bluuebunny/crossref_metadata_2025_split huggingface dataset:
MESH-FREE HIGH-RESOLUTION SIMULATION OF CEREBROCORTICAL OXYGEN SUPPLY WITH FAST FOURIER PRECONDITIONING
Authors: Ventimiglia Thomas , Linninger Andreas A 
Published: January 2023

AbstractOxygen transfer from blood vessels to cortical brain tissue is representative of a class of problems with mixed-domain character. Large-scale efficient computation of tissue oxygen concentration is dependent on the manner in which the tubular network of blood vessels is coupled to the tissue mesh. Models which explicitly resolve the interface between the tissue and vasculature with a contiguous mesh are prohibitively expensive for very dense cerebral microvasculature. We propose amixed-domain mesh-freetechnique whereby a vascular anatomical network (VAN) represented as a thin directed graph serves for convection of blood oxygen, and the surrounding extravascular tissue is represented as a Cartesian grid of 3D voxels throughout which oxygen is transported by diffusion. We split the network and tissue meshes by the Schur complement method of domain decomposition to obtain a reduced set of system equations for the tissue oxygen concentration. The use of a Cartesian grid allows the corresponding matrix equation to be solved approximately with a fast Fourier transform based Poisson solver, which serves as an effective preconditioner for Krylov subspace iteration. The performance of this method enables the steady state simulation of cortical oxygen perfusion for anatomically accurate vascular networks down to single micron resolution without the need for supercomputers.Practitioner PointsWe present a novel mixed-domain framework for efficiently modeling O2extraction kinetics in the brain.Model equations are generated by graph-theoretic methods for mixed domains.Dual mesh domain decomposition with FFT preconditioning yields very fast simulation times for extremely high spatial resolution.
Dopamine and norepinephrine differentially mediate the exploration-exploitation tradeoff
Authors: Chen Cathy S. , Mueller Dana , Knep Evan , Ebitz R. Becket , Grissom Nicola M. 
Published: January 2023

AbstractThe catecholamines dopamine (DA) and norepinephrine (NE) have been implicated in neuropsychiatric vulnerability, in part via their roles in mediating the decision making processes. Although the two neuromodulators share a synthesis pathway and are co-activated, they engage in distinct circuits and roles in modulating neural activity across the brain. However, in the computational neuroscience literature, they have been assigned similar roles in modulating the exploration-exploitation tradeoff. Revealing how each neuromodulator contributes to this explore-exploit process is important in guiding mechanistic hypotheses emerging from computational psychiatric approaches. To understand the differences and overlaps of the roles of dopamine and norepinephrine in mediating exploration, a direct comparison using the same dynamic decision making task is needed. Here, we ran mice in a restless bandit task, which encourages both exploration and exploitation. We systemically administered a nonselective DA antagonist (flupenthixol), a nonselective DA agonist (apomorphine), a NE beta-receptor antagonist (propranolol), and a NE beta-receptor agonist (isoproterenol), and examined changes in exploration within subjects across sessions. We found a bidirectional modulatory effect of dopamine receptor activity on exploration - increasing dopamine activity decreased exploration and decreasing dopamine activity increased exploration. The modulation of exploration via beta-noradrenergic activity was mediated by sex. Computational model parameters revealed that dopamine modulation affected exploration via decision noise and norepinephrine modulation via outcome sensitivity. Together, these findings suggested that the mechanisms that govern the transition between exploration and exploitation are sensitive to changes in both catecholamine functions and revealed differential roles for NE and DA in mediating exploration.Significance StatementBoth dopamine (DA) and norepinephrine (NE) has been implicated in the decision making process. Although these two catecholamines have shared aspects of their biosynthetic pathways and projection targets, they are thought to exert many core functions via distinct neural targets and receptor subtypes. However, the computational neuroscience literature often ascribes similar roles to these catecholamines, despite the above evidence. Resolving this discrepancy is important in guiding mechanistic hypotheses emerging from computational psychiatric approaches. This study examines the role of dopamine and norepinephrine on the explore-exploit tradeoff. By testing mice, we were able to compare multiple pharmacological agents within subjects, and examine source of individual differences, allowing direct comparison between the effects of these two catecholamines in modulating decision making.
Aclarubicin stimulates RNA polymerase II elongation at closely spaced divergent promoters
Authors: Wooten Matthew , Takushi Brittany , Ahmad Kami , Henikoff Steven 
Published: January 2023

