bluuebunny/crossref_metadata_2025_split huggingface dataset:
The association of MEG3 lncRNA with nuclear speckles in living cells
Authors: Hasenson Sarah E. , Alkalay Ella , Atrash Mohammad K. , Boocholez Alon , Gershbaum Julianna , Hochberg-Laufer Hodaya , Shav-Tal Yaron 
Published: May 2022

AbstractNuclear speckles are nuclear bodies containing RNA-binding proteins as well as RNAs including long non-coding RNAs (lncRNAs). MEG3 is a nuclear retained lncRNA that was identified to be associated with nuclear speck-les. To understand the association dynamics of MEG3 lncRNA with nuclear speckles in living cells we generated a fluorescently-tagged MEG3 transcript that could be detected in real-time. Under regular conditions, transient association of MEG3 with nuclear speckles was observed, including a nucleoplasmic fraction. Conditions under which transcription or splicing were inactive, which are known to affect nuclear speckle structure, showed prominent and increased association of MEG3 lncRNA with the nuclear speckles, specifically forming a ring-like structure around the nuclear speckles. This contrasted with MALAT1 lncRNA that is normally highly associated with nuclear speckles, which was released and dispersed in the nucleoplasm. Under normal conditions MEG3 dynamically associated with the periphery of the nuclear speckles, but under transcription or splicing inhibition, MEG3 could also enter the center of the nuclear speckle. Altogether, using live-cell imaging approaches we find that MEG3 lncRNA is a transient resident of nuclear speckles and that its association with this nuclear body is modulated by the levels of transcription and splicing activities in the cell.
MAP1LC3C regulates lysosomal exocytosis and induces zinc reprogramming in renal cancer cells
Authors: Verma Rita , Aggarwal Parul , Reigle James , Secic Dina , Wetzel Collin , Bischoff Megan E. , VandenHeuvel Katherine , Biesiada Jacek , Ehmer Birgit , Landero Figueroa Julio A. , Plas David R. , Medvedovic Mario , Meller Jarek , Czyzyk-Krzeska Maria F. 
Published: May 2022

AbstractMAP1LC3C (LC3C) is a member of the microtubule associated family of proteins that are essential in the formation of autophagosomes and lysosomal degradation of cargo. LC3C has tumor suppressing activity and its expression is dependent on kidney cancer tumor suppressors, such as VHL and FLCN. Recently we demonstrated that LC3C autophagy is regulated by noncannonical upstream regulatory complexes and targets for degradation postdivision midbody rings associated with cancer cells stemness. Here we show that loss of LC3C leads to peripheral positioning of the lysosomes and lysosomal exocytosis (LE) in a subset of cells. This process is independent of the autophagic activity of LC3C. Analysis of isogenic cells with low and high LE shows substantial transcriptomic reprogramming with altered expression of Zn-related genes and activity of Polycomb Repressor Complex 2 (PRC2), accompanied by a robust decrease in intracellular Zn. Metabolomic analysis revealed alterations in amino acid steady-state levels. Cells with augmented LE show tumor initiation properties and form aggressive tumors in xenograft models. Immunocytochemistry identified high levels of LAMP1 on the plasma membrane of cancer cells in human ccRCC and reduced levels of Zn, an indication that LE is a frequent event in ccRCC, potentially contributing to the loss of Zn. Overall, these data indicate that an important tumor suppressing activity of LC3C is contributing to the reprogramming of lysosomal activity and Zn metabolism with implication for epigenetic remodeling in a subpopulation of tumor propagating properties of cancer cells.
Impaired dendritic spike generation in the Fragile X prefrontal cortex is due to loss of dendritic sodium channels
Authors: Brandalise Federico , Kalmbach Brian E. , Cook Erik P. , Brager Darrin H. 
Published: May 2022

