aggressive facial expressions or social scenes with corresponding aggressive vocalizations and escape visual scenes with scream vocalizations. In contrast, vocalizations that are incompatible with the visual information are fully suppressed, suggesting top-down regulation over the processing of sensory input. The process of binding audio-visual semantic and contextual information relies on a core functional network involving the superior temporal sulcus (STS) and lateral sulcus (LS). Peak activations in both sulci co-localize with face or voice patches that have been previously described. While all of these regions of interest (ROIs) respond to both auditory and visual information, LS ROIs have a preference for auditory and audio-visual congruent stimuli while STS ROIs equally respond to auditory, visual and audio-visual congruent stimuli. To further specify the cortical network involved in the control of this semantic association, we performed a whole brain gPPI functional connectivity analysis on the LS and STS cumulated ROIs. This gPPI analysis highlights a functional network connected to the LS and STS, involving the anterior cingulate cortex (ACC), area 46 in the dorsolateral prefrontal cortex (DLPFC), the orbitofrontal cortex (OFC), the intraparietal sulcus (IPS), the insular cortex and subcortically, the amygdala and the hippocampus. Comparing human and macaque results, we propose that the integration of audio-visual information for congruent, meaningful social events involves homologous neural circuitry, specifically, an emotional network composed of the STS, LS, ACC, OFC, and limbic areas, including the amygdala, and an attentional network including the STS, LS, IPS and DLPFC. As such, these networks are critical to the amodal representation of social meaning, thereby providing an explanation for some of deficits observed in autism.
Experimental evidence for delayed post-conflict management behaviour in wild dwarf mongooses
Authors: Morris-Drake Amy , Kern Julie M. , Radford Andrew N. 
Published: May 2021

AbstractIn many species, within-group conflict leads to immediate avoidance of potential aggressors or increases in affiliation, but no studies have investigated delayed post-conflict management behaviour. Here, we experimentally test that possibility using wild dwarf mongooses (Helogale parvula). First, we used natural and playback-simulated foraging displacements to demonstrate that bystanders take notice of the vocalisations produced during such within-group conflict events. We then used another playback experiment to assess delayed effects of within-group conflict on grooming interactions. Overall, fewer individuals groomed on evenings following an afternoon of simulated conflict, but those that did groomed more than on control evenings. Subordinate bystanders groomed with the simulated aggressor significantly less, and groomed more with one another, on conflict compared to control evenings. Our study provides experimental evidence that dwarf mongooses acoustically obtain information about within-group contests (including protagonist identity), retain that information and use it to inform conflict-management decisions with a temporal delay.
SeqScreen: Accurate and Sensitive Functional Screening of Pathogenic Sequences via Ensemble Learning
Authors: Balaji Advait , Kille Bryce , Kappell Anthony D. , Godbold Gene D. , Diep Madeline , Elworth R. A. Leo , Qian Zhiqin , Albin Dreycey , Nasko Daniel J. , Shah Nidhi , Pop Mihai , Segarra Santiago , Ternus Krista L. , Treangen Todd J. 
Published: May 2021

AbstractThe COVID-19 pandemic has emphasized the importance of detecting known and emerging pathogens from clinical and environmental samples. However, robust characterization of pathogenic sequences remains an open challenge. To this end, we developed SeqScreen, which can accurately characterize short nucleotide sequences using taxonomic and functional labels, and a customized set of curated Functions of Sequences of Concern (FunSoCs) specific to microbial pathogenesis. We show our ensemble machine learning model can label protein-coding sequences with FunSoCs with high recall and precision. SeqScreen is a step towards a novel paradigm of functionally informed pathogen characterization and is available for download at:www.gitlab.com/treangenlab/seqscreen
Skeletal maturity predicts cognitive abilities in human adolescents
Authors: Kovács Ilona , Kovács Kristóf , Gerván Patrícia , Utczás Katinka , Oláh Gyöngyi , Tróznai Zsófia , Berencsi Andrea , Szakács Hanna , Gombos Ferenc 
Published: May 2021