AbstractAnthracyclines are a class of widely prescribed anti-cancer drugs that disrupt chromatin by intercalating into DNA and enhancing nucleosome turnover. To understand the molecular consequences of anthracycline-mediated chromatin disruption, we utilized CUT&Tag to profile RNA polymerase II during anthracycline treatment inDrosophilacells. We observed that treatment with the anthracycline aclarubicin leads to elevated levels of elongating RNA polymerase II and changes in chromatin accessibility. We found that promoter proximity and orientation impacts chromatin changes during aclarubicin treatment, as closely spaced divergent promoter pairs show greater chromatin changes when compared to codirectionally-oriented tandem promoters. We also found that aclarubicin treatment changes the distribution of non-canonical DNA G-quadruplex structures both at promoters and at G-rich pericentromeric repeats. Our work suggests that the anti-cancer activity of aclarubicin is driven by the effects of nucleosome disruption on RNA polymerase II, chromatin accessibility and DNA structures.
Sirtuin 2 inhibition modulates chromatin landscapes genome-wide to induce senescence in ATRX-deficient malignant glioma
Authors: Malgulwar Prit Benny , Danussi Carla , Dharmaiah Sharvari , Johnson William E. , Rao Arvind , Huse Jason T. 
Published: January 2023

ABSTRACTInactivating mutations inATRXcharacterize large subgroups of malignant gliomas in adults and children. ATRX deficiency in glioma induces widespread chromatin remodeling, driving transcriptional shifts and oncogenic phenotypes. Effective strategies to therapeutically target these broad epigenomic sequelae remain undeveloped. We utilized integrated mulit-omics and the Broad Institute Connectivity Map (CMAP) to identify drug candidates that could potentially revert ATRX-deficient transcriptional changes. We then employed disease-relevant experimental models to evaluate functional phenotypes, coupling these studies with epigenomic profiling to elucidate molecular mechanim(s). CMAP analysis and transcriptional/epigenomic profiling implicated the Class III HDAC Sirtuin2 (Sirt2) as a central mediator of ATRX-deficient cellular phenotypes and a driver of unfavorable prognosis in ATRX-deficient glioma. Sirt2 inhibitors reverted Atrx-deficient transcriptional signatures in murine neuroprogenitor cells (mNPCs) and impaired cell migration in Atrx/ATRX-deficient mNPCs and human glioma stem cells (GSCs). While effects on cellular proliferation in these contexts were more modest, markers of senescence significantly increased, suggesting that Sirt2 inhibition promotes terminal differentiation in ATRX-deficient glioma. These phenotypic effects were accompanied by genome-wide shifts in enhancer-associated H3K27ac and H4K16ac marks, with the latter in particular demonstrating compelling transcriptional links to Sirt2-dependent phenotypic reversals. Motif analysis of these data identified the transcription factor KLF16 as a mediator of phenotype reversal in Atrx-deficient cells upon Sirt2 inhibition. Finally, Sirt2 inhibition impaired growth and increased senescence in ATRX-deficient GSCsin vivo. Our findings indicate that Sirt2 inhibition selectively targets ATRX-deficient gliomas through global chromatin remodeling, while demonstrating more broadly a viable approach to combat complex epigenetic rewiring in cancer.Graphical AbstractOne Sentence SummaryOur study demonstrates that SIRT2 inhibition promotes senescence in ATRX-deficient glioma model systems through global epigenomic remodeling, impacting key downstream transcriptional profiles.
Genome-wide analysis of anterior-posterior mRNA regionalization inStentor coeruleusreveals a role for the microtubule cytoskeleton
Authors: Albright Ashley R. , Yan Connie , Angeles-Albores David , Makushok Tatyana , Allen-Henderson Jamarc , Marshall Wallace F. 
Published: January 2023

