bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of early geometric confinement on the transcriptomic profile of human cerebral organoids
Authors: Sen Dilara , Voulgaropoulos Alexis , Keung Albert J. 
Published: February 2021

ABSTRACTBackgroundBiophysical factors such as shape and mechanical forces are known to play crucial roles in stem cell differentiation, embryogenesis and neurodevelopment. However, the complexity and experimental challenges capturing such early stages of development, and ethical concerns associated with human embryo and fetal research, limit our understanding of how these factors affect human brain organogenesis. Human cerebral organoids (hCO) are attractive models due to their ability to model important brain regions and transcriptomics of earlyin vivobrain development. Furthermore, they provide three-dimensional environments that better mimic the in vivo environment. To date, they have been used to understand the effects of genetics and soluble factors on neurodevelopment. Establishing links between spatial factors and hCO development will require the development of new approaches.ResultsHere, we investigated the effects of early geometric confinements on transcriptomic changes during hCO differentiation. Using a custom and tunable agarose microwell platform we generated embryoid bodies (EB) of diverse shapes and then further differentiated those EBs to whole brain hCOs. Our results showed that the microwells did not have negative gross impacts on the ability of the hCOs to differentiate generally towards neural fates, and there were clear shape dependent effects on neural lineage specification. In particular, we observed that non-spherical shapes showed signs of altered neurodevelopmental kinetics and favored the development of medial ganglionic eminence-associated brain regions and cell types over cortical regions.ConclusionsThe findings presented here suggest a role for spatial factors in brain region specification during hCO development. Understanding these spatial patterning factors will not only improve understanding ofin vivodevelopment and differentiation, but also provide important handles with which to advance and improve control over human model systems forin vitroapplications.
Toxoplasma gondiiinjected neurons localize to the cortex and striatum and have altered firing
Authors: Mendez Oscar A. , Machado Emiliano Flores , Lu Jing , Koshy Anita A. 
Published: February 2021

AbstractToxoplasma gondiiis an intracellular parasite that causes a long-term latent infection of neurons. Using a custom MATLAB-based mapping program in combination with a mouse model that allows us to permanently mark neurons injected with parasite proteins, we found thatToxoplasma-injected neurons (TINs) are heterogeneously distributed in the brain, primarily localizing to the cortex followed by the striatum. Using immunofluorescence co-localization assays, we determined that cortical TINs are commonly (>50%) excitatory neurons (FoxP2+) and that striatal TINs are often (>65%) medium spiny neurons (MSNs) (FoxP2+). As MSNs have highly characterized electrophysiology, we usedex vivoslices from infected mice to perform single neuron patch-clamping on striatal TINs and neighboring uninfected MSNs (bystander MSNs). These studies demonstrated that TINs have highly abnormal electrophysiology, while the electrophysiology of bystander MSNs was akin to that of MSNs from uninfected mice. Collectively, these data offer new neuroanatomic and electrophysiologic insights into CNS toxoplasmosis.
BRAF inhibitors reprogram cancer-associated fibroblasts to drive matrix remodeling and therapeutic escape in melanoma
Authors: Liu Tianyi , Zhou Linli , Xiao Yao , Andl Thomas , Zhang Yuhang 
Published: February 2021

