bluuebunny/crossref_metadata_2025_split huggingface dataset:
Right Anterior Theta Connectivity Predicts Autistic Social Traits in Neurotypical Children
Authors: Hill Aron T. , Van Der Elst Jodie , Bigelow Felicity J. , Lum Jarrad A. G. , Enticott Peter G. 
Published: March 2022

AbstractGrowing evidence supports functional network alterations in autism spectrum disorder, however much less is known about the neural mechanisms underlying autistic traits in typically developing children. Using resting-state electroencephalographic (EEG) recordings, we examined whether functional connectivity could predict autistic trait expression in 127 children aged between 4-12 years. Regression models showed that right anterior theta connectivity was a significant predictor of autistic traits (p = 0.013), with increased connectivity in this region associated with greater autistic trait expression. These results corroborate similar recent findings in adults, extending this observation to a cohort of children spanning early-to-middle childhood. These findings further highlight EEG-derived functional connectivity as a sensitive physiological correlate of autistic trait expression in neurotypical children.
Costimulation of TLR8 responses by CXCL4 in Human Monocytes Mediated by TBK1-IRF5 Signaling and Epigenomic Remodeling
Authors: Yang Chao , Bachu Mahesh , Du Yong , Brauner Caroline , Yuan Ruoxi , Ah Kioon Marie Dominique , Chesi Giancarlo , Barrat Franck J. , Ivashkiv Lionel B. 
Published: March 2022

AbstractRegulation of endosomal TLR responses by the chemokine CXCL4 is implicated in inflammatory and fibrotic diseases. The current paradigm is that CXCL4 potentiates TLR responses by binding and facilitating endosomal delivery of nucleic acid TLR ligands. We report that in human monocytes/macrophages, CXCL4 initiates signaling cascades and downstream epigenomic reprogramming that change the profile of the TLR8 response by selectively and dramatically amplifying inflammatory gene transcription and IL-1β production, while partially attenuating the IFN response. Mechanistically, costimulation by CXCL4 and TLR8 synergistically activated TBK1/IKKε and repurposed these kinases towards an inflammatory response via coupling with IRF5, and by activating the NLRP3 inflammasome without the need for an exogenous activator of a second signal for IL-1β maturation. CXCL4 signaling strongly induced chromatin remodeling and de novo enhancers associated with inflammatory genes in a cooperative and synergistic manner with TLR8. These findings identify new mechanisms of regulation of TLR responses relevant for cytokine storm, and suggest targeting the TBK1/IKKε-IRF5 axis may be beneficial in inflammatory diseases.
Post-activation depression produces extensor H-reflex suppression following flexor afferent conditioning
Authors: Metz K. , Concha-Matos I. , Hari K. , Bseis O. , Afsharipour B. , Lin S. , Li Y. , Singla R. , Fenrich K , Bennett DJ. , Gorassini MA. 
Published: March 2022

AbstractSuppression of the extensor H-reflex by flexor afferent conditioning is thought to be produced by a long-lasting inhibition of extensor Ia-afferent terminals via primary afferent depolarization (PAD) activated by GABAAreceptors. Considering the recent finding that PAD does not produce presynaptic inhibition of Ia-afferent terminals, we examined if H-reflex suppression is instead mediated by post-activation depression of the test extensor Ia-afferents triggered by PAD-evoked spikes and/or by a long-lasting inhibition of the extensor motoneurons. A brief conditioning vibration of the flexor tendon suppressed both the extensor soleus H-reflex and the tonic discharge of soleus motor units for 300 ms, indicating that part of the H-reflex suppression was mediated by a long-lasting inhibition of the extensor motoneurons. When activating the flexor afferents electrically to produce conditioning, the soleus H-reflex was also suppressed for 300 ms, but only when a short-latency reflex was evoked in the soleus muscle by the conditioning input itself. In mice, a similar short-latency reflex was evoked when optogenetic or afferent activation of GABAergic (GAD2+) neurons produced PAD large enough to evoke orthodromic spikes in the test Ia-afferents, causing post-activation depression of subsequent monosynaptic excitatory-post-synaptic potentials. The time course of this post-activation depression and related H-reflex suppression (lasting 2 s) was like rate-dependent depression that is also due to post-activation depression. We conclude that extensor H-reflex inhibition by brief flexor afferent conditioning is produced by both post-activation depression of extensor Ia-afferents and long-lasting inhibition of extensor motoneurons, rather than from PAD directly inhibiting Ia afferent terminals.
Slc9a6 mutation causes Purkinje cell loss and ataxia in the shaker rat
Authors: Figueroa Karla , Anderson Collin J. , Paul Sharan , Dansithong Warunee , Gandelman Mandi , Scoles Daniel R. , Pulst Stefan M. 
Published: March 2022

