bluuebunny/crossref_metadata_2025_split huggingface dataset:
Realistic alpha oscillations and transient responses in a cortical microcircuit model
Authors: Kiani Andres A. , Netoff Theoden I. , Ghose Geoffrey M. 
Published: November 2021

AbstractNeural-mass modeling of neural population data (EEG, ECoG, or LFPs) has shown promise both in elucidating the neural processes underlying cortical rhythms and changes in brain state, as well as offering a framework for testing the interplay between these rhythms and information processing. Models of cortical alpha rhythms (8 - 12 Hz) and their impact in visual sensory processing have been at the forefront of this effort, with the Jansen-Rit being one of the more popular models in this domain. The Jansen-Rit model, however, fails in reproducing key physiological observations including the level of inputs that cortical neurons receive and their responses to visual transients. To address these issues we generated a neural mass model that complies better with synaptic mediated dynamics, intrinsic alpha behavior, and produces realistic responses. The model is robust to many changes in parameter values but critically depends on the ratio of excitation to inhibition, producing response transients whose features are dependent on this ratio and alpha phase and power. The model is sufficiently flexible so as to be able to easily replicate the range of low frequency oscillations observed in different studies. Consistent with experimental observations, we find phase-dependent response dynamics to both visual and electrical stimulation using this model. The model suggests that stimulation facilitates alpha at particular phases and suppresses it in others due to a phase dependent lag in inhibitory responses. Hence, the model generates insight into the physiological parameters responsible for intrinsic oscillations and testable hypotheses regarding the interactions between visual and electrical stimulation on those oscillations.Author summaryWhile there is increasing evidence of the fundamental role brain states play in shaping information processing in the cerebral cortex, a mechanistic understanding of how those brain states are manifested and alter the signals underlying sensory processing and decision making has proved challenging. To address this issue we have modeled a well established signature of inattention in visual cortex: synchronized low frequency (8 - 12 Hz) oscillations. To allow for inferences regarding the local generation of these rhythms within a cortical microcircuit we used a neural mass model approach that incorporates physiologically realistic interactions between 3 populations of neurons. Our model is able to explain a variety of experimental observations that previous neural mass models have not, including spontaneous rhythms in the absence of input, the faithful transmission of strong input transients, a range of oscillation frequencies, and phase dependent visual responses. The model is robust to a range of parameters, but critically depends on the balance between local excitation and inhibition.
A Graph Neural Network Approach to Molecule Carcinogenicity Prediction
Authors: Fradkin Philip , Young Adamo , Atanackovic Lazar , Frey Brendan , Lee Leo J. , Wang Bo 
Published: November 2021

AbstractMolecular carcinogenicity is a preventable cause of cancer, however, most experimental testing of molecular compounds is an expensive and time consuming process, making high throughput experimental approaches infeasible. In recent years, there has been substantial progress in machine learning techniques for molecular property prediction. In this work, we propose a model for carcinogenicity prediction, CONCERTO, which uses a graph transformer in conjunction with a molecular fingerprint representation, trained on multi-round muta-genicity and carcinogenicity objectives. To train and validate CONCERTO, we augment the training dataset with more informative labels and utilize a larger external validation dataset. Extensive experiments demonstrate that our model yields results superior to alternate approaches for molecular carcinogenicity prediction.
IFN-γ stimulated murine and human neurons mount anti-parasitic defenses against the intracellular parasiteToxoplasma gondii
Authors: Chandrasekaran Sambamurthy , Kochanowsky Joshua A. , Merritt Emily F. , Lagas Joseph S. , Swannigan Ayesha , Koshy Anita A. 
Published: November 2021