AbstractCells have complex and beautiful structures that are important for their function. However, understanding the molecular mechanisms that produce these structures is a challenging problem due to the gap in size scales between molecular interactions and cellular structures. The giant ciliateStentor coeruleusis a unicellular model organism whose large size, reproducible structure, and ability to heal wounds and regenerate have historically allowed the formation of structure in a single cell to be addressed using methods of experimental embryology. Such studies have shown that specific cellular structures, such as the membranellar band, always form in particular regions of the cell, which raises the question: what is the source of positional information within this organism? By analogy with embryonic development, in which regionalized mRNA is often used to mark position, we asked whether specific regionalized mRNAs might mark position along the anterior-posterior axis ofStentor. By physically bisecting cells and conducting bulk RNA sequencing, we were able to identify sets of messages enriched in either the anterior or posterior half. We then conducted half-cell RNA-sequencing in paired anteriors and posteriors of cells in which the microtubule cytoskeleton was disrupted by RNAi of β-tubulin or dynein intermediate chains. We found that many messages either lost their regionalized distribution or switched to an opposite distribution, such that anterior-enriched messages in control became posterior-enriched in the RNAi cells, or vice versa. This study indicates that mRNA can be regionalized within a single giant cell and that microtubules may play a role, possibly by serving as tracks for the movement of the messages.
Metagenomic Data Reveal Type I Polyketide Synthase Distributions Across Biomes
Authors: Singh Hans W. , Creamer Kaitlin E. , Chase Alexander B. , Klau Leesa J. , Podell Sheila , Jensen Paul R. 
Published: January 2023

AbstractMicrobial polyketide synthase (PKS) genes encode the biosynthesis of many biomedically important natural products, yet only a small fraction of nature’s polyketide biosynthetic potential has been realized. Much of this potential originates from type I PKSs (T1PKSs), which can be delineated into different classes and subclasses based on domain organization and structural features of the compounds encoded. Notably, phylogenetic relationships among PKS ketosynthase (KS) domains provide a method to classify the larger and more complex genes in which they occur. Increased access to large metagenomic datasets from diverse habitats provides opportunities to assess T1PKS biosynthetic diversity and distributions through the analysis of KS domain sequences. Here, we used the webtool NaPDoS2 to detect and classify over 35,000 type I KS domains from 137 metagenomic data sets reported from eight diverse biomes. We found biome-specific separation with soils enriched in modularcis-AT and hybridcis-AT KSs relative to other biomes and marine sediments enriched in KSs associated with PUFA and enediyne biosynthesis. By extracting full-length KS domains, we linked the phylum Actinobacteria to soil-specific enediyne andcis-AT clades and identified enediyne and monomodular KSs in phyla from which the associated compound classes have not been reported. These sequences were phylogenetically distinct from those associated with experimentally characterized PKSs suggesting novel structures or enzyme functions remain to be discovered. Lastly, we employed our metagenome-extracted KS domains to evaluate commonly used type I KS PCR primers and identified modifications that could increase the KS sequence diversity recovered from amplicon libraries.ImportancePolyketides are a crucial source of medicines, agrichemicals, and other commercial products. Advances in our understanding of polyketide biosynthesis coupled with the accumulation of metagenomic sequence data provide new opportunities to assess polyketide biosynthetic potential across biomes. Here, we used the webtool NaPDoS2 to assess type I PKS diversity and distributions by detecting and classifying KS domains across 137 metagenomes. We show that biomes are differentially enriched in KS domain classes, providing a roadmap for future biodiscovery strategies. Further, KS phylogenies reveal both biome-specific clades that do not include biochemically characterized PKSs, highlighting the biosynthetic potential of poorly explored environments. The large metagenome-derived KS dataset allowed us to identify regions of commonly used type I KS PCR primers that could be modified to capture a larger extent of KS diversity. These results facilitate both the search for novel polyketides and our understanding of the biogeographical distribution of PKSs across earth’s major biomes.
Tomato brown rugose fruit virus Mo gene is a novel microbial source tracking marker
Authors: Natarajan Aravind , Fremin Brayon J. , Schmidtke Danica T. , Wolfe Marlene K. , Zlitni Soumaya , Graham Katherine E. , Brooks Erin F. , Severyn Christopher J. , Sakamoto Kathleen M. , Lacayo Norman J. , Kuersten Scott , Koble Jeff , Caves Glorianna , Kaplan Inna , Singh Upinder , Jagannathan Prasanna , Rezvani Andrew R. , Bhatt Ami S. , Boehm Alexandria B. 
Published: January 2023

