bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered brain network topology in children with Auditory Processing Disorder: a resting-state multi-echo fMRI study
Authors: Alvand Ashkan , Kuruvilla-Mathew Abin , Kirk Ian J. , Roberts Reece P. , Pedersen Mangor , Purdy Suzanne C. 
Published: April 2022

AbstractChildren with auditory processing disorder (APD) experience hearing difficulties, particularly in the presence of competing sounds, despite having normal audiograms. There is considerable debate on whether APD symptoms originate from bottom-up (e.g., auditory sensory processing) and/or top-down processing (e.g., cognitive, language, memory). A related issue is that little is known about whether functional brain network topology is altered in APD. Therefore, we used resting-state functional magnetic resonance imaging data to investigate the functional brain network organization of 57 children from 8 to 13 years old, diagnosed with APD (n=28) and without hearing difficulties (healthy control, HC; n=29). We applied complex network analysis using graph theory to assess the whole-brain integration and segregation of functional networks and brain hub architecture. Our results showed children with APD and HC have similar global network properties and modular organization. Still, the APD group showed different hub architecture. At the nodal level, we observed decreased participation coefficient (PC) in auditory cortical regions in APD, including bilateral superior temporal gyrus and left middle temporal gyrus. Beyond auditory regions, PC was also decreased in APD in bilateral posterior temporo-occipital cortices, left intraparietal sulcus, and right posterior insular cortex. Correlation analysis suggested a positive association between PC in the left parahippocampal gyrus and the listening-in-spatialized-noise-sentences task where APD children were engaged in auditory perception. In conclusion, our findings provide evidence of altered brain network organization in children with APD, specific to auditory networks, and shed new light on the neural systems underlying children’s listening difficulties.
Mapping phenotypic heterogeneity in melanoma onto the epithelial-hybrid-mesenchymal axis
Authors: Pillai Maalavika , Rajaram Gouri , Thakur Pradipti , Agarwal Nilay , Muralidharan Srinath , Ray Ankita , Somarelli Jason A , Jolly Mohit Kumar 
Published: April 2022

SummaryEpithelial to mesenchymal transition (EMT) is a well-studied hallmark of epithelial-like cancers that is characterized by loss of epithelial markers and gain of mesenchymal markers. Interestingly, melanoma, which is derived from melanocytes of the skin, also undergo phenotypic plasticity toward mesenchymal-like phenotypes under the influence of various micro-environmental cues. Our study connects EMT to the phenomenon of de-differentiation (i.e., transition from proliferative to more invasive phenotypes) observed in melanoma cells during drug treatment. By analyzing 78 publicly available transcriptomic melanoma datasets, we found that de-differentiation in melanoma is accompanied by upregulation of mesenchymal genes, but not necessarily a concomitant loss of an epithelial program, suggesting a more “one-dimensional” EMT that leads to a hybrid epithelial/ mesenchymal phenotype. Samples lying in the hybrid epithelial/mesenchymal phenotype also correspond to the intermediate phenotypes in melanoma along the proliferative-invasive axis - neural crest and transitory ones. Interestingly, as melanoma cells progress along the invasive axis, the mesenchymal signature does not increase monotonically. Instead, we observe a peak in mesenchymal scores followed by a decline, as cells further de-differentiate. This biphasic response recapitulates the dynamics of melanocyte development, suggesting close interactions among genes controlling differentiation and mesenchymal programs in melanocytes. Similar trends were noted for metabolic changes often associated with EMT in carcinomas in which progression along mesenchymal axis correlates with the downregulation of oxidative phosphorylation, while largely maintaining glycolytic capacity. Overall, these results provide an explanation for how EMT and dedifferentiation axes overlap with respect to their transcriptional and metabolic programs in melanoma.
Deploying genomics workflows on high performance computing (HPC) platforms: storage, memory, and compute considerations
Authors: Powers Marissa E. , Mannthey Keith , Sebastian Priyanka , Adsule Snehal , Kiernan Elizabeth , Smith Jonathan T. , Way Jessica , Shifaw Beri , Roazen David , Narvaez Paolo 
Published: April 2022