SummaryDogma holds thatToxoplasma gondiipersists in neurons because neurons cannot clear intracellular parasites, even with IFN-γ stimulation. As several recent studies questioned this idea, we used primary murine neuronal cultures from wild-type and transgenic mice in combination with IFN-γ stimulation and parental and transgenic parasites to reassess IFN-γ dependent neuronal clearance of intracellular parasites. We found that neurons respond to IFN-γ and that a subset of neurons clear intracellular parasites via immunity regulated GTPases. Whole neuron reconstructions from mice infected with parasites that trigger neuron GFP expression only after full invasion revealed that ∼40% of theseT. gondii-invaded neurons no longer harbor parasites. Finally, IFN-γ stimulated human stem cell derived neurons showed a ∼ 50% decrease in parasite infection rate when compared to unstimulated cultures. This work highlights the capability of human and murine neurons to mount cytokine-dependent anti-T. gondiidefense mechanismsin vitroandin vivo.
Trisomy 21 induces pericentrosomal crowding disrupting early stages of primary ciliogenesis and mouse cerebellar development
Authors: Jewett Cayla E , McCurdy Bailey L , O’Toole Eileen T , Given Katherine S , Lin Carrie H , Olsen Valerie , Martin Whitney , Reinholdt Laura G , Espinosa Joaquin M , Sullivan Kelly D , Macklin Wendy B , Prekeris Rytis , Pearson Chad G 
Published: November 2021

SummaryPrimary cilia are signaling organelles essential for development and homeostasis. Loss of primary cilia is lethal, and decreased or defective cilia cause multisystemic conditions called ciliopathies. Down syndrome shares clinical overlap with ciliopathies. We previously showed that trisomy 21 diminishes primary cilia formation and function due to elevated Pericentrin, a centrosome protein encoded on chromosome 21. Pericentrin is mislocalized, creating aggregates that disrupt pericentrosomal trafficking and microtubule organization. Here, we examine the cilia-related molecules and pathways disrupted in trisomy 21 and their in vivo phenotypic relevance. Utilizing ciliogenesis time course experiments, we reveal how Pericentrin, microtubule networks, and components of ciliary vesicles are reorganized for ciliogenesis in euploid cells. Early in ciliogenesis, chromosome 21 polyploidy results in elevated Pericentrin and microtubule networks away from the centrosome that ensnare MyosinVA and EHD1, blocking mother centriole uncapping that is essential for ciliogenesis. Ciliated trisomy 21 cells have persistent trafficking defects that reduce transition zone protein localization, which is critical for Sonic hedgehog signaling. Sonic hedgehog signaling is decreased and anticorrelates with Pericentrin levels in trisomy 21 primary mouse embryonic fibroblasts. Finally, we observe decreased ciliation in vivo. A mouse model of Down syndrome with elevated Pericentrin has fewer primary cilia in cerebellar granule neuron progenitors and thinner external granular layers. Our work reveals that elevated Pericentrin in trisomy 21 disrupts multiple early steps of ciliogenesis and creates persistent trafficking defects in ciliated cells. This pericentrosomal crowding results in signaling defects consistent with the neurological deficits found in individuals with Down syndrome.
CORSID enables de novo identification of transcription regulatory sequences and genes in coronaviruses
Authors: Zhang Chuanyi , Sashittal Palash , El-Kebir Mohammed 
Published: November 2021

AbstractGenes in coronaviruses are preceded by transcription regulatory sequences (TRSs), which play a critical role in gene expression mediated by the viral RNA-dependent RNA-polymerase via the process of discontinuous transcription. In addition to being crucial for our understanding of the regulation and expression of coronavirus genes, we demonstrate for the first time how TRSs can be leveraged to identify gene locations in the coronavirus genome. To that end, we formulate the TRS AND Gene Identification (TRS-Gene-ID) problem of simultaneously identifying TRS sites and gene locations in unannotated coronavirus genomes. We introduce CORSID (CORe Sequence IDentifier), a computational tool to solve this problem. We also present CORSID-A, which solves a constrained version of the TRS-Gene-ID problem, the TRS Identification (TRS-ID) problem, identifying TRS sites in a coronavirus genome with specified gene annotations. We show that CORSID-A outperforms existing motif-based methods in identifying TRS sites in coronaviruses and that CORSID outperforms state-of-the-art gene finding methods in finding genes in coronavirus genomes. We demonstrate that CORSID enables de novo identification of TRS sites and genes in previously unannotated coronaviruses. CORSID is the first method to perform accurate and simultaneous identification of TRS sites and genes in coronavirus genomes without the use of any prior information.
Centrosomal Enrichment and Proteasomal Degradation of SYS-1/β-catenin Requires the Microtubule Motor Dynein
Authors: Thompson Joshua W. , Valdes Michel Maria F. , Phillips Bryan T. 
Published: November 2021