ABSTRACTThe tumor stroma and its cellular components are known to play an important role in tumor resilience towards treatment. Here, we report a novel resistance mechanism in melanoma that is elicited by BRAF inhibitors (BRAFi)-induced non-canonical nuclear β-catenin signaling in cancer-associated fibroblasts (CAFs). Our study reveals that BRAFi leads to an expanded CAF population with increased β-catenin nuclear accumulation and enhances their biological properties. This CAF subpopulation is essential for melanoma cells to grow and resist to BRAFi/MEK inhibitors (MEKi). Mechanistically, BRAFi induces BRAF and CRAF dimerization and subsequently the activation of ERK signaling in CAFs, leading to the inactivation of the β-catenin destruction complex. By RNA-Seq, periostin (POSTN) is identified as a major downstream effector of β catenin in CAFs and can compensate for the loss of β-catenin in CAFs in conferring melanoma cell BRAFi/MEKi resistance. Moreover, POSTN reactivates the ERK pathway, which is inhibited by BRAFi/MEKi, in melanoma cells through PI3K/AKT signaling. Our data underscore the roles of BRAFi-induced CAF reprogramming in matrix remodeling and therapeutic escape of melanoma cells and reveal POSTN as an important matrix target to eliminate BRAFi/MEKi resistance in melanoma.
Viral route of infection determines the effect ofDrosophila melanogastergut bacteria on host resistance and tolerance to disease
Authors: Landum Miguel , Silva Marta Salvado , Martins Nelson , Teixeira Luís 
Published: February 2021

AbstractThe microbial community interacting with a host can modulate the outcome of pathogenic infections. For instance,Wolbachia, one of the most prevalent invertebrate endosymbionts, strongly increases resistance ofDrosophila melanogasterand other insect hosts, to many RNA viruses.D. melanogasteris also in continuous association with gut bacteria, whose role in antiviral immunity is poorly characterized. Here we asked how gut-colonizing bacteria impact viral titres and host survival, and how these interact with route of infection orWolbachiapresence. We compared germ-free flies and flies associated with two gut bacteria species recently isolated from wild flies (Acetobacter thailandicus and Lactobacillus brevis). We found thatWolbachia-conferred protection to both DCV or FHV is not affected by the presence or absence of these gut bacteria. Flies carryingA. thailandicushave lower DCV loads than germ-free flies, upon systemic infection, but reduced survival, indicating that these bacteria increase resistance to virus and decrease disease tolerance. Association withL. brevis, alone or in combination withA. thailandicus, did not lead to changes in survival to systemic infection. In contrast to the effect on systemic infection, we did not observe an impact of these bacteria on survival or viral loads after oral infection. Overall, the impact of gut-associated bacteria in resistance and tolerance to viruses was mild, when compared withWolbachia. These results indicate that the effect of gut-associated bacteria to different viral infections, and different routes of infection, is complex and understanding it requires a detailed characterization of several parameters of infection.
Cellular, Circuit and Transcriptional Framework for Modulation of Itch in the Central Amygdala
Authors: Samineni Vijay K , Grajales-Reyes Jose G. , Grajales-Reyes Gary E , Tycksen Eric , Copits Bryan A , Pedersen Christian , Ankudey Edem S , Sackey Julian N , Sewell Sienna B , Bruchas Michael R , Gereau Robert W. 
Published: February 2021

AbstractItch is an unpleasant sensation that elicits robust scratching and active avoidance. However, the identity of the cells and neural circuits that organize this information remains elusive. Here we show the necessity and sufficiency of itch-activated neurons in the central amygdala (CeA) for both itch sensation and active avoidance. Further, we show that itch-activated CeA neurons play important roles in itch-related comorbidities, including anxiety-like behaviors, but not in some aversive and appetitive behaviors previously ascribed to CeA neurons. RNA-sequencing of itch-activated CeA neurons identified several differentially expressed genes as well as potential key signaling pathways in regulating pruritis. Finally, viral tracing experiments demonstrate that these neurons send a critical projection to the periaqueductal gray to mediate modulation of itch. These findings reveal a cellular and circuit signature of CeA neurons orchestrating behavioral and affective responses to pruritus in mice.
Detailed characterization of the UMAMITs provides insight into their evolution, functional properties as amino acid transporters and role in the plant
Authors: Zhao Chengsong , Pratelli Réjane , Yu Shi , Shelley Brett , Collakova Eva , Pilot Guillaume 
Published: February 2021