AbstractBackgroundThe shaker rat carries a naturally occurring mutation leading to progressive ataxia characterized by Purkinje cell (PC) loss. We previously reported on fine-mapping the shaker locus to the long arm of the rat X chromosome. In this work, we sought to identify the mutated gene underlying the shaker phenotype and confirm its identity by functional complementation.MethodsWe fine-mapped the candidate region and analyzed cerebellar transcriptomes to identify deleterious variants. We generated an adeno-associated virus (AAV) targeting solute carrier family 9, member A6 (Slc9a6) expression to PCs using a mouse L7-6 (L7) promoter, as well as a control green fluorescent protein (GFP)-expressing virus. We administered AAVs prior to the onset of PC degeneration through intracerebroventricular injection and evaluated the molecular, cellular, and motor phenotypes.ResultsWe identified a XM_217630.9 (Slc9a6):c.[191_195delinsA] variant in the Slc9a6 gene that segregated with disease. This mutation is predicted to generate a truncated sodium-hydrogen exchanger 6 (NHE6) protein, p.(Ala64Glufs*23). Administration of AAV9-PHP.eB expressing rat Slc9a6 prior to symptom onset reduced the shaker motor, molecular, and cellular phenotypes.InterpretationSlc9a6 is mutated in shaker and also in human Christianson syndrome, an epileptic encephalopathy. AAV-based gene therapy may be a viable therapeutic strategy for Christianson syndrome, and the shaker rat model may aid in therapeutic development.
Mutated Tumor Suppressors Follow Oncogenes Profile by the Gene Hypermethylation of Partners in the Protein Interaction Networks
Authors: Tagore Somnath , Frenkel-Morgenstern Milana 
Published: March 2022

SummaryAs a result of current advances in the analysis of patient sequencing data, many tumors have been characterized in a personalized manner. Such data can also be used to characterize genes that act as either oncogenes or tumor suppressors. These include “defective” tumor suppressor genes which may function as driver oncogenes that play a key role in cancer proliferation due to various genetic alterations, specifically, chromosomal translocations. In this study, we considered protein networks, mutations, methylation data and cancer fusions to classify tumor suppressors that may convert into oncogenes. Moreover, we developed a novel network-based parameter called the ‘preferential attachment score’ to categorize genes as oncogenes and/or tumor suppressors. Such classification was achieved using a naïve Bayes computation approach. We used an ABC-MCMC method for selecting features for training our classification algorithm. We then performed a survey of tumor suppressors and oncogenes from the perspective of somatic mutations and network properties for 691 TCGA cases. For comparative purposes, we chose currently well-established methods, such as MutSigCV, OncodriveCLUST, Oncodrive-FM, 20/20+, ActiveDriver, MuSiC, TUSON, OncodriveFML, and found that our algorithm outperformed these other tolls, with 93.3% efficiency. Based on 691 TCGA cohorts, we found that tumor suppressors presented the highest mutation frequency in most tumor types, relative to oncogenes. Using protein-protein interaction data, we found that essential proteins, tumor suppressors and oncogenes had higher degrees of connectivity and betweenness centrality, relative to normal proteins. Similarly, tumor suppressors and oncogenes had lower clustering coefficients, as well as shortest path distances (FDR < 0.05). Finally, most mutated tumor suppressors integrate hyper-methylated partners in the protein interaction networks of 3091 fusions, following the patterns of oncogenes (43%). Thus, these results further characterize cancer oncogenes and tumor suppressors in the context of deep analysis of cancer network alterations.AvailabilitySource scripts are available at https://github.com/somnathtagore/NBC and the resource is available at http://ontum.md.biu.ac.il/index.html
Xanthomonas infection transforms the apoplast into an accessible and habitable niche for Salmonella enterica
Authors: Dixon Megan H. , Cowles Kimberly N. , Zaacks Sonia C. , Marciniak Isabel N. , Barak Jeri D. 
Published: March 2022