AbstractNext Generation Sequencing (NGS) workloads largely consist of pipelines of tasks with heterogeneous compute, memory, and storage requirements. Identifying the optimal system configuration has historically required expertise in both system architecture and bioinformatics. This paper outlines infrastructure recommendations for one commonly used genomics workload based on extensive benchmarking and profiling, along with recommendations on how to tune genomics workflows for high performance computing (HPC) infrastructure. The demonstrated methodology and learnings can be extended for other genomics workloads and for other infrastructures such as the cloud.
Phosphorylation of SAMHD1 Thr592 increases C-terminal domain dynamics, tetramer dissociation, and ssDNA binding kinetics
Authors: Orris Benjamin , Huynh Kevin W. , Ammirati Mark , Han Seungil , Bolaños Ben , Carmody Jason , Petroski Matthew D. , Bosbach Benedikt , Shields David J. , Stivers James T. 
Published: April 2022

AbstractSAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) is driven into its activated tetramer form by binding of GTP activator and dNTP activators/substrates. In addition, the inactive monomeric and dimeric forms of the enzyme bind to single-stranded (ss) nucleic acids. During DNA replication SAMHD1 can be phosphorylated by CDK1 and CDK2 at its C-terminal threonine 592 (pSAMHD1), enabling the enzyme to localize to stalled replication forks (RFs) and promote their restart. Since localization of a potent dNTPase at stalled RFs is not harmonious with DNA replication, we used a series of kinetic and thermodynamic measurements to explore a hypothesis where the combined effects of T592 phosphorylation and ssDNA binding serves as a dual switch to turn-off SAMHD1 dNTPase activity. We report that phosphorylation has only a small effect on the dNTPase activity and ssDNA binding affinity of SAMHD1. However, perturbation of the native T592 by phosphorylation decreased the thermal stability of tetrameric SAMHD1 and accelerated tetramer dissociation in the absence and presence of ssDNA (~15-fold). In addition, we found that ssDNA binds competitively with GTP to the A1 site. A full-length SAMHD1 cryo-EM structure revealed substantial baseline dynamics in the C-terminal domain (which contains T592) which may be modulated by phosphorylation. We propose that T592 phosphorylation increases tetramer dynamics and allows invasion of ssDNA into the A1 site and the previously characterized DNA binding surface at the dimer-dimer interface. These features are consistent with rapid and regiospecific inactivation of pSAMHD1 dNTPase at RFs or other sites of free ssDNA in cells.
Epistasis between synonymous and nonsynonymous mutations in Dictyostelium discoideum ammonium transporter amtA drives functional complementation in Saccharomyces cerevisiae
Authors: Densi Asha , Iyer Revathi S , Bhat Paike Jayadeva 
Published: April 2022

AbstractRole of Horizontal Gene Transfer (HGT) in evolution transcends across the three domains of life. Ammonium transporters are present in all species and therefore offer an excellent paradigm to study protein evolution following HGT. While investigating HGT through complementation assay, we observed that synonymous and nonsynonymous mutations follow an epistastic relationship. As a proxy for HGT, we attempted to complement a mep1mep2mep3Δ strain of S. cerevisiae (triple deletion strain) which cannot grow on ammonium as a sole nitrogen source below a concentration of 3 mM, with amtA of D. discoideum. As the wild type amtA did not complement, we isolated two mutant derivatives of amtA that complemented the triple deletion strain of S. cerevisiae. amtA M1 bears three nonsynonymous and two synonymous substitutions and these substitutions are necessary for its functionality. amtA M2 bears two nonsynonymous and one synonymous substitution, all of which are necessary for functionality. These mutants were then studied at phenotypic, cell biological, and biochemical level. Interestingly, AmtA M1 transports ammonium but does not confer toxicity to methylamine while AmtA M2 transports ammonium as well as confers methylamine toxicity, demonstrating functional diversification. Based on the results presented, we suggest that protein evolution cannot be fathomed by studying nonsynonymous and synonymous substitutions separately. This is because, protein evolution entails an interaction between synonymous and nonsynonymous substitution, which seems to have gone unnoticed thus far. Above observations have significant implications in various facets of biological processes and are discussed in detail.HighlightsAmmonium transporters (Amts) from bacteria to humans complement in yeastAmtA of D. discoideum does not complement yeast defective for ammonium uptakeSynonymous & nonsynonymous mutations are essential for AmtA functionality in yeastConformational differences underlie functionality & functional diversificationProtein evolution entails interaction of synonymous & nonsynonymous mutations
A visual representation of the hand in the resting somatomotor regions of the human brain
Authors: El Rassi Yara , Handjaras Giacomo , Leo Andrea , Papale Paolo , Corbetta Maurizio , Ricciardi Emiliano , Betti Viviana 
Published: April 2022