AbstractThe C. elegans Wnt/β-catenin Asymmetry (WβA) pathway utilizes asymmetric regulation of SYS- 1/β-catenin and POP-1/TCF coactivators. WβA differentially regulates gene expression during cell fate decisions, specifically by asymmetric localization of determinants in mother cells to produce daughters biased towards their appropriate cell fate. Despite the induction of asymmetry, β-catenin localizes symmetrically to mitotic centrosomes in both mammals and C. elegans. Due to the mitosis-specific localization of SYS-1 to centrosomes and enrichment of SYS-1 at kinetochore microtubules when SYS-1 centrosomal loading is disrupted, we investigated active trafficking in SYS-1 centrosomal localization. Here, we demonstrate that trafficking by microtubule motor dynein is required to maintain SYS-1 centrosomal enrichment, by dynein RNAi-mediated decreases in SYS-1 centrosomal enrichment and by temperature-sensitive allele of the dynein heavy chain. Conversely, we observe depletion of microtubules by nocodazole treatment or RNAi of dynein-proteasome adapter ECPS-1 exhibits increased centrosomal enrichment of SYS-1. Moreover, disruptions to SYS-1 or negative regulator microtubule trafficking are sufficient to significantly exacerbate SYS-1 dependent cell fate misspecifications. We propose a model whereby retrograde microtubule-mediated trafficking enables SYS-1 enrichment at centrosomes, enhancing its eventual proteasomal degradation. These studies support the link between centrosomal localization and enhancement of proteasomal degradation, particularly for proteins not generally considered ‘centrosomal’.
A large-scale genome and transcriptome sequencing analysis reveals the mutation landscapes induced by high-activity adenine base editors in plants
Authors: Li Shaofang , Liu Lang , Sun Wenxian , Zhou Xueping , Zhou Huanbin 
Published: November 2021

AbstractBackgroundThe high-activity adenine base editors (ABEs), engineered with the recently-developed tRNA adenosine deaminases (TadA8e and TadA9), show robust base editing activity but raise concerns about off-target effects.ResultsIn this study, we performed a comprehensive evaluation of ABE8e- and ABE9-induced DNA and RNA mutations in Oryza sativa. Whole-genome sequencing analysis of plants transformed with four ABEs, including SpCas9n-TadA8e, SpCas9n-TadA9, SpCas9n-NG-TadA8e, and SpCas9n-NG-TadA9, revealed that ABEs harboring TadA9 lead to a higher number of off-target A-to-G (A>G) single-nucleotide variants (SNVs), and that those harboring the CRISPR/SpCas9n-NG lead to a higher total number of off-target SNVs in the rice genome. An analysis of the T-DNAs carrying the ABEs indicated that the on-target mutations could be introduced before and/or after T-DNA integration into plant genomes, with more off-target A>G SNVs forming after the ABEs had integrated into the plant genome. Furthermore, we detected off-target A>G RNA mutations in plants with high expression of ABEs but not in plants with low expression of ABEs. The off-target A>G RNA mutations tended to cluster, while off-target A>G DNA mutations rarely clustered.ConclusionOur findings that Cas proteins, TadA variants, temporal expression of ABEs, and expression levels of ABEs contribute to ABE specificity in rice provide insight into the specificity of ABEs and suggest alternative ways to increase ABE specificity besides engineering TadA variants.
Nebulized delivery of a broadly neutralizing SARS-CoV-2 RBD-specific nanobody prevents clinical, virological and pathological disease in a Syrian hamster model of COVID-19
Authors: Esparza Thomas J. , Chen Yaozong , Martin Negin P. , Bielefeldt-Ohmann Helle , Bowen Richard A. , Tolbert William D. , Pazgier Marzena , Brody David L. 
Published: November 2021