AbstractAmino acid transporters play a critical role in distributing amino acids within the cell compartments and between the plant organs. Despite this importance, relatively few amino acid transporter genes have been characterized and their role elucidated with certainty. Two main families of proteins encode amino acid transporters in plants: the Amino Acid-Polyamine-Organocation superfamily, containing mostly importers, and the Usually Multiple Acids Move In and out Transporter family, apparently encoding exporters, totaling about 100 genes in Arabidopsis alone. Knowledge on UMAMITs is scarce, focused on six Arabidopsis genes and a handful of genes from other species. To get insight into the role of the members of this family and provide data to be used for future characterization, we studied the evolution of the UMAMITs in plants, and determined the functional properties, the structure, and the localization of the 44 Arabidopsis UMAMITs. Our analysis showed that the AtUMAMIT are essentially localized at the tonoplast or the plasma membrane, and that most of them are able to export amino acids from the cytosol, confirming a role in intra- and inter-cellular amino acid transport. As an example, this set of data was used to hypothesize the role of a few AtUMAMITs in the plant and the cell.
Light and noise pollution impacts specialist wildlife species disproportionately
Authors: Ditmer Mark A. , Francis Clinton D. , Barber Jesse R. , Stoner David C. , Seymoure Brett M. , Fristrup Kurt M. , Carter Neil H. 
Published: February 2021

AbstractGlobal expansion of lighting and noise pollution alters how animals receive and interpret environmental cues. Yet we lack a cross-taxon understanding of how animal traits influence species vulnerability to this growing phenomenon. This knowledge is needed to improve the design and implementation of policies that mitigate or reduce sensory pollutants. We present results from an expert knowledge survey that quantified the relative influence of several ecological, anatomical, and physiological traits on the vulnerability of terrestrial vertebrates to elevated levels of anthropogenic lighting and noise. Our findings, based on 280 responses, highlight the increasing recognition among experts that sensory pollutants are important to consider in management and conservation decisions. Participant responses show mounting threats to species with narrow niches; especially habitat specialists, nocturnal species, and those with the greatest ability to differentiate environmental visual and auditory cues. Our results call attention to the threat specialist species face and provide a generalizable understanding of which species require additional considerations when developing conservation policies and mitigation strategies in a world altered by expanding sensory pollutant footprints. We provide a step-by-step example for translating these results to on-the-ground conservation planning using two species as case studies.
Glioblastoma remodeling of neural circuits in the human brain decreases survival
Authors: Krishna Saritha , Choudhury Abrar , Seo Kyounghee , Ni Lijun , Kakaizada Sofia , Lee Anthony , Aabedi Alexander , Cao Caroline , Sudharshan Rasika , Egladyous Andrew , Almeida Nyle , Venkatesh Humsa S. , Findlay Anne , Nagarajan Srikantan , Raleigh David , Brang David , Monje Michelle , Hervey-Jumper Shawn L. 
Published: February 2021

SummaryGliomas synaptically integrate into neural circuits. Prior work has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth and gliomas increasing neuronal excitability. In this study we wanted to know how glioma induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. We use intracranial brain recordings during lexical retrieval language tasks in awake humans in addition to site specific tumor tissue biopsies and cell biology experiments. We find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumor-infiltrated cortex, beyond cortical excitation normally recruited in the healthy brain. Site-directed biopsies from functionally connected regions within the tumor are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumor cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron-glioma interactions observed in functionally connected tumor regions compared to tumor regions with less functional connectivity. The degree of functional connectivity between glioblastoma and the normal brain negatively impacts both patient survival and language task performance. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumor proliferation and impairs cognition.
Inferring Ecosystem Networks as Information Flows
Authors: Li Jie , Convertino Matteo 
Published: February 2021

