bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adar1 deletion causes degeneration of exocrine pancreas via Mavs-dependent interferon signaling
Authors: Rupani Dhwani N. , Cowan Robert W. , Thege Fredrik I. , Chandra Vidhi , Wörmann Sonja M. , Rajaei Hajar , Malaney Prerna , Le Roux Olivereen , Manning Sara L. , Hashem Jack , Bailey-Lundberg Jennifer , McAllister Florencia , Rhim Andrew D. 
Published: November 2021

ABSTRACTAdenosine deaminase acting on RNA 1 (ADAR1) is an RNA-binding protein that deaminates adenosine(A) to inosine(I). A-to-I editing alters post-transcriptional RNA processing making ADAR1 a critical regulator of gene expression. Consequently, Adar1 has been implicated in organogenesis. To determine the role of Adar1 in pancreatic development and homeostasis, we specifically deleted Adar1 from the murine pancreas (Ptf1aCre/+; Adar1Fl/Fl). The resulting mice had stunted growth likely due to malabsorption associated with exocrine pancreas insufficiency. Analyses of pancreases revealed ductal expansion, heightened interferon-stimulated gene expression and an increased influx of immune cells. In addition, we observed an increased prevalence of CD4+ T and natural killer cells in their splenic tissue. These results indicate an association between loss of pancreatic Adar1 with dysregulation of systemic immunity. Concurrent deletion of Adar1 and Mavs, a signaling protein implicated in the innate immune pathway rescued the degenerative phenotype and resulted in normal pancreatic development. Taken together, our work suggests that the primary function of Adar1 in the pancreas is to prevent aberrant activation of the Mavs-mediated innate immune pathway, thereby maintaining pancreatic homeostasis.Summary statementThis work defines the role of Adar1 in pancreatic development and homeostasis.
A comparison of single and multi-echo processing of fMRI data during overt autobiographical recall
Authors: Gilmore Adrian W. , Agron Anna M. , González-Araya Estefanía I. , Gotts Stephen J. , Martin Alex 
Published: November 2021

ABSTRACTRecent years have seen an increase in the use of multi-echo fMRI designs by cognitive neuroscientists. Acquiring multiple echoes allows one to reduce thermal noise and identify nuisance signal components in BOLD data (Kundu et al., 2012). At the same time, multi-echo acquisitions increase data processing complexity and may incur a cost to the temporal and spatial resolution of the acquired data. Here, we re-examine a multi-echo dataset (Gilmore et al., 2021a) analyzed using multi-echo ICA (ME-ICA) and focused on hippocampal activity during the overly spoken recall of recent and remote autobiographical memories. The goal of the present series of analyses was to determine if ME-ICA’s theoretical denoising benefits might lead to a practical difference in the overall conclusions reached. Compared to single echo data, ME-ICA led to qualitatively different conclusions regarding hippocampal contributions to autobiographical recall: whereas the single echo analysis largely failed to reveal hippocampal activity relative to an active baseline, ME-ICA results supported predictions of the Standard Model of Consolidation and a time limited hippocampal involvement (Alvarez and Squire, 1994). These data provide a practical example of the benefits multi-echo denoising in a naturalistic memory paradigm and demonstrate how they can be used to address long-standing theoretical questions.
A high-fat diet changes astrocytic metabolism to enhance synaptic plasticity and promote exploratory behavior
Authors: Popov Alexander , Brazhe Nadezda , Fedotova Anna , Tiaglik Alisa , Bychkov Maxim , Morozova Kseniia , Brazhe Alexey , Aronov Dmitry , Lyukmanova Ekaterina , Lazareva Natalia , Li Li , Verkhratsky Alexei , Semyanov Alexey 
Published: November 2021