AbstractMicrobial source tracking (MST) identifies sources of fecal contamination in the environment using fecal host-associated markers. While there are numerous bacterial MST markers, there are few viral markers. Here we design and test novel viral MST markers based on tomato brown rugose fruit virus (ToBRFV) genomes. We assembled eight nearly complete genomes of ToBRFV from wastewater and stool samples from the San Francisco Bay Area in the United States of America. Next, we developed two novel probe-based RT-PCR assays based on conserved regions of the ToBRFV genome, and tested the markers’ sensitivities and specificities using human and non-human animal stool as well as wastewater. TheToBRFV markers are sensitive and specific; in human stool and wastewater, they are more prevalent and abundant than a currently used marker, the pepper mild mottle virus (PMMoV) coat protein (CP) gene. We applied the assays to detect fecal contamination in urban stormwater samples and found that the ToBRFV markers matched cross-assembly phage (crAssphage), an established viral MST marker, in prevalence across samples. Taken together, ToBRFV is a promising viral human-associated MST marker.ImportanceHuman exposure to fecal contamination in the environment can cause transmission of infectious diseases. Microbial source tracking (MST) can identify sources of fecal contamination so that contamination can be remediated and human exposures can be reduced. MST requires the use of fecal host-associated MST markers. Here we design and test novel MST markers from genomes of tomato brown rugose fruit virus (ToBRFV). The markers are sensitive and specific to human stool, and highly abundant in human stool and wastewater samples.
Neural phoneme discrimination in variable speech in newborns – associations with dyslexia risk and later language skills
Authors: Virtala P. , Kujala T. , Partanen E. , Hämäläinen J. A. , Winkler I. 
Published: January 2023

AbstractA crucial skill in infant language acquisition is learning of the native language phonemes. This requires the ability to group complex sounds into distinct auditory categories based on their shared features. Problems in phonetic learning have been suggested to underlie language learning difficulties in dyslexia, a developmental reading-skill deficit. We investigated auditory abilities important for language acquisition in newborns with or without a familial risk for dyslexia with electrophysiological mismatch responses (MMRs). We presented vowel changes in a sequence of acoustically varying vowels, requiring grouping of the stimuli to two phoneme categories. The vowel changes elicited an MMR which was significantly diminished in infants whose parents had the most severe dyslexia in our sample. Phoneme-MMR amplitude and its hemispheric lateralization were associated with language test outcomes assessed at 28 months, an age at which it becomes possible to behaviourally test children and several standardized tests are available. In addition, statistically significant MMRs to violations of a complex sound-order rule were only found in infants without dyslexia risk, but these results are very preliminary due to small sample size. The results demonstrate the relevance of the newborn infants’ readiness for phonetic learning for their emerging language skills. Phoneme extraction difficulties in infants at familial risk may contribute to the phonological deficits observed in dyslexia.Research highlightsWe recorded mismatch responses (MMRs) to vowel changes in a variable speech streamNewborns extracted relevant phonetic information from the stream, evidenced by MMRsHigh dyslexia risk infants had diminished MMRs to vowel changesMMR amplitudes and hemispheric lateralization correlated with later language skillsPoor phoneme extraction may compromise phonological and language development
To be or not to be an anti-CRISPR: AcrIII-1 and the importance of working with native biological systems
Authors: Martínez-Alvarez Laura , Stickel Dominic , Salegi-Díez Andrea , Bhoobalan-Chitty Yuvaraj , Peng Xu 
Published: January 2023