SUMMARYHands are regularly in sight in everyday life. This visibility affects motor control, perception, and attention, as visual information is integrated into an internal model of sensorimotor control. Spontaneous brain activity, i.e., ongoing activity in the absence of an active task (rest), is correlated among somatomotor regions that are jointly activated during motor tasks1. Moreover, recent studies suggest that spontaneous activity patterns do not only replay at rest task activation patterns, but also maintain a model of the statistical regularities (priors) of the body and environment, which may be used to predict upcoming behavior2–4. Here we test whether spontaneous activity in the human somatomotor cortex is modulated by visual stimuli that display hands vs. non-hand stimuli, and by the use/action they represent. We analyzed activity with fMRI and multivariate pattern analysis to examine the similarity between spontaneous (rest) activity patterns and task-evoked patterns to the presentation of natural hands, robot hands, gloves, or control stimuli (food). In the left somatomotor cortex we observed a stronger (multi-voxel) spatial correlation between resting-state activity and natural hand picture patterns, as compared to other stimuli. A trend analysis showed that task-rest pattern similarity was influenced by inferred visual and motor attributes (i.e., correlation for hand>robot>glove>food). We did not observe any task-rest similarity in the visual cortex. We conclude that somatomotor brain regions code at rest for visual representations of hand stimuli and their inferred use.
Understanding the Spin Crossover Dynamical Effects of the Dioxygen Binding and Activation on HOD enzyme
Authors: Du Likai 
Published: April 2022

AbstractFor the cofactor-free 1-H-3-hydroxy-4-oxoquinaldine-2,4-dioxygenase (HOD), the dioxygen (O2) dependent steps are rate-limiting along with a spin state crossover to the singlet spin state. Here, the primary triplet O2 molecule activation on the 2-methyl-3-hydroxy-4(1H)-quinolone (MHQ) is investigated, and the catalytic role of the intersystem crossing effects is highlighted by directly comparing results from the Born-Oppenheimer dynamics and non-adiabatic surface hopping dynamics. This work confirms non-adiabatic dynamical effects are essential to modulate the O2 activation on the substrate MHQ. The time scale of the equilibration and conversion from triplet to singlet state should be in the range of a few hundreds of femtoseconds. We hope this work provides us a fresh look at the underlying physics of dioxygen activation reactions involving more than one spin state.
Multiple congenital malformations arise from somatic mosaicism for constitutively active Pik3ca signaling
Authors: Marechal Elise , Poliard Anne , Henry Kilian , Moreno Mathias , Legrix Mathilde , Macagno Nicolas , Mondielli Grégoire , Fauquier Teddy , Barlier Anne , Etchevers Heather C. 
Published: April 2022

AbstractRecurrent missense mutations of the PIK3CA oncogene are among the most frequent drivers of human cancers. These often lead to constitutive activation of its product p110α, a phosphatidylinositol 3-kinase (PI3K) catalytic subunit. In addition to causing a broad range of cancers, the H1047R mutation is also found in affected tissues of a distinct set of congenital tumors and malformations. Collectively termed PIK3CA-related disorders (PRDs), these lead to overgrowth of brain, adipose, connective and musculoskeletal tissues and/or blood and lymphatic vessel components. Vascular malformations are frequently observed in PRD, due to cell-autonomous activation of PI3K signaling within endothelial cells. These, like most muscle, connective tissue and bone, are derived from the embryonic mesoderm. However, important organ systems affected in PRDs are neuroectodermal derivatives. To further examine their development, we drove the most common post-zygotic activating mutation of Pik3ca in neural crest and related embryonic lineages. Outcomes included macrocephaly, cleft secondary palate and more subtle skull anomalies. Surprisingly, Pik3ca-mutant subpopulations of neural crest origin were also associated with widespread cephalic vascular anomalies. Mesectodermal neural crest is a major source of non-endothelial connective tissue in the head, but not the body. To examine the response of vascular connective tissues of the body to constitutive Pik3ca activity during development, we expressed the mutation by way of an Egr2 (Krox20) Cre driver. Lineage tracing led us to observe new lineages that had normally once expressed Krox20 and that may be co-opted in pathogenesis, including vascular pericytes and perimysial fibroblasts. Finally, Schwann cell precursors having transcribed either Krox20 or Sox10 and induced to express constitutively active PI3K were associated with vascular and other tumors. These murine phenotypes may aid discovery of new candidate human PRDs affecting craniofacial and vascular smooth muscle development as well as the reciprocal paracrine signaling mechanisms leading to tissue overgrowth.
CARP2 regulates the Golgi dynamics upon EGF stimulation
Authors: Sharma Rahul , Srinivasula Srinivasa M. 
Published: April 2022