ABSTRACTThe physiology of plant hosts can be dramatically altered by phytopathogens. Xanthomonas hortorum pv. gardneri is one such pathogen that creates an aqueous niche within the leaf apoplast by manipulating the plant via the transcription activator-like effector AvrHah1. Simultaneous immigration of X. gardneri and Salmonella enterica to healthy tomato leaves results in increased survival of S. enterica as Xanthomonas infection progresses. However, the fate of S. enterica following arrival on actively infected leaves has not been examined. We hypothesized that the water-soaking caused by X. gardneri could facilitate the ingression of S. enterica into the apoplast, and that this environment would be conducive for growth. We found that a water-soaked apoplast, abiotically or Xanthomonas-infected, enabled surface S. enterica to passively localize to the protective apoplast and facilitated migration of S. enterica to distal sites within the aqueous apoplast. AvrHah1 contributed to the protection and migration of S. enterica early in X. gardneri infection. Xanthomonas-infected apoplasts facilitated prolonged survival and promoted S. enterica replication compared to healthy apoplasts. Access to an aqueous apoplast in general protects S. enterica from immediate exposure to irradiation whereas, the altered environment created by Xanthomonas infection provides growth-conducive conditions for S. enterica. Overall, we have characterized an ecological relationship in which host infection converts an unreachable niche to a habitable environment.ImportanceBacterial spot disease caused by Xanthomonas species devastates tomato production worldwide. Salmonellosis outbreaks from consumption of raw produce have been linked to the arrival of Salmonella enterica on crop plants in the field via contaminated irrigation water. Considering that Xanthomonas is difficult to eradicate, it is highly likely that S. enterica arrives on leaves pre-colonized by Xanthomonas with infection underway. Our study demonstrates that infection and disease fundamentally alter the leaf, resulting in redistribution and change in abundance of a phyllosphere bacterial member. These findings contribute to our understanding of how S. enterica manages to persist on leaf tissue despite lacking the ability to liberate nutrients from plant cells. More broadly, this study reveals a mechanism by which physiochemical changes to a host environment imposed by a plant pathogen can convert an uninhabitable leaf environment into a hospitable niche for select epiphytic microbes.
An atypical ABC transporter is involved in antifungal resistance and host interactions in the pathogenic fungus Cryptococcus neoformans
Authors: Winski Christopher J. , Qian Yuanyuan , Mobashery Shahriar , Santiago-Tirado Felipe H. 
Published: March 2022