ABSTRACTViral members of the protein family DUF1874 have been reported to act as anti-CRISPR (acr) proteins that degrade cyclic tetra-adenylate (cA4), a nucleotide second messenger produced after the activation of several type III CRISPR-Cas systems in bacteria and archaea. Specifically, protein SIRV1 gp29 inhibits type III-A and type III-B CRISPR systems in plasmid-born assays in heterologous systems. In this work, we investigate the function of SIRV1 gp29 and its close homolog SIRV2 gp37 in a native biological context, i.e. in cultures infected by SIRV2. SIRV2 was selected instead of SIRV1 because the latter is not available any more from any laboratories. We demonstrate that gp37 has no anti-CRISPR activity during infection ofSaccharolobus islandicusLAL14/1 with SIRV2, although it is able to protect SIRV2 from type III targeting when expressed from a plasmid. The inability of gp37 to act as an acr in the native, biological system is due to the protein expression timing: gp37 is a middle/late gene, thus unable to inhibit CRISPR-Cas targeting at the onset of infection. On the other hand, we find that while gp37 is a non-essential gene, it confers a mild replicative advantage to the virus. This advantage is mediated, in hosts with active CRISPR-Cas targeting, by the interaction between gp37 and host protein SiL_1451, which results in the inhibition of the lysine methyltransferase activity of SiL_1451, responsible for extensive methylation of surface lysines of two-thirds of the cellular proteins. Heterologous gene expression from a plasmid-borne non-native promoter has allowed the discovery and characterization of dozens of prokaryotic defense systems in recent years. Although this experimental strategy has several advantages, our study highlights the importance of validating relevant results under native conditions, and the limitations of extrapolating results obtained using heterologous systems.
A class-specific effect of dysmyelination on the excitability of hippocampal interneurons
Authors: Pinatel Delphine , Pearlstein Edouard , Bonetto Giulia , Goutebroze Laurence , Karagogeos Domna , Crépel Valérie , Faivre-Sarrailh Catherine 
Published: January 2023

AbstractThe role of myelination for axonal conduction is well-established in projection neurons but little is known about its significance in GABAergic interneurons. Myelination is discontinuous along interneuron axons and the mechanisms controlling myelin patterning and segregation of ion channels at the nodes of Ranvier have not been elucidated. Protein 4.1B is implicated in the organization of the nodes of Ranvier as a linker between paranodal and juxtaparanodal membrane proteins to the spectrin cytoskeleton. In the present study, 4.1B KO mice are used as a genetic model to analyze the functional role of myelin in Lhx6-positive parvalbumin and somatostatin neurons, two major classes of GABAergic neurons in the hippocampus. We show that deletion of 4.1B induces disruption of juxtaparanodal K+channel clustering and mislocalization of nodal or heminodal Na+channels. Strikingly, 4.1B-deficiency causes loss of myelin in GABAergic axons in the hippocampus. In particular, stratum oriens O-LM cells display severe axonal dysmyelination and a reduced excitability. This reduced excitability is associated with a decrease in occurrence probability of small amplitude synaptic inhibitory events on pyramidal cells. In contrast, stratum pyramidale fast-spiking basket cells do not appear affected. The aberrant myelination of hippocampal interneurons is also correlated with impairment of spatial memory in 4.1B KO mice. In conclusion, our results indicate a class-specific effect of dysmyelination on the excitability of hippocampal interneurons associated with a functional alteration of inhibitory drive and impairment of spatial memory.
Human iPS cell-derived sensory neurons can be infected by SARS-CoV-2 strain WA1/2020 as well as variants delta and omicron
Authors: Flamier Anthony , Bisht Punam , Richards Alexsia , Tomasello Danielle , Jaenisch Rudolf 
Published: January 2023

SummaryCOVID-19 has impacted billions of people in the world since 2019 and unfolded a major healthcare crisis. With an increasing number of deaths and the emergence of more transmissible variants, it is crucial to better understand the biology of the disease-causing virus, the SARS-CoV-2. Peripheral neuropathies appeared as a specific COVID-19 symptom occurring at later stages of the disease. In order to understand the impact of SARS-CoV-2 on the peripheral nervous system, we generated human sensory neurons from induced pluripotent stem cells that we infected with the SARS-CoV-2 strain WA1/2020 and the variants delta and omicron. Using single cell RNA sequencing, we found that human sensory neurons can be infected by SARS-CoV-2 but are unable to produce new viruses. Our data suggests that sensory neurons can be infected by the original WA1/2020 strain of SARS-CoV-2 as well as the delta and omicron variants.