AbstractAdolescent human development is not only shaped by the mere passing of time and accumulating experience, but it also depends on pubertal timing and the cascade of maturational processes orchestrated by gonadal hormones. Although individual variability in puberty onset confounds adolescent studies, it has not been efficiently controlled for. Here we introduce ultrasonic bone age assessment to estimate biological maturity and disentangle the independent effects of chronological and biological age on adolescent cognitive abilities. Comparing cognitive performance of participants with different skeletal maturity we uncover the striking impact of biological age on both IQ and specific abilities. We find that biological age has a selective effect on abilities: more mature individuals within the same age group have higher working memory capacity and processing speed, while those with higher chronological age have better verbal abilities, independently of their maturity. Bone age appears to be a surprisingly strong predictor of cognitive abilities, and it seems that a teen’s IQ is determined by biological age.
Hepatic mTORC1 signaling activates ATF4 as part of its metabolic response to feeding and insulin
Authors: Byles Vanessa , Cormerais Yann , Kalafut Krystle , Barrera Victor , Hughes Hallett James E. , Sui Shannan Ho , Asara John M. , Adams Christopher M. , Hoxhaj Gerta , Ben-Sahra Issam , Manning Brendan D. 
Published: May 2021

AbstractObjectiveThe mechanistic target of rapamycin complex 1 (mTORC1) is dynamically regulated by fasting and feeding cycles in the liver to promote protein and lipid synthesis while suppressing autophagy. However, beyond these functions, the metabolic response of the liver to feeding and insulin signaling orchestrated by mTORC1 remains poorly defined. Here, we determine whether ATF4, a stress responsive transcription factor recently found to be independently regulated by mTORC1 signaling in proliferating cells, is responsive to hepatic mTORC1 signaling to alter hepatocyte metabolism.MethodsATF4 protein levels and expression of canonical gene targets were analyzed in the liver following fasting and physiological feeding in the presence or absence of the mTORC1 inhibitor rapamycin. Primary hepatocytes from wild-type or liver-specificAtf4knockout (LAtf4KO) mice were used to characterize the effects of insulin-stimulated mTORC1-ATF4 function on hepatocyte gene expression and metabolism. Both unbiased steady-state metabolomics and stable-isotope tracing methods were employed to define mTORC1 and ATF4-dependent metabolic changes. RNA-sequencing was used to determine global changes in feeding-induced transcripts in the livers of wild-type versusLAtf4KOmice.ResultsWe demonstrate that ATF4 and its metabolic gene targets are stimulated by mTORC1 signaling in the liver in response to feeding and in a hepatocyte-intrinsic manner by insulin. While we demonstrate thatde novopurine and pyrimidine synthesis is stimulated by insulin through mTORC1 signaling in primary hepatocytes, this regulation was independent of ATF4. Metabolomics and metabolite tracing studies revealed that insulin-mTORC1-ATF4 signaling stimulates pathways of non-essential amino acid synthesis in primary hepatocytes, including those of alanine, aspartate, methionine, and cysteine, but not serine.ConclusionThe results demonstrate that ATF4 is a novel metabolic effector of mTORC1 in liver, extending the molecular consequences of feeding and insulin-induced mTORC1 signaling in this key metabolic tissue to the control of amino acid metabolism.
yEvo: Experimental evolution in high school classrooms selects for novel mutations and epistatic interactions that impact clotrimazole resistance inS. cerevisiae
Authors: Taylor M. Bryce , Skophammer Ryan , Warwick Alexa R. , Boyer Josephine M. , Students yEvo , Walson Margaux , Large Christopher R. L. , Hickey Angela Shang-Mei , Rowley Paul A. , Dunham Maitreya J. 
Published: May 2021