ABSTRACTPatients with Fragile X syndrome, the leading monogenetic cause of autism, suffer from impairments related to the prefrontal cortex including working memory and attention. Synaptic inputs to the distal dendrites of layer 5 pyramidal neurons in the prefrontal cortex have a weak influence on the somatic membrane potential. To overcome this filtering, distal inputs are transformed into local dendritic Na+ spikes, which propagate to the soma and trigger action potential output. Layer 5 extratelencephalic (ET) PFC neurons project to the brainstem and various thalamic nuclei and are therefore well positioned to integrate task-relevant sensory signals and guide motor actions. We used current clamp and outside-out patch clamp recording to investigate dendritic spike generation in ET neurons from male wild type and Fmr1 knockout (FX) mice. The threshold for dendritic spikes was more depolarized in FX neurons compared to wild type. Analysis of voltage responses to simulated in vivo “noisy” current injections showed that a larger dendritic input stimulus was required to elicit dendritic spikes in FX ET dendrites compared wild type. Patch clamp recordings revealed that the dendritic Na+ conductance was significantly smaller in FX ET dendrites. Taken together, our results suggest that input-output transformation is impaired in ET neurons of the PFC in FX mice. Considering our prior findings that somatic D-type K+ and dendritic HCN-channel function is reduced in ET neurons, we suggest that the integration of information by PFC circuits is fundamentally altered in Fragile X syndrome.KEY POINTSDendritic spike threshold is depolarized in Layer 5 PFC neurons in FX miceSimultaneous somatic and dendritic recording with white noise current injections revealed that larger dendritic stimuli were required to elicit dendritic spikes in FX ET neuronsOutside-out patch clamp recording revealed that dendritic sodium conductance density was lower in FX ET neurons
Multimodal disease transmission as a limiting factor for the spatial extent of a host plant
Authors: Uricchio Lawrence H. , Bruns Emily L. , Hood Michael , Boots Mike , Antonovics Janis 
Published: May 2022

AbstractTheoretical models suggest that infectious diseases could play a substantial role in determining species’ ranges, but few studies have collected the empirical data required to test this hypothesis. Pathogens that sterilize their hosts or spread through frequency-dependent transmission could have especially strong effects on the limits of species’ distributions because sterilized hosts can serve as long-lived disease reservoirs and frequency-dependent transmission mechanisms are effective even at very low population densities. We collected spatial disease prevalence data and population abundance data for alpine carnations infected by the sterilizing pathogen M. violaceum, a disease that is spread through both frequency-dependent (vector-borne) and density-dependent (aerial spore transmission) mechanisms. Our 13-year study reveals rapid declines in population abundance without a compensatory decrease in disease prevalence. We apply a stochastic, spatial model of disease spread that accommodates spatial habitat heterogeneity to investigate how the population dynamics depend on multimodal (frequency-dependent and density-dependent) transmission. We found that the observed rate of population decline can be readily explained by multimodal transmission, but is unlikely to be explained by either frequency-dependent or density-dependent mechanisms alone. Multimodal disease transmission rates high enough to explain the observed decline predicted that eventual local extinction of the host species is highly likely. Our results add to a growing body of literature showing how multimodal transmission can constrain species distributions in nature.Open ResearchAll scripts associated with the analyses in this manuscript, as well as the data we collected, are available at https://github.com/uricchio/antherSmutDis.
A dynamicin vitromodel of Down Syndrome neurogenesis with Trisomy 21 gene dosage correction
Authors: Bansal Prakhar , Banda Erin. C , Glatt-Deeley Heather R. , Stoddard Christopher E. , Linsley Jeremy W. , Arora Neha , Ahern Darcy T. , Kondaveeti Yuvabharath , Nicouleau Michael , Sabariego-Navarro Miguel , Dierssen Mara , Finkbeiner Steven , Pinter Stefan F. 
Published: May 2022

ABSTRACT/SUMMARYExcess gene dosage from human chromosome 21 (chr21) causes Down syndrome (DS), spanning developmental as well as acute phenotypes in terminal cell types. Which phenotypes remain amenable to intervention after development is unknown. To address this question in a model of DS neurogenesis, we generated trisomy 21 (T21) human induced pluripotent stem cells (hiPSCs) alongside otherwise isogenic euploid controls from mosaic DS fibroblasts, and integrated an inducibleXISTtransgene on one chr21 copy. Monoallelic chr21 silencing byXISTwas near-complete and irreversible in hiPSCs. Differential expression reveals T21 neural lineages and T21 hiPSCs suppress similar translation and mitochondrial pathways, and activate cellular stress responses. WhenXISTis induced before the neural progenitor stage, T21 dosage correction mitigates a pronounced skew towards astrogenesis in differentiation. Because our transgene remained inducible in post-mitotic T21 neurons and astrocytes, we demonstrateXISTefficiently represses genes even after terminal differentiation, which will empower exploration of cell type-specific T21 phenotypes that remain responsive to chr21 dosage.
The arrow-of-time in neuroimaging time series identifies causal triggers of brain function
Authors: Bolton Thomas A. W. , Van De Ville Dimitri , Amico Enrico , Preti Maria G. , Liégeois Raphaël 
Published: May 2022