AbstractThe detection of causal interactions is of great importance when inferring complex ecosystem functional and structural networks for basic and applied research. Convergent cross mapping (CCM) based on nonlinear state-space reconstruction made substantial progress about network inference by measuring how well historical values of one variable can reliably estimate states of other variables. Here we investigate the ability of a developed Optimal Information Flow (OIF) ecosystem model to infer bidirectional causality and compare that to CCM. Results from synthetic datasets generated by a simple predator-prey model, data of a real-world sardine-anchovy-temperature system and of a multispecies fish ecosystem highlight that the proposed OIF performs better than CCM to predict population and community patterns. Specifically, OIF provides a larger gradient of inferred interactions, higher point-value accuracy and smaller fluctuations of interactions andα-diversity including their characteristic time delays. We propose an optimal threshold on inferred interactions that maximize accuracy in predicting fluctuations of effectiveα-diversity, defined as the count of model-inferred interacting species. Overall OIF outperforms all other models in assessing predictive causality (also in terms of computational complexity) due to the explicit consideration of synchronization, divergence and diversity of events that define model sensitivity, uncertainty and complexity. Thus, OIF offers a broad ecological information by extracting predictive causal networks of complex ecosystems from time-series data in the space-time continuum. The accurate inference of species interactions at any biological scale of organization is highly valuable because it allows to predict biodiversity changes, for instance as a function of climate and other anthropogenic stressors. This has practical implications for defining optimal ecosystem management and design, such as fish stock prioritization and delineation of marine protected areas based on derived collective multispecies assembly. OIF can be applied to any complex system and used for model evaluation and design where causality should be considered as non-linear predictability of diverse events of populations or communities.
ESC - a comprehensive resource for SARS-CoV-2 immune escape variants
Authors: Rophina Mercy , Pandhare Kavita , Shamnath Afra , Imran Mohamed , Jolly Bani , Scaria Vinod 
Published: February 2021

ABSTRACTEver since the breakout of COVID-19 disease, ceaseless genomic research to inspect the epidemiology and evolution of the pathogen has been undertaken globally. Large scale viral genome sequencing and analysis have uncovered the functional impact of numerous genetic variants in disease pathogenesis and transmission. Emerging evidence of mutations in spike protein domains escaping antibody neutralization is reported. We have built a database with precise collation of manually curated variants in SARS-CoV-2 from literature with potential escape mechanisms from a range of neutralizing antibodies. This comprehensive repository encompasses a total of 5258 variants accounting for 2068 unique variants tested against 230 antibodies, patient convalescent plasma and vaccine breakthrough events. This resource enables the user to gain access to an extensive annotation of SARS-CoV-2 escape variants which would contribute to exploring and understanding the underlying mechanisms of immune response against the pathogen. The resource is available athttp://clingen.igib.res.in/esc/GRAPHICAL ABSTRACT
Concentration and dosage sensitivity of proteins driving liquid-liquid phase separation
Authors: Farahi Nazanin , Lazar Tamas , Wodak Shoshana J. , Tompa Peter , Pancsa Rita 
Published: February 2021

AbstractLiquid-liquid phase separation (LLPS) is a molecular process that leads to the formation of membraneless organelles (MLOs), i.e. functionally specialized liquid-like cellular condensates formed by proteins and nucleic acids. Integration of data on LLPS-associated proteins from dedicated databases revealed only modest overlap between them and resulted in a confident set of 89 human LLPS driver proteins. Since LLPS is highly concentration-sensitive, the underlying experiments are often criticized for applying higher-than-physiological protein concentrations. To clarify this issue, we performed anaivecomparison ofin vitroapplied and quantitative proteomics-derived protein concentrations and discuss a number of considerations that rationalize the choice of apparently highin vitroconcentrations in most LLPS studies. The validity ofin vitroLLPS experiments is further supported byin vivophase-separation experiments and by the observation that the corresponding genes show a strong propensity for dosage sensitivity. This observation implies that the availability of the respective proteins is tightly regulated in cells to avoid erroneous condensate formation. In all, we propose that although local protein concentrations are practically impossible to determine in cells, proteomics-derived cellular concentrations should rather be considered as lower limits of protein concentrations, than strict upper bounds, to be respected byin vitroexperiments.
Analysis of motor unit spike trains estimated from high-density surface electromyography is highly reliable across operators
Authors: Hug François , Avrillon Simon , Del Vecchio Alessandro , Casolo Andrea , Ibanez Jaime , Nuccio Stefano , Rossato Julien , Holobar Aleš , Farina Dario 
Published: February 2021