AbstractAntifungal resistance in pathogenic fungi is a growing global health concern. Non-pathogenic laboratory strains ofSaccharomyces cerevisiaeare a useful model for studying mechanisms of antifungal resistance that are relevant to understanding the same processes in pathogenic fungi. We developed a series of lab modules in which high school students used experimental evolution to study antifungal resistance by isolating azole-resistantS. cerevisiaeand examining the genetic basis of resistance. All 99 sequenced clones from these experiments possessed mutations previously shown to impact azole resistance, demonstrating the efficacy of our protocols. We additionally found recurrent mutations in an mRNA degradation pathway and an uncharacterized mitochondrial protein (Csf1) that have possible mechanistic connections to azole resistance. The scale of replication in this high school-led initiative allowed us to identify epistatic interactions, as evidenced by pairs of mutations that occur in the same clone more frequently than expected by chance (positive epistasis) or less frequently (negative epistasis). We validated one of these pairs, a negative epistatic interaction between gain-of-function mutations in the multidrug resistance transcription factors Pdr1 and Pdr3. This high school-university collaboration can serve as a model for involving members of the broader public in the scientific process to make meaningful discoveries in biomedical research.
Validating atlas-based lesion disconnectomics in multiple sclerosis: a retrospective multi-centric study
Authors: Ravano Veronica , Andelova Michaela , Fartaria Mário João , A-Wali Mahdi Mazen Fouad , Maréchal Bénédicte , Meuli Reto , Uher Tomas , Krasensky Jan , Vaneckova Manuela , Horakova Dana , Kober Tobias , Richiardi Jonas 
Published: May 2021

AbstractThe translational potential of MR-based connectivity modelling is limited by the need for advanced diffusion imaging, which is not part of clinical protocols for many diseases. In addition, where diffusion data is available, brain connectivity analyses rely on tractography algorithms which imply two major limitations. First, tracking algorithms are known to be sensitive to the presence of white matter lesions and therefore leading to interpretation pitfalls and poor inter-subject comparability in clinical applications such as multiple sclerosis. Second, tractography quality is highly dependent on the acquisition parameters of diffusion sequences, leading to a trade-off between acquisition time and tractography precision.Here, we propose an atlas-based approach to study the interplay between structural disconnectivity and lesions without requiring individual diffusion imaging. In a multi-centric setting involving three distinct multiple sclerosis datasets (containing both 1.5T and 3T data), we compare our atlas-based structural disconnectome computation pipeline to disconnectomes extracted from individual tractography and explore its clinical utility for reducing the gap between radiological findings and clinical symptoms in multiple sclerosis. Results using topological graph properties showed that overall, our atlas-based disconnectomes were suitable approximations of individual disconnectomes from diffusion imaging. Small-worldness was found to decrease for larger total lesion volumes thereby suggesting a loss of efficiency in brain connectivity of MS patients. Finally, the global efficiency of the created brain graph, combined with total lesion volume, allowed to stratify patients into subgroups with different clinical scores in all three cohorts.
Agrochemical control of gene expression using evolved split RNA polymerase
Authors: Yuan Yuan , Miao Jin 
Published: May 2021

AbstractChemical inducible gene expression systems are valuable tools for rational control of gene expression both for basic research and biotechnology. However, most chemical inducers are confined to certain groups of organisms. Therefore, dissecting interaction between different organisms could be challenging using existing chemical inducible systems. We engineered a mandipropamid induced gene expression system (Mandi-T7) based on evolved split T7 RNAP system. As a proof-of-principle, we induced GFP expression inE. colicells grown inside plant tissue.
The oncogenic Runx3–Myc axis definesp53-deficient osteosarcomagenesis
Authors: Otani Shohei , Date Yuki , Ueno Tomoya , Ito Tomoko , Kajikawa Shuhei , Omori Keisuke , Taniuchi Ichiro , Umeda Masahiro , Komori Toshihisa , Toguchida Junya , Ito Kosei 
Published: May 2021

AbstractOsteosarcoma (OS) in human patients is characterized by genetic alteration ofTP53. Osteoprogenitor-specificp53-deleted mice (OSmice) have been widely used to study the process of osteosarcomagenesis. However, the molecular mechanisms responsible for the development of OS upon p53 inactivation remain largely unknown. In this study, we detected prominent RUNX3/Runx3 expression in human and mousep53-deficient OS. Myc was aberrantly upregulated by Runx3 via mR1, a consensus Runx site in theMycpromoter, in a manner dependent onp53deficiency. Reduction of the Myc level by disruption of mR1 or Runx3 knockdown decreased the tumorigenicity ofp53-deficient OS cells and effectively suppressed OS development inOSmice. Furthermore, Runx inhibitors exerted therapeutic effects onOSmice. Together, these results show thatp53deficiency promotes osteosarcomagenesis in human and mouse by allowing Runx3 to induce oncogenic Myc expression.
Cryo-EM structures of the Caspase activated protein XKR9 involved in apoptotic lipid scrambling
Authors: Straub Monique S. , Alvadia Carolina , Sawicka Marta , Dutzler Raimund 
Published: May 2021