AbstractMoving from association to causal analysis of neuroimaging data is crucial to advance our understanding of brain function. The arrow-of-time (AoT), i.e., the known asymmetric nature of the passage of time, is the bedrock of causal structures shaping physical phenomena. However, almost all current time series metrics do not exploit this asymmetry, probably due to the difficulty to account for it in modelling frameworks. Here, we introduce an AoT-sensitive metric that captures the intensity of causal effects in multivariate time series, and apply it to high-resolution functional neuroimaging data. We find that that causal effects underlying brain function are more clearly localized in space and time than functional activity or connectivity, thereby allowing us to trace neural pathways recruited in different conditions. Overall, we provide a mapping of the causal brain that challenges the association paradigm of brain function.
Shared and distinctive neighborhoods of emerin and LBR revealed by proximity labeling and quantitative proteomics
Authors: Cheng Li-Chun , Zhang Xi , Abhinav Kanishk , Nguyen Julie A , Baboo Sabyasachi , Martinez-Bartolomé Salvador , Branon Tess C , Ting Alice Y , Loose Esther , Yates John R , Gerace Larry 
Published: May 2022

AbstractEmerin and LBR are abundant transmembrane proteins of the nuclear envelope (NE) that are concentrated at the inner nuclear membrane (INM). Although both proteins interact with chromatin and nuclear lamins, they have distinctive biochemical and functional properties. Here we have deployed proximity labeling using the engineered biotin ligase TurboID (TbID) and quantitative proteomics to compare the neighborhoods of emerin and LBR in cultured mouse embryonic fibroblasts (MEFs). Our analysis revealed 232 high confidence proximity partners (HCPP) that interact selectively with emerin and/or LBR, 49 of which are shared by both. These included previously characterized NE-concentrated proteins, as well as a host of additional proteins not previously linked to emerin or LBR functions. Many of these are TM proteins of the ER and include two E3 ubiquitin ligases. Using the proximity ligation assay as an orthogonal approach, we validated the interactions described by proximity labeling for 11/12 proteins analyzed, supporting the robustness of our analysis. Overall, this work presents methodology that may be used for large-scale mapping of the landscape of the INM and reveals a group of new proteins with potential functional connections to emerin and LBR.
Microbiome assembly and maintenance across the lifespan of bumble bee workers
Authors: Hammer Tobin J. , Easton-Calabria August , Moran Nancy A. 
Published: May 2022

AbstractHow a host’s microbiome changes over its lifespan can influence development and aging. As these temporal patterns have only been described in detail for humans and a handful of other hosts, an important next step is to compare microbiome dynamics across a broader array of host-microbe symbioses, and to investigate how and why they vary. Here we characterize the temporal dynamics and stability of the bumblebee worker gut microbiome. Bumblebees are a useful symbiosis model given their relatively well-understood life history and simple, host-specific gut bacterial communities. Furthermore, microbial dynamics may influence bumblebee health and pollination services. We combined high-temporal-resolution sampling with 16S rRNA gene sequencing, quantitative PCR, and shotgun metagenomics to characterize gut microbiomes over the adult lifespan of Bombus impatiens workers. To understand how hosts may control (or lose control of) the gut microbiome as they age, we also sequenced hindgut transcriptomes. We found that, at the community level, microbiome assembly is highly predictable and similar to patterns of primary succession observed in the human gut. At the same time, partitioning of strain-level bacterial variants among colonies suggests stochastic colonization events similar to those observed in flies and nematodes. We also find strong differences in temporal dynamics among symbiont species, suggesting ecological differences among microbiome members in colonization and persistence. Finally, we show that both the gut microbiome and host transcriptome—including expression of key immunity genes—stabilize, as opposed to senesce, with age. We suggest that in highly social groups such as bumblebees, maintenance of both microbiomes and immunity contribute to the inclusive fitness of workers, and thus remain under selection even in old age. Our findings provide a foundation for exploring the mechanisms and functional outcomes of bee microbiome succession, and for comparative analyses with other host-microbe symbioses.
Mechanism of Lys6 poly-ubiquitin specificity by the L. pneumophila deubiquitinase LotA
Authors: Warren Gus D. , Kitao Tomoe , Franklin Tyler G. , Nguyen Justine V. , Geurink Paul P. , Kubori Tomoko , Nagai Hiroki , Pruneda Jonathan N. 
Published: May 2022