ABSTRACTThere remains an unmet need for globally deployable, low-cost therapeutics for the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Previously, we reported on the isolation and in vitro characterization of a potent single-domain nanobody, NIH-CoVnb-112, specific for the receptor binding domain (RBD) of SARS-CoV-2. Here, we report on the molecular basis for the observed broad in vitro neutralization capability of NIH-CoVnb-112 against variant SARS-CoV-2 pseudoviruses, including the currently dominant Delta variant. The structure of NIH-CoVnb-112 bound to SARS-CoV-2 RBD reveals a large contact surface area overlapping the angiotensin converting enzyme 2 (ACE2) binding site, which is largely unencumbered by the common RBD mutations. In an in vivo pilot study, we demonstrate effective reductions in weight loss, viral burden, and lung pathology in a Syrian hamster model of COVID-19 following nebulized delivery of NIH-CoVnb-112. These findings support the further development of NIH-CoVnb-112 as a potential adjunct preventative therapeutic for the treatment of SARS-CoV-2 infection.
The Drosophila RNA binding protein Nab2 patterns dendritic arbors and axons via the planar cell polarity pathway
Authors: Corgiat Edwin B. , List Sara M. , Rounds J. Christopher , Yu Dehong , Chen Ping , Corbett Anita H. , Moberg Kenneth H. 
Published: November 2021

AbstractRNA binding proteins support neurodevelopment by modulating numerous steps in post-transcriptional regulation, including splicing, export, translation, and turnover of mRNAs that can traffic into axons and dendrites. One such RBP is ZC3H14, which is lost in an inherited intellectual disability. The Drosophila melanogaster ZC3H14 ortholog, Nab2, localizes to neuronal nuclei and cytoplasmic ribonucleoprotein granules, and is required for olfactory memory and proper axon projection into brain mushroom bodies. Nab2 can act as a translational repressor in conjunction with the Fragile-X mental retardation protein homolog Fmr1 and shares target RNAs with the Fmr1-interacting RBP Ataxin-2. However, neuronal signaling pathways regulated by Nab2 and their potential roles outside of mushroom body axons remain undefined. Here, we demonstrate that Nab2 restricts branching and projection of larval sensory dendrites via the planar cell polarity pathway, and that this link may provide a conserved mechanism through which Nab2/ZC3H14 modulates projection of both axons and dendrites. Planar cell polarity proteins are enriched in a Nab2-regulated brain proteomic dataset. Complementary genetic data indicate that Nab2 guides dendrite and axon growth through the planar-cell-polarity pathway. Analysis of the core planar cell polarity protein Vang, which is depleted in the Nab2 mutant whole-brain proteome, uncovers selective and dramatic loss of Vang within axon/dendrite-enriched brain neuropil relative to brain regions containing cell bodies. Collectively, these data demonstrate that Nab2 regulates dendritic arbors and axon projection by a planar-cell-polarity-linked mechanism and identify Nab2 as required for accumulation of the core planar cell polarity factor Vang in distal neuronal projections.
Crystal structure of Arabidopsis thaliana HPPK/DHPS, a bifunctional enzyme and target of the herbicide asulam
Authors: Vadlamani Grishma , Sukhoverkov Kirill V. , Haywood Joel , Breese Karen J. , Fisher Mark F. , Stubbs Keith A. , Bond Charles S. , Mylne Joshua S. 
Published: November 2021

AbstractHerbicides are vital for modern agriculture, but their utility is threatened by genetic or metabolic resistance in weeds as well as heightened regulatory scrutiny. Of the known herbicide modes of action, 6-hydroxymethyl-7,8-dihydropterin synthase (DHPS) which is involved in folate biosynthesis, is targeted by just one commercial herbicide, asulam. A mimic of the substrate para-aminobenzoic acid, asulam is chemically similar to sulfonamide antibiotics – and while still in widespread use, asulam has faced regulatory scrutiny. With an entire mode of action represented by just one commercial agrochemical, we sought to improve the understanding of its plant target. Here we solve a 2.6 Å resolution crystal structure for Arabidopsis thaliana DHPS that is conjoined to 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) and reveal a strong structural conservation with bacterial counterparts at the sulfonamide-binding pocket of DHPS. We demonstrate asulam and the antibiotics sulfacetamide and sulfamethoxazole have herbicidal as well as antibacterial activity and explore the structural basis of their potency by modelling these compounds in mitochondrial HPPK/DHPS. Our findings suggest limited opportunity for the rational design of plant selectivity from asulam and that pharmacokinetic or delivery differences between plants and microbes might be the best approaches to safeguard this mode of action.
Identification of Escherichia coli Genes Essential for High-Level, Clinically Relevant, Resistance to Antibiotics
Authors: Reyes-Fernández Esmeralda Z. , Cudkowicz Noemie Alon , Steiner-Mordoch Sonia , Schuldiner Shimon 
Published: November 2021