AbstractThere is a growing interest in decomposing high-density surface electromyography (HDsEMG) into motor unit spike trains to improve knowledge on the neural control of muscle contraction. However, the reliability of decomposition approaches is sometimes questioned, especially because they require manual editing of the outputs. We aimed to assess the inter-operator reliability of the identification of motor unit spike trains. Eight operators with varying experience in HDsEMG decomposition were provided with the same data extracted using the convolutive kernel compensation method. They were asked to manually edit them following established procedures. Data included signals from three lower leg muscles and different submaximal intensities. After manual analysis, 126 ± 5 motor units were retained (range across operators: 119-134). A total of 3380 rate of agreement values were calculated (28 pairwise comparisons × 11 contractions/muscles × 4-28 motor units). The median rate of agreement value was 99.6%. Inter-operator reliability was excellent for both mean discharge rate and time at recruitment (intraclass correlation coefficient > 0.99). These results show that when provided with the same decomposed data and the same basic instructions, operators converge toward almost identical results. Our data have been made available so that they can be used for training new operators.
Somatic hypomethylation of pericentromeric SST1 repeats and tetraploidization in human colorectal cancer cells
Authors: González Beatriz , Navarro-Jiménez Maria , Alonso-De Gennaro María José , Jansen Sanne Marcia , Granada Isabel , Perucho Manuel , Alonso Sergio 
Published: February 2021

AbstractSomatic DNA hypomethylation and aneuploidy are hallmarks of cancer, and there is evidence for a causal relationship between them in knockout mice, but not in human cancer. The non-mobile pericentromeric repetitive elements SST1 are hypomethylated in about 17% of human colorectal cancers (CRC) with some 5-7% exhibiting a more severe age-independent demethylation. Tetraploidy is a common and early event in solid tumors generating subsequent aneuploidy. We compared the relative frequency of chromosomal variations during culture of randomly selected single cell clones of diploid LS174T human CRC cells differing in their levels of SST1 demethylation. Diploid cells underwent frequent genome reduplication events generating tetraploid clones that correlated with SST1 demethylation. In primary CRC, severe SST1 hypomethylation was significantly associated with global genomic hypomethylation and mutations inTP53. This work uncovers the association of the naturally occurring demethylation of the SST1 pericentromeric repeat with the onset of spontaneous tetraploidization in human CRC cells in culture, and withTP53mutations in primary CRCs. Altogether, our findings provide further support for an oncogenic pathway linking somatic epigenetic and genetic alterations in a subset of human CRC.
Combined Metabolic Activators decrease liver steatosis by activating mitochondrial metabolism in a Golden Syrian hamster study
Authors: Yang Hong , Mayneris-Perxachs Jordi , Boqué Noemí , del Bas Josep M , Arola Lluís , Yuan Meng , Turkez Hasan , Uhlén Mathias , Borén Jan , Cheng Zhang , Mardinoglu Adil , Caimari Antoni 
Published: February 2021

AbstractThe prevalence of non-alcohol fatty liver disease (NAFLD), defined as the liver’s excessive fat accumulation, continues to increase dramatically. We have recently revealed the molecular mechanism underlying NAFLD using in-depth multi-omics profiling and identified that combined metabolic activators (CMA) could be administered to decrease the amount of hepatic steatosis (HS) in mouse model and NAFLD patients based on systems analysis. Here, we investigated the effects of a CMA including L-carnitine, N-acetyl-l-cysteine, nicotinamide riboside and betaine on a Golden Syrian hamster NAFLD model fed with HFD, and found that HS was decreased with the administration of CMA. To explore the mechanisms involved in the clearance HS, we generated liver transcriptomics data before and after CMA administration, and integrated these data using liver-specific genome-scale metabolic model of liver tissue. We systemically determined the molecular changes after the supplementation of CMAs and found that it activates mitochondria in the liver tissue by modulating the global fatty acid, amino acids, antioxidant and folate metabolism.