ABSTRACTThe versatility of ubiquitination to impose control over vast domains of eukaryotic biology is due, in part, to diversification through differently-linked poly-ubiquitin chains. Deciphering the signaling roles for some poly-ubiquitin chain types, including those linked via K6, has been stymied by a lack of stringent linkage specificity among the implicated regulatory proteins. Forged through strong evolutionary pressures, pathogenic bacteria have evolved intricate mechanisms to regulate host ubiquitin, and in some cases even with exquisite specificity for distinct poly-ubiquitin signals. Herein, we identify and characterize a deubiquitinase domain of the secreted effector protein LotA from Legionella pneumophila that specifically regulates K6-linked poly-ubiquitin during infection. We demonstrate the utility of LotA as a tool for studying K6 poly-ubiquitin. By determining apo and diUb-bound structures, we identify the mechanism of LotA activation and K6 poly-ubiquitin specificity, and identify a novel ubiquitin-binding domain utilized among bacterial deubiquitinases.
Phosphorylation Status of B Beta Subunit Controls PP2A activity in Ethylene-mediated Root Growth Inhibition
Authors: Shao Zhengyao , Zhao Bo , Kotla Prashanth , Burns Jackson G. , Tran Jaclyn , Ke Meiyu , Chen Xu , Browning Karen S. , Qiao Hong 
Published: May 2022

AbstractThe various combinations and regulations of different subunits of phosphatase PP2A holoenzymes underlie their functional complexity and importance. We found that phosphorylation status of Bβ of PP2A acts as a switch to regulate the activity of PP2A. In the absence of ethylene, phosphorylated Bβ leads to an inactivation of PP2A; the substrate EIR1 remains to be phosphorylated, preventing the EIR1 mediated auxin transport in epidermis, leading to normal root growth. Upon the ethylene treatment, the dephosphorylated Bβ mediates the formation of A2-C4-Bβ protein complex to activate PP2A, resulting in the dephosphorylation of EIR1 to promote auxin transport in epidermis of elongation zone, leading to root growth inhibition. Altogether, our research revealed a novel molecular mechanism by which the dephosphorylation of Bβ subunit switches on the PP2A activity to dephosphorylate EIR1 to establish EIR1 mediated auxin transport in epidermis in elongation zone for root growth inhibition in response to ethylene.Significance StatementRoot growth is critical to the establishment of planted seedlings. Ethylene plays an important role in the root growth. Yet, the molecular mechanisms that how ethylene regulates the root growth are largely unexplored. This research sheds light on the molecular mechanisms of the determination of the functional specificity and activity of PP2A in response to stimulus in cell type specific manner and reveals the novel molecular mechanism through which ethylene signaling regulates EIR1 dephosphorylation through Bβ dephosphorylation to active EIR1 mediated auxin transport in epidermis in elongation zone, leading to root growth inhibition.
Drosophila melanogasteris a powerful host model to study mycobacterial virulence
Authors: Fuentes Esther , Sivakumar Niruja , Selvik Linn-Karina , Arch Marta , Cardona Pere Joan , Ioerger Thomas R. , Dragset Marte Singsås 
Published: May 2022