ABSTRACTATP-binding cassette (ABC) transporters represent one of the largest protein superfamilies. Functionally diverse, ABC transporters have been implicated in many aspects of microbial physiology. The genome of the human fungal pathogen Cryptococcus neoformans encodes 54 putative ABC transporters and the majority of them remain uncharacterized. In a previous genetic screen for fungal regulators of phagocytosis, we identified an uncharacterized gene, CNAG_06909, that modulates host interactions. This gene encodes a half-size ABC transporter of the PDR-type, and phenotypic studies of a strain with this gene deleted revealed an altered antifungal susceptibility profile, including hypersensitivity to fluconazole (FLC). This gene, which we have named PDR6, localizes to the endoplasmic reticulum (ER) and plasma membrane (PM), and when absent, less ergosterol is observed in the PM. Additionally, we observed that the pdr6Δ strain displays a reduction in secreted polysaccharide capsular material. These changes to the cellular surface may explain the observed increased uptake by macrophages and the reduced intracellular survival. Finally, studies in mice demonstrate that Pdr6 function is required for normal progression of cryptococcal infection. Taken together, this study demonstrates a novel dual role for PDR transporters in C. neoformans, which could represent a potential target for antifungal therapeutics. Furthermore, the atypical half-size transporter encoded by PDR6 is conserved in many fungal pathogens, but absent in model non-pathogenic fungi. Hence, this study provides for the first time, a function for this unique group of fungal half-size PDR transporters that, although conserved, remain largely understudied.IMPORTANCEConserved across all kingdoms of life, ABC transporters comprise one of the largest protein families. They are associated with multidrug resistance, affecting aspects such as resistance to antimicrobials or anti-cancer drugs. Despite their importance, they are understudied in fungal pathogens. In the environmental fungus Cryptococcus neoformans, a leading cause of fungal infections, only a few ABC transporters have been studied. Here we characterize an atypical, half-size, ABC transporter of the PDR-type, that affects both antifungal resistance and host-pathogen interactions. PDR-type transporters are only present in fungi and plants, and this subgroup of half-size transporters is conserved in fungal pathogens, yet their function was completely unknown. Because the current treatments for cryptococcal infection are suboptimal, understanding the mechanisms of antifungal resistance and the host interactions that drive the infection is critical to improve the management of this disease. Here we provide insights into these important aspects of cryptococcal pathogenesis.
Nectar compounds impact bacterial and fungal growth and shift community dynamics in a nectar analog
Authors: Mueller Tobias G. , Francis Jacob S. , Vannette Rachel L. 
Published: March 2022

AbstractFloral nectar is frequently colonized by fungi and bacteria. However, within individual flowers, nectar microbial communities are typically species-poor and dominated by few cosmopolitan genera. One hypothesis is that nectar constituents may act as a strong environmental filter. Non-sugar constituents in nectar could affect species composition via broad antimicrobial activity or differential effects on nectar microbial species. Here, we tested how five non-sugar nectar compounds as well as elevated sugar impacted the growth of 12 fungal and bacterial species isolated from flowers, pollinators, and the environment. We hypothesized that microbes isolated from nectar would be better able to grow in the presence of these compounds. Additionally, to test if nectar compounds could affect the outcome of competition among microbial taxa, we grew a subset of microbes in co-culture assays across a subset of treatments.We found that some compounds such as H2O2broadly suppressed microbial growth across many but not all microbes tested. Other tested compounds were more specialized in the microbes they impacted. As hypothesized, the nectar specialistMetschnikowia reukaufiiwas unaffected by most nectar compounds assayed. However, many non-nectar specialist microbes remained unaffected by compounds thought to reduce microbial growth in nectar. Our results show that nectar chemistry can influence nectar microbial communities but that microbe-specific responses to nectar compounds are common. Nectar chemistry also affected the outcome of species interactions among microbial taxa, suggesting that non-sugar compounds in nectar can affect microbial community assembly and abundance in flowers.
Base editing screens map mutations affecting IFNγ signalling in cancer
Authors: Coelho Matthew A. , Karakoc Emre , Bhosle Shriram , Gonçalves Emanuel , Burgold Thomas , Cooper Sarah , Cattaneo Chiara M. , Veninga Vivien , Consonni Sarah , Dinçer Cansu , Vieira Sara F. , Gibson Freddy , Barthorpe Syd , Hardy Claire , Rein Joel , Thomas Mark , Voest Emile , Bassett Andrew , Garnett Mathew J. 
Published: March 2022