SummaryA high-fat diet (HFD) is generally considered to negatively influence the body, the brain, and cognitive abilities. On the other hand, fat and fatty acids are essential for nourishing and constructing brain tissue. Astrocytes are central for lipolysis and fatty acids metabolism. Here we show that exposure of young mice to one month of HFD elevates lipid content and increases the relative amount of reduced cytochromes in astrocytes but not in neurons. Metabolic changes were paralleled with an enlargement of astrocytic territorial domains due to an increased outgrowth of branches and leaflets. Astrocyte remodeling was associated with an increase in expression of ezrin and with no changes in glial fibrillary acidic protein (GFAP), glutamate transporter-1 (GLT-1), and glutamine synthetase (GS). Such physiological (non-reactive) enlargement of astrocytes in the brain active milieu promoted glutamate clearance and long-term potentiation. These changes translated into improved exploratory behavior. Thus, dietary fat intake is not invariably harmful and might exert beneficial effects depending on the biological context.In BriefA high-fat diet stimulates the metabolism and growth of astrocytes, which improves glutamate clearance, synaptic plasticity, and exploratory behavior in young mice. Thus, dietary fat arguably is an essential component of the diet for children and young adults, supporting the optimal development of the brain.HighlightsExposure of young mice to a high-fat diet elevated lipid content and increased amount of reduced cytochromes in astrocytes but not in neurons.Metabolic changes were paralleled with an enlargement of astrocytic territorial domains due to an increased outgrowth of branches and leaflets.Astrocytic enlargement was associated with increased expression of ezrin but not GFAP, hence was not reactive but physiologicalExpansion of astrocytes in the brain active milieu improved glutamate clearance and long-term potentiation.The high-fat diet improved exploratory behavior in young mice.
A phosphoinositide and RAB switch controls early macropinocytosis
Authors: Spangenberg Hélène , Sneeggen Marte , Tortola Maria Mateo , Valenzuela Camila , Chang Yuen-Yan , Stenmark Harald , Raiborg Camilla , Schink Kay Oliver 
Published: November 2021

AbstractMacropinocytosis is a non-selective endocytic process by which cells take up large amounts of extracellular fluids into giant vesicles known as macropinosomes. This mechanism is used by immune cells to sample the surroundings for antigens and can be exploited by cancer cells for nutrient uptake. What determines the fate of macropinosomes after they have been internalized is largely unknown. Here we investigate the role of the phosphatidylinositol 3-kinase VPS34/PIK3C3 and its product phosphatidylinositol 3-phosphate (PtdIns3P) in macropinosome fate determination. Inhibition of VPS34 led to a decrease in macropinosome survival and fluid phase uptake as well as preventing recruitment of early endosomal factors, including the small GTPase RAB5 and its effectors, to the forming macropinosomes. Instead, forming macropinosomes under VPS34 inhibition accumulated regulators of endocytic recycling, including RAB8A, RAB10, RAB11A, and PtdIns4P, which led to fusion of macropinosomes with the plasma membrane.Whereas RAB5 was critical for macropinosome formation, macropinosome fusion with the plasma membrane depended on RAB8A. Thus, macropinosome maturation is regulated by a PtdIns3P-controlled switch that balances macropinosome fate between the default, endolysosomal maturation and an alternative, secretory route.
Cone-driven retinal responses are shaped by rod but not cone HCN1
Authors: Lankford Colten K. , Umino Yumiko , Poria Deepak , Kefalov Vladimir , Solessio Eduardo , Baker Sheila A. 
Published: November 2021

ABSTRACTSignal integration of converging neural circuits is poorly understood. One example is in the retina where the integration of rod and cone signaling is responsible for the large dynamic range of vision. The relative contribution of rods versus cones is dictated by a complex function involving background light intensity and stimulus temporal frequency. One understudied mechanism involved in coordinating rod and cone signaling onto the shared retinal circuit is the hyperpolarization activated current (Ih) mediated by HCN1 channels. Ih opposes membrane hyperpolarization driven by activation of the phototransduction cascade and modulates the strength and kinetics of the photoreceptor voltage response. We examined conditional knockout of HCN1 from rods using electroretinography. In the absence of HCN1, rod responses are prolonged in dim light which altered the response to slow modulation of light intensity both at the level of retinal signaling and behavior. Under brighter intensities, cone-driven signaling was suppressed. To our surprise, conditional knockout of HCN1 from cones had no effect on cone-mediated signaling. We propose that Ih is dispensable in cones due to the high level of temporal control of cone phototransduction. Thus, HCN1 is required for cone-driven retinal signaling only indirectly by modulating the voltage response of rods to limit their output.GRAPHICAL ABSTRACT
Catalytic mechanism of the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2)
Authors: Zhao Li Na , Kaldis Philipp 
Published: November 2021

AbstractMethylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) is a new drug target that is expressed in cancer cells but not in normal adult cells, which provides an Achilles heel to selectively kill cancer cells. Despite the availability of crystal structures of MTHFD2 in the inhibitor- and cofactor-bound forms, key information is missing due to technical limitations, including (a) the location of absolutely required Mg2+ion, and (b) the substrate-bound form of MTHFD2. Using homology modeling and simulation studies, we propose that two magnesium ions are present at the active site whereby (i) Arg233, Asp225, and two water molecules coordinate MgA, while MgAtogether with Arg233 stabilize the inorganic phosphate (Pi); (ii) Asp168 and three water molecules coordinate MgB, and MgBfurther stabilizes Piby forming a hydrogen bond with two oxygens of Pi; (iii) Arg201 directly coordinates the Pi; and (iv) through three water-mediated interactions, Asp168 contributes to the positioning and stabilization of MgA, MgBand Pi. Our computational study at the empirical valence bond level allowed us to elucidate the detailed reaction mechanisms. We found that the dehydrogenase activity features a proton-coupled electron transfer with charge redistribution coupled to the reorganization of the surrounding water molecules which further facilitates the subsequent cyclohydrolase activity. The cyclohydrolase activity then drives the hydration of the imidazoline ring and the ring opening in a concerted way. Furthermore, we have uncovered that two key residues Ser197/Arg233 are key factors in determining the cofactor (NADP+/NAD+) preference of the dehydrogenase activity. Our work sheds new light on the structural and kinetic framework of MTHFD2, which will be helpful to design small molecule inhibitors that can be used for cancer therapy.
Two-speed genome expansion drives the evolution of pathogenicity in animal fungal pathogens
Authors: Wacker Theresa , Helmstetter Nicolas , Wilson Duncan , Fisher Matthew C. , Studholme David J. , Farrer Rhys A. 
Published: November 2021

AbstractThe origins of virulence in amphibian-infecting chytrids Batrachochytrium dendrobatidis (Bd) and Batrachochytrium salamandrivorans (Bsal) are largely unknown. Here, we use deep nanopore sequencing of Bsal and comparative genomics against 21 high-quality genome assemblies that span the fungal Chytridiomycota. Bsal has the most repeat-rich genome, comprising 40.9% repetitive elements, which has expanded to more than 3X the length of its conspecific Bd. M36 metalloprotease virulence factors are highly expanded in Bsal and 53% of the 177 unique genes are flanked by transposable elements, suggesting repeat-driven expansion. The largest M36 sub-family are mostly (84%) flanked upstream by a novel LINE element, a repeat superfamily implicated with gene copy number variations. We find that Bsal has a highly compartmentalized genome architecture, with virulence factors enriched in gene-sparse/repeat-rich compartments, while core conserved genes occur in gene-rich/repeat-poor compartments. This is a hallmark of two-speed genome evolution. Furthermore, genes with signatures of positive selection in Bd are enriched in repeat-rich regions, suggesting they are a cradle for chytrid pathogenicity evolution, and Bd also has a two-speed genome. This is the first evidence of two-speed genomes in any animal pathogen, and sheds new light on the evolution of fungal pathogens of vertebrates driving global declines and extinctions.
Autoinhibition and regulation by phosphoinositides of ATP8B1, a human lipid flippase associated with intrahepatic cholestatic disorders
Authors: Dieudonné Thibaud , Herrera Sara Abad , Laursen Michelle Juknaviciute , Lejeune Maylis , Stock Charlott , Slimani Kahina , Jaxel Christine , Lyons Joseph A. , Montigny Cédric , Pomorski Thomas Günther , Nissen Poul , Lenoir Guillaume 
Published: November 2021

