bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery of E6AP AZUL binding to UBQLN1/2 in cells, phase-separated droplets, and an AlphaFold-NMR integrated structure
Authors: Buel Gwen R. , Chen Xiang , Myint Wazo , Kayode Olumide , Folimonova Varvara , Cruz Anthony , Skorupka Katarzyna A , Matsuo Hiroshi , Walters Kylie J. 
Published: October 2022

AbstractThe E3 ligase E6AP/UBE3A has a dedicated binding site in the 26S proteasome provided by the RAZUL domain of substrate receptor hRpn10/S5a/PSMD4. Guided by RAZUL sequence similarity, we test and demonstrate here that the E6AP AZUL binds transiently to the UBA of proteasomal shuttle factor UBQLN1/2. Despite a weak binding affinity, E6AP AZUL is recruited to UBQLN2 phase-separated droplets and E6AP interacts with UBQLN1/2 in cells. Steady-state and transfer NOE experiments indicate direct interaction of AZUL with the UBQLN1 UBA domain. Intermolecular contacts identified by NOESY data were combined with AlphaFold2-Multimer predictions to yield an AZUL:UBA model structure. We also identify a concentration-dependent oligomerization domain directly adjacent to UBQLN1/2 UBA (UBA-adjacent, UBAA) that is α-helical and allosterically reconfigured by AZUL binding to UBA. These data lead to a model of E6AP recruitment to UBQLN1/2 by AZUL:UBA interaction and provide fundamental information on binding requirements for interactions in droplets and cells.
Detecting and dissecting signaling crosstalk via the multilayer network integration of signaling and regulatory interactions
Authors: Halu Arda , Baek Seung Han , Lo