AbstractIFNγsignalling underpins host responses to infection, inflammation and anti-tumour immunity. Mutations in the IFNγsignalling pathway cause immunological disorders, haematological malignancies, and resistance to immune checkpoint blockade (ICB) in cancer, however the function of most clinically observed variants remain unknown. Here, we systematically investigate the genetic determinants of IFNγresponse in colorectal cancer cells using CRISPR-Cas9 screens and base editing mutagenesis. Deep mutagenesis of JAK1 with cytidine and adenine base editors, combined with pathway-wide screens, reveal loss-of-function and gain-of-function mutations with clinical precedence, including causal variants in haematological malignancies and mutations detected in patients refractory to ICB. We functionally validate variants of uncertain significance in primary tumour organoids, where engineering missense mutations in JAK1 enhanced or reduced sensitivity to autologous tumour-reactive T cells. By classifying > 300 missense variants altering IFNγ pathway activity, we demonstrate the utility of base editing for mutagenesis at scale, and generate a resource to inform genetic diagnosis.
The human placenta shapes the phenotype of decidual macrophages
Authors: Vondra Sigrid , Höbler Anna-Lena , Lackner Andreas Ian , Raffetseder Johanna , Mihalic Zala Nikita , Vogel Andrea , Saleh Leila , Kunihs Victoria , Haslinger Peter , Wahrmann Markus , Husslein Heinrich , Oberle Raimund , Kargl Julia , Haider Sandra , Latos Paulina , Schabbauer Gernot , Knöfler Martin , Ernerudh Jan , Pollheimer Jürgen 
Published: March 2022

AbstractDuring human pregnancy, placenta-derived extravillous trophoblasts (EVT) invade the decidua and communicate with maternal immune cells. The decidua can be distinguished into basalis (decB) and parietalis (decP), the latter being unaffected by placentation. By defining a novel gating strategy, we report accumulation of myeloid cells in decB. We identified a decidua basalis-associated macrophage (decBAM) population with a differential transcriptome and secretome when compared to decidua parietalis-associated macrophages (decPAMs). decBAMs are CD11chiand efficient inducers of Tregs, proliferatein situand secrete high levels of CXCL1, CXCL5, M-CSF, and IL-10. In contrast, decPAMs exert a dendritic cell-like, motile phenotype characterized by induced expression of HLA class II molecules, enhanced phagocytosis, and the ability to activate T cells. Strikingly, EVT-conditioned media are able to convert decPAMs into a decBAM phenotype. Cumulatively, these findings assign distinct macrophage phenotypes to decidual areas depending on placentation and further highlight a critical role for EVTs in the induction of pregnancy-tolerant macrophage polarization.Graphical AbstractHighlightsIn this study, we identified so far unrecognized, placenta-induced immune responses at the maternal-fetal interface. Altogether, we imply that placenta-derived trophoblasts induce a pregnancy-tolerant phenotype by suppressing antigen-presenting cell-like functions in maternal tissue macrophages.
Lifting the ban on nuclear import activates Gdown1-mediated modulation of global transcription and facilitates adaptation to cellular stresses
Authors: Zhu Zhanwu , Liu Jingjing , Feng Huan , Zhang Yanning , Huang Ruiqi , Pan Qiaochu , Nan Jing , Miao Ruidong , Cheng Bo 
Published: March 2022

ABSTRACTDynamic regulation of transcription is crucial for cellular response to various environmental or developmental cues. Gdown1 is a ubiquitously expressed, RNA polymerase II (Pol II) interacting protein, essential for embryonic development. It tightly binds Pol IIin vitroand competitively blocks binding of TFIIF and other transcriptional regulatory factors, yet its cellular functions and regulatory circuits remain unclear. Here, we show that Gdown1 strictly localizes in the cytoplasm of mammalian somatic cells and exhibits potent resistance to the imposed driving force for nuclear localization. Combined with genetic and microscope-based approaches, two types of functionally coupled and evolutionally conserved localization regulatory motifs are identified, including the CRM1-dependent nucleus export signal (NES) and a novel Cytoplasm Anchoring Signal (CAS) which mediates nuclear pore retention. Mutagenesis of CAS alleviates the cytoplasmic retention activity thus unlocks its nucleocytoplasmic shuttling properties, and increased nuclear import of Gdown1 causes drastic reduction of Pol II levels and global transcription. Importantly, nuclear translocation of Gdown1 occurs in a stress-responsive manner and ablation ofGDOWN1significantly weakens cellular tolerance. Collectively, our work uncovers the molecular basis of the localization of Gdown1 and highlights that its controlled nuclear translocation serves as a key strategy in modulating global transcription and stress-adaptation.