AbstractP4-ATPases flip lipids from the exoplasmic to the cytosolic leaflet, thus maintaining lipid asymmetry in eukaryotic cell membranes. Mutations in several human P4-ATPase genes are associated with severe diseases, e.g. in ATP8B1 causing progressive familial intrahepatic cholestasis, a rare inherited disorder progressing toward liver failure. ATP8B1 forms a binary complex with CDC50A and displays a broad specificity to glycerophospholipids, but regulatory mechanisms are unknown. Here, we report functional studies and the cryo-EM structure of the human lipid flippase ATP8B1-CDC50A at 3.1 Å resolution. We find that ATP8B1 is autoinhibited by its N- and C-terminal tails, which form extensive interactions with the catalytic sites and flexible domain interfaces. Consistently, ATP hydrolysis is unleashed by truncation of the C-terminus, but also requires phosphoinositides, most markedly phosphatidylinositol-3,4,5-phosphate (PI(3,4,5)P3), and removal of both N- and C- termini results in full activation. Restored inhibition of ATP8B1 truncation constructs with a synthetic peptide mimicking the C-terminal segment further suggests molecular communication between N- and C-termini in the autoinhibition and demonstrates that the regulatory mechanism can be interfered with by exogenous compounds. A recurring (G/A)(Y/F)AFS motif of the C-terminal segment suggests that this mechanism is employed widely across P4-ATPase lipid flippases in plasma membrane and endomembranes.
Selecting coral species for reef restoration
Authors: Madin Joshua S. , McWilliam Michael , Quigley Kate , Bay Line K. , Bellwood David , Doropoulos Christopher , Fernandes Leanne , Harrison Peter , Hoey Andrew S. , Mumby Peter J. , Ortiz Juan C. , Richards Zoe T. , Riginos Cynthia , Schiettekatte Nina , Suggett David J. , van Oppen Madeleine J. H. 
Published: November 2021

AbstractHumans have long sought to restore species, but little attention has been directed at how to best select a subset of foundation species for maintaining rich assemblages that support ecosystems, like coral reefs and rainforests that are increasingly threatened by environmental change.We propose a two-part hedging approach that selects optimized sets of species for restoration. The first part acknowledges that biodiversity supports ecosystem functions and services, and so it takes precaution against loss by ensuring an even spread of phenotypic traits. The second part maximizes species and ecosystem persistence by weighting species based on characteristics that are known to improve ecological persistence—e.g., abundance, species range and tolerance to environmental change.Using existing phenotypic trait and ecological characteristic data for reef building corals, we identified sets of ecologically persistent species by examining marginal returns in occupancy of phenotypic trait space. We compared optimal sets of species with those from the world’s southern-most coral reef which naturally harbors low coral diversity to show these occupy much of the trait space. Comparison with an existing coral restoration program indicated that current corals used for restoration only cover part of the desired trait space and may be improved by including species with different traits.Synthesis and applications. While there are many possible criteria for selecting species for restoration, the approach proposed here addresses the need to insure against unpredictable losses of ecosystem services by focusing on a wide range of phenotypic traits and ecological characteristics. Furthermore, the flexibility of the approach enables the functional goals of restoration to vary depending on environmental context, stakeholder values, and the spatial and temporal scales at which meaningful impacts can be achieved.
PEPc-mediated CO2assimilation provides carbons to gluconeogenesis and the TCA cycle in both dark-exposed and illuminated guard cells
Authors: Lima Valéria F. , Medeiros David B. , Cândido-Sobrinho Silvio A. , Freire Francisco Bruno S. , Porto Nicole P. , Erban Alexander , Kopka Joachim , Schwarzländer Markus , Fernie Alisdair R. , Daloso Danilo M. 
Published: November 2021

AbstractEvidence suggests that guard cells have higher rate of phosphoenolpyruvate carboxylase (PEPc)-mediated dark CO2assimilation than mesophyll cells. However, it is unknown which metabolic pathways are activated following dark CO2assimilation in guard cells. Furthermore, it remains unclear how the metabolic fluxes throughout the tricarboxylic acid (TCA) cycle and associated pathways are regulated in illuminated guard cells. Here we used13C-HCO3labelling of tobacco guard cells harvested under continuous dark or during the dark-to-light transition to elucidate principles of metabolic dynamics downstream of CO2assimilation. Most metabolic changes were similar between dark-exposed and illuminated guard cells. However, illumination increased the13C-enrichment in sugars and metabolites associated to the TCA cycle. Sucrose was labelled in the dark, but light exposure increased the13C-labelling into this metabolite. Fumarate was strongly labelled under both dark and light conditions, while illumination increased the13C-enrichment in pyruvate, succinate and glutamate. Only one13C was incorporated into malate and citrate in either dark or light conditions. Our results collectively suggest that the PEPc-mediated CO2assimilation provides carbons for gluconeogenesis, the TCA cycle and glutamate synthesis and that previously stored malate and citrate are used to underpin the specific metabolic requirements of illuminated guard cells.HighlightPEPc-mediated CO2assimilation provides carbons for gluconeogenesis and the TCA cycle, whilst previously stored malate and citrate are used to underpin the specific metabolic requirements of illuminated guard cells.
miR-409-3p represses Cited2 at the evolutionary emergence of the callosal and corticospinal projections
Authors: Wagner Nikolaus R. , Sinha Ashis , Siththanandan Verl , Kowalchuk Angelica N. , MacDonald Jessica , Tharin Suzanne 
Published: November 2021