ABSTRACTAntibiotic resistance is one of the biggest public health challenges of our time. Here we present a novel approach to recognizing molecular mechanisms essential for maintaining high-level clinically relevant antibiotic resistance. To identify essential genes in this context, we subjected Escherichia coli EV18, a strain highly resistant to quinolones, to random transposon mutagenesis. This strain’s unique advantage is that the screen is performed at very high concentrations of the antibiotic, non-permissive for most strains. The transposon’s insertion affected the transcription of five genes required for the maintenance of resistance in EV18. Three of these genes (YihO, YhdP, and WaaY) have not been previously identified as essential for high-level antimicrobial resistance (AMR). Our work provides a new perspective to identify and characterize novel players crucial for maintaining AMR in E. coli.
Physical activity and health: Findings from Finnish monozygotic twin pairs discordant for physical activity
Authors: Kujala Urho M. , Leskinen Tuija , Rottensteiner Mirva , Aaltonen Sari , Ala-Korpela Mika , Waller Katja , Kaprio Jaakko 
Published: November 2021

AbstractGenetic and early environmental differences including early health habits associate with future health. To provide insight on the causal nature of these associations, monozygotic (MZ) twin pairs discordant for health habits provide an interesting natural experiment. Twin pairs discordant for leisure-time physical activity (LTPA) in early adult life are thus a powerful study design to investigate the associations between long-term LTPA and indicators of health and wellbeing. We have used this study design by identifying 17 LTPA discordant twin pairs from two Finnish twin cohorts and summarize key findings of these studies in this paper. The carefully characterized rare long-term LTPA discordant MZ twin pairs have participated in multi-dimensional clinical examinations. The occurrence of type 2 diabetes and death has been evaluated on the basis of prospective questionnaire data and register follow-up among a larger number of twin pairs. Key findings highlight that, compared to less active twins in such MZ twin pairs, the twins with higher long-term LTPA have higher physical fitness, reduced body fat, reduced visceral fat, reduced liver fat, increased lumen diameters of conduit arteries to the lower limbs, increased bone mineral density in loaded bone areas, increased high-density lipoprotein cholesterol levels and reduced occurrence of type 2 diabetes. However, we have not been able to document differences in the life expectancy between the less and more active twin siblings of the LTPA discordant MZ twin pairs. The findings are in agreement with intervention studies but not with all observational studies in which genetic factors are not controlled for.
Machine Learning Based Prediction of COVID-19 Mortality Suggests Repositioning of Anticancer Drug for Treating Severe Cases
Authors: Linden Thomas , Hanses Frank , Domingo-Fernández Daniel , DeLong Lauren Nicole , Kodamullil Alpha Tom , Schneider Jochen , Vehreschild Maria J.G.T. , Lanznaster Julia , Ruethrich Maria Madeleine , Borgmann Stefan , Hower Martin , Wille Kai , Feldt Thorsten , Rieg Siegbert , Hertenstein Bernd , Wyen Christoph , Roemmele Christoph , Vehreschild Jörg Janne , Jakob Carolin E. M. , Stecher Melanie , Kuzikov Maria , Zaliani Andrea , Fröhlich Holger ,   LEOSS study group
Published: November 2021

AbstractDespite available vaccinations COVID-19 case numbers around the world are still growing, and effective medications against severe cases are lacking. In this work, we developed a machine learning model which predicts mortality for COVID-19 patients using data from the multi-center ‘Lean European Open Survey on SARS-CoV-2-infected patients’ (LEOSS) observational study (>100 active sites in Europe, primarily in Germany), resulting into an AUC of almost 80%. We showed that molecular mechanisms related to dementia, one of the relevant predictors in our model, intersect with those associated to COVID-19. Most notably, among these molecules was tyrosine kinase 2 (TYK2), a protein that has been patented as drug target in Alzheimer’s Disease but also genetically associated with severe COVID-19 outcomes. We experimentally verified that anti-cancer drugs Sorafenib and Regorafenib showed a clear anti-cytopathic effect in Caco2 and VERO-E6 cells and can thus be regarded as potential treatments against COVID-19. Altogether, our work demonstrates that interpretation of machine learning based risk models can point towards drug targets and new treatment options, which are strongly needed for COVID-19.