AbstractGolgi apparatus regulate diverse cellular functions like protein sorting, vesicular trafficking, secretion, protein modifications like glycosylation etc. In mammalian cells though, Golgi apparatus appear as ribbon architecture, individual stacks laterally linked to each other by tubular structure, it’s architecture changes dynamically to cater to the needs of the cell under physiological and stress conditions. Loss of Golgi integrity is reported to be associated with pathological conditions like cancer and neurodegeneration. Very little is known of molecular regulators of Golgi dynamics. Here, we demonstrate that CARP2 (Caspase −8 and −10 associated RING containing protein 2), an endosomal ubiquitin ligase and a known regulator of cell migration, modulates the Golgi structure. Stimulation with EGF (Epidermal growth factor) modestly increased CARP2 protein levels. CARP2 exogenous expression or EGF treatment resulted in dispersal of the Golgi apparatus. Conversely, CARP2 deletion suppressed EGF induced Golgi dispersal. CARP2 variants that are defective in their endosomal-association or E3 ligase activity were unable to exhibit Golgi dispersal, indicating importance of both the endosomal localization and the E3 activity for this function. Importantly, we provide evidence that in EGF stimulated cells CARP2 mechanistically functions by targeting one of the Golgi structural proteins, Golgin45 for ubiquitination and degradation. Taken together, our findings unravel the existence of crosstalk between endosomal ubiquitin signaling and the Golgi dynamics.SignificanceThe Golgi is an organelle that exists in mammals in ribbon form - individual stacks laterally linked with each other - is central to protein and lipid modifications, trafficking and secretion. The Golgi architecture is changed dynamically to cater to the physiological needs of the cells (eg: cell division, migration). Dysfunctional or altered Golgi is reported under pathological conditions like cancer, neurodegenerative diseases etc. This study unravels a complex signaling between endosomal ubiquitin ligase, CARP2 and one of the Golgi structural proteins, Golgin45. Here, we delineate CARP2-Golgin45 signaling as a fundamental mechanism that regulates Golgi dynamics underlying in EGF-stimulated cell migration.
Development of the adult-like larval stomach of Lepidobatrachus laevis
Authors: Austiff Jennifer K. , Hanken James 
Published: April 2022

ABSTRACTMost frogs’ diets shift between the larval and adult phases, from a filter-feeding herbivore to a bulk-feeding carnivore. This change in diet corresponds to a biphasic mode of gut development that begins during embryogenesis and resumes at metamorphosis, when nearly the entire anatomy of the tadpole is reorganized into its adult morphology. The frog Lepidobatrachus laevis forgoes this metamorphic shift in feeding mode and instead consumes a bulk-feeding, carnivorous diet both as a larvae and as an adult. This unusual larval diet is enabled by the presence of an adult-like stomach in the tadpole. This study investigates the anatomy and embryonic development of the larval stomach of L. laevis and what, if any, further changes occur during metamorphosis. The histology of embryonic and metamorphic stomach development is compared to that of Xenopus tropicalis, a frog with a typical larval stomach. We find that L. laevis directly forms an adult-like stomach during embryonic development without first forming a larval-like configuration. Moreover, no additional major remodeling of the stomach occurs during metamorphosis, although the stomach does gradually and slightly increase in complexity, proliferating more glands and increasing connective tissue and muscle layers, between hatching and the end of metamorphosis. This developmental trajectory of the stomach in L. laevis corresponds with the megalophagous, carnivorous diet these frogs maintain from tadpole to adult, as well as the maintenance of active feeding throughout metamorphosis. These results will facilitate future investigations into the mechanisms underlying the evolution of this unusual larval anuran feeding strategy, as well as the broader study of how development mediates evolutionary change.
SARS-CoV-2 Omicron (BA.1 and BA.2) specific novel CD8+ and CD4+ T cell epitopes targeting spike protein
Authors: Parn Simone , Savsani Kush , Dakshanamurthy Sivanesan 
Published: April 2022

AbstractThe Omicron (BA.1/B.1.1.529) variant of SARS-CoV-2 harbors an alarming 37 mutations on its spike protein, reducing the efficacy of current COVID-19 vaccines. This study identified CD8+ and CD4+ T cell epitopes from SARS-CoV-2 S protein mutants. To identify the highest quality CD8 and CD4 epitopes from the Omicron variant, we selected epitopes with a high binding affinity towards both MHC I and MHC II molecules and applied other clinical checkpoint predictors including immunogenicity, antigenicity, allergenicity, instability, and toxicity. Subsequently, we found eight Omicron (BA.1/B.1.1.529) specific CD8+ and eleven CD4+ T cell epitopes with a world population coverage of 76.16% and 97.46%, respectively. Additionally, we identified common epitopes across Omicron BA.1 and BA.2 lineages that target mutations critical to SARS-CoV-2 virulence. Further, we identified common epitopes across B.1.1.529 and other circulating SARS-CoV-2 variants, such as B.1.617.2 (Delta). We predicted CD8 epitopes’ binding affinity to murine MHC alleles to test the vaccine candidates in preclinical models. The CD8 epitopes were further validated using our previously developed software tool PCOptim. We then modeled the three-dimensional structures of our top CD8 epitopes to investigate the binding interaction between peptide-MHC and peptide-MHC-TCR complexes. Importantly, our identified epitopes are targeting the mutations on the RNA-binding domain and the fusion sites of S protein. This could potentially eliminate viral infections and form long-term immune responses compared to rather short-lived mRNA vaccines and maximize the efficacy of vaccine candidates against the current pandemic and potential future variants.
Propofol disrupts alpha dynamics in distinct thalamocortical networks underlying sensory and cognitive function during loss of consciousness
Authors: Weiner Veronica S. , Zhou David W. , Kahali Pegah , Stephen Emily P. , Peterfreund Robert A. , Aglio Linda S. , Szabo Michele D. , Eskandar Emad N. , Salazar-Gomez Andrés F. , Sampson Aaron L. , Cash Sydney S. , Brown Emery N. , Purdon Patrick L. 
Published: April 2022

AbstractDuring propofol-induced general anesthesia, alpha rhythms undergo a striking shift from posterior to anterior, termed anteriorization. We combined human intracranial recordings with diffusion imaging to show that anteriorization occurs with opposing dynamics in two distinct thalamocortical subnetworks. The cortical and thalamic anatomy involved, as well as their known functional roles, suggest multiple means by which propofol dismantles sensory and cognitive processes to achieve loss of consciousness.
Sequential addition of neuronal stem cell temporal cohorts generates a feed-forward circuit in the Drosophila larval nerve cord
Authors: Wang Yi-wen , Wreden Chris C , Levy Maayan , Marshall Zarion D , MacLean Jason N , Heckscher Ellie S 
Published: April 2022

AbstractUnderstanding how circuits self-assemble starting from neuronal stem cells is a fundamental question in developmental biology. Here, we addressed how neurons from different lineages wire with each other to form a specific circuit motif. To do so, we combined developmental genetics—Twin spot MARCM, Multi-color Flip Out, permanent labeling—with circuit analysis—calcium imaging, connectomics, and network science analyses. We find many lineages are organized into temporal cohorts, which are sets of lineage-related neurons born within a tight time window, and that temporal cohort boundaries have sharp transitions in patterns of input connectivity. We identify a feed-forward circuit motif that encodes the onset of vibration stimuli. This feed-forward circuit motif is assembled by preferential connectivity between temporal cohorts from different neuronal stem cell lineages. Further, connectivity does not follow the often-cited early-to-early, late-to-late model. Instead, the feed-forward motif is formed by sequential addition of temporal cohorts, with circuit output neurons born before circuit input neurons. Further, we generate multiple new tools for the fly community. Ultimately, our data suggest that sequential addition of neurons (with outputs neurons being oldest and input neurons being youngest) could be a fundamental strategy for assembling feed-forward circuits.