AbstractThe exposure of the negatively charged lipid phosphatidylserine on the cell-surface, catalyzed by lipid scramblases, is an important signal for the clearance of apoptotic cells by macrophages. The protein XKR9 is a member of a conserved family that has been associated with apoptotic lipid scrambling. Here, we describe structures of full-length and caspase-treated XKR9 in complex with a synthetic nanobody determined by cryo-electron microscopy. The 43 kDa monomeric membrane protein contains eight membrane-spanning helices, two segments that are partly inserted into the lipid bilayer and is organized as two structurally related repeats. In the full-length protein, the C-terminus interacts with a hydrophobic site located at the intracellular side acting as an inhibitor of protein function. Cleavage by caspase-3 at a specific site releases 16 residues of the C-terminus thus making the binding site accessible to the cytoplasm. Collectively, the work has revealed the unknown architecture of the XKR family and has provided initial insight into its activation by caspases.
A genome-wide knock-out screen for actors of epigenetic silencing reveals new regulators of germline genes and 2-cell like cell state
Authors: Gupta Nikhil , Yakhou Lounis , Albert Julien Richard , Miura Fumihito , Ferry Laure , Kirsh Olivier , Laisné Marthe , Yamaguchi Kosuke , Domrane Cécilia , Bonhomme Frédéric , Sarkar Arpita , Delagrange Marine , Ducos Bertrand , Greenberg Maxim V. C. , Cristofari Gael , Bultmann Sebastian , Ito Takashi , Defossez Pierre-Antoine 
Published: May 2021

AbstractEpigenetic mechanisms are essential to establish and safeguard cellular identities in mammals. They dynamically regulate the expression of genes, transposable elements, and higher-order chromatin structures. Expectedly, these chromatin marks are indispensable for mammalian development and alterations often lead to diseases such as cancer. Molecularly, epigenetic mechanisms rely on factors to establish patterns, interpret them into a transcriptional output, and maintain them across cell divisions. A global picture of these phenomena has started to emerge over the years, yet many of the molecular actors remain to be discovered. In this context, we have developed a reporter system sensitive to epigenetic perturbations to report on repressive pathways based onDazl,which is normally repressed in mouse ES cells. We used this system for a genome-wide CRISPR knock-out screen, which yielded expected hits (DNMT1, UHRF1, MGA), as well as novel candidates. We prioritized the candidates by secondary screens, and led further experiments on 6 of them: ZBTB14, KDM5C, SPOP, MCM3AP, BEND3, and KMT2D. Our results show that all 6 candidates regulate the expression of germline genes. In addition, we find that removal of ZBTB14, KDM5C, SPOP and MCM3AP led to similar transcriptional responses, including a reactivation of the 2-cell like cell (2CLC) signature. Therefore, our genetic screen has identified new regulators of key cellular states.
The mouse brain after foot-shock in 4D: temporal dynamics at a single-cell resolution
Authors: Bonapersona V. , Schuler H. , Damsteegt R.D. , Adolfs Y. , Pasterkamp R.J. , van den Heuvel M.P. , Joëls M. , Sarabdjitsingh R.A. 
Published: May 2021

AbstractAcute stress leads to sequential activation of functional brain networks. The challenge is to get insight in whole brain activity at multiple scales, beyond the level of (networks of) nuclei. We developed a novel pre-processing and analytical pipeline to chart whole-brain immediate early genes’ expression – as proxy for cellular activity – after a single stressful foot-shock in 4 dimensions; that is, from functional networks up to 3D single-cell resolution, and over time. The pipeline is available as R-package. Most brain areas (96%) showed increased numbers of c-fos+ cells after foot-shock, yet hypothalamic areas stood out as being most active and prompt in their activation, followed by amygdalar, prefrontal, hippocampal and finally thalamic areas. At the cellular level, c-fos+ density clearly shifted over time across subareas, as illustrated for the basolateral amygdala. Moreover, some brain areas showed increased numbers of c-fos+ cells, while others dramatically increased c-fos intensity in just a subset of cells; this ‘strategy’ changed after foot-shock in half of the brain areas. All single-cell data can be visualized for each of the 90 brain areas examined through our interactive web-portal.