AbstractCallosal projection neurons are a broad population of interhemispheric projection neurons that extend an axon across the corpus callosum to connect the two cerebral hemispheres. The corticospinal tract, comprised of the axons of corticospinal projection neurons, is unique to mammals, and its full extension to the lumbar segments that control walking is, like the corpus callosum, unique to placental mammals. The emergence of these two distinct axonal tracts is thought to underpin the evolutionary expansion of complex motor and cognitive abilities. The molecular mechanisms regulating the divergence of corticospinal and callosal projection neurons are incompletely understood. Our recent work identifies a genomic cluster of microRNAs (12qF1/Mirg) unique to placental mammals. These clustered miRNAs are specifically expressed by corticospinal vs. callosal projection neurons during the molecular refinement of corticospinal vs. callosal projection neuron fate (1). One of these, miR-409-3p, can convert layer V callosal into corticospinal projection neurons, acting in part through repression of the callosal-expressed transcriptional regulator Lmo4. This conversion is partial, however, suggesting that miR-409-3p represses multiple callosal projection neuron control genes in order to specify corticospinal projection neurons. One potential additional target of miR-409-3p repression is the callosal-expressed transcriptional co-activator Cited2. Cited2 interacts genetically with Lmo4, and Lmo4 can partially functionally compensate for Cited2 in thymus development(2). Further, Cited2 and Lmo4 function as opposing molecular controls over specific areal identity within superficial layer callosal projection neurons of the somatosensory and motor cortices, respectively (3). Cited2 is highly expressed by callosal, relative to corticospinal, projection neurons from the earliest stages of neurogenesis. Cited2 is necessary for the expansion of intermediate progenitor cells (IPCs) in the subventricular zone (SVZ), and the resulting generation of superficial layer callosal projection neurons. Here we show that miR-409-3p and Cited2 interact in IPCs and in corticospinal vs. deep layer callosal projection neuron development. miR-409-3p represses the Cited2 3’UTR in luciferase assays. Mirg, which encodes miR-409-3p, and Cited2, are reciprocally expressed in IPCs at e15.5 by qPCR. Furthermore, miR-409-3p gain-of-function results in a phenocopy of established Cited2 loss-of-function in IPCs. Later on, miR-409-3p and Cited2 exert opposing effects on the adoption of corticospinal vs. callosal projection neuron subtype identity. Taken together, our work suggests that miR-409-3p, and possibly other 12qF1 miRNAs, represses Cited2 in IPCs to limit their proliferation, and in developing corticospinal and deep layer callosal projection neurons to favor corticospinal fate.
Applications of AlphaFold beyond Protein Structure Prediction
Authors: Zhang Yuan , Li Peizhao , Pan Feng , Liu Hongfu , Hong Pengyu , Liu Xiuwen , Zhang Jinfeng 
Published: November 2021

AbstractPredicting structures accurately for natural protein sequences by DeepMind’s AlphaFold is certainly one of the greatest breakthroughs in biology in the twenty-first century. For designed or engineered sequences, which can be unstable, predicting the stabilities together with their structures is essential since unstable structures will not function properly. We found that experimentally measured stability changes of point mutations correlate poorly with the confidence scores produced by AlphaFold. However, the stability changes can be accurately predicted using features extracted from the representations learned by AlphaFold, indicating greater generalizability of AlphaFold to designed or engineered sequences than previously thought. We then used AlphaFold to validate our previously developed protein design method, ProDCoNN, that designs sequences to fold to target protein structures given only the backbone structure information of the target proteins. We showed that ProDCoNN was able to design sequences that fold to structures very close to target structures. By combining a modified ProDCoNN, AlphaFold, and sequential Monte Carlo, we designed a novel framework to estimate the designability of protein structures. The designability of a protein structure is defined as the number of sequences, which encode the protein structure, and is an indicator of the functional robustness of proteins. For the first time, we estimated the designability of a real protein structure, chain A of FLT3 ligand (PDB ID: 1ETE) with 134 residues, as 3.12±2.14E85.