ABSTRACTDrosophila melanogaster(Drosophila), the common fruit fly, is one of the most extensively studied animal models we have, with a broad, advanced, and organized research community with tools and mutants readily available at low cost. Yet,Drosophilahas barely been exploited to understand the underlying mechanisms of mycobacterial infections, including those caused by the top-killer pathogenMycobacterium tuberculosis(Mtb). In this study, we aimed to investigate whetherDrosophilais a suitable host model to study mycobacterial virulence, usingMycobacterium marinum(Mmar) to model mycobacterial pathogens. First, we validated that an established mycobacterial virulence factor, EccB1 of the ESX-1 Type VII secretion system, is required forMmargrowth within the flies. Second, we identifiedMmarvirulence factors inDrosophilain a high-throughput genome-wide manner using transposon insertion sequencing (TnSeq). Of the 181 identified virulence genes, the vast majority (91%) had orthologs inMtb, suggesting that the encoded virulence mechanisms may be conserved acrossMmarandMtb. Finally, we validated one of the novelMmarvirulence genes we identified, a putative ATP-binding protein ABC transporter encoded bymmar_1660, as required for full virulence during bothDrosophilaand human macrophage infection. Together, our results show thatDrosophilais a powerful host model to study and identify novel mycobacterial virulence factors relevant to human infection.
Adult-born granule cells improve stimulus encoding and discrimination in the dentate gyrus
Authors: Arribas Diego M. , Marin-Burgin Antonia , Morelli Luis G. 
Published: May 2022

AbstractHeterogeneity plays an important role in diversifying neural responses to support brain function. Adult neurogenesis provides the dentate gyrus with a heterogeneous population of granule cells (GCs) that were born and developed their properties at different times. Immature GCs have distinct intrinsic and synaptic properties than mature GCs and are needed for correct encoding and discrimination in spatial tasks. How immature GCs enhance the encoding of information to support these functions is not well understood. Here, we record the responses to fluctuating current injections of GCs of different ages to study how they encode stimuli. Immature GCs produce unreliable responses compared to mature GCs, exhibiting imprecise spike timings across repeated stimulation. We use a statistical model to describe the stimulus-response transformation performed by GCs of different ages. We fit this model to the data and obtain parameters that capture GCs encoding properties. Parameter values from this fit reflect the maturational differences of the population and indicate that immature GCs perform a differential encoding of stimuli. To study how this age heterogeneity influences encoding by a population, we perform stimulus decoding using populations that contain GCs of different ages. We find that, despite their individual unreliability, immature GCs enhance the fidelity of the signal encoded by the population and improve the discrimination of similar time dependent stimuli. Thus, the observed heterogeneity confers the population with enhanced encoding capabilities.
A human and rhesus macaque interferon-stimulated gene screen reveals ARHGEF3/XPLN as an antiviral gene against hepatitis C virus and other flaviviruses
Authors: G Bamford Connor G , Cortes Elihu-Aranday , Sanchez-Velazquez Ricardo , Mullan Catrina , Kohl Alain , Patel Arvind H. , Wilson Sam J. , McLauchlan John 
Published: May 2022

AbstractNatural hepatitis C virus (HCV) infection is restricted to humans whereas in other primates such as rhesus macaques, the virus is non-permissive. To identify human and rhesus macaque genes that differ or share the ability to inhibit HCV replication, we conducted a medium-throughput screen of lentivirus-expressed host genes that disrupt replication of HCV subgenomic replicon RNA expressing secreted Gaussia luciferase. A combined total of >800 interferon-stimulated genes (ISGs) were screened. Our findings confirmed established anti-HCV ISGs, such as IRF1, PKR and DDX60. Novel species-specific inhibitors were also identified and independently validated. Using a cell-based system that recapitulates productive HCV infection, we identified the ‘Rho Guanine Nucleotide Exchange Factor 3’ gene (ARHGEF3) from both species as a restriction factor for full-length virus replication. Mechanistically, ARHGEF3-mediated inhibition was ablated by mutating a critical GEF active site residue and deleting the N-terminal portion of the protein. Additionally, replication of two mosquito-borne flaviviruses, yellow fever virus (YFV) and Zika virus (ZIKV), were reduced in ARHGEF3-expressing cell lines compared to controls. In conclusion, we ascribe novel antiviral activity to the cellular gene ARHGEF3 that inhibits replication of HCV and other important human viral pathogens belonging to the Flaviviridae, and is conserved between humans and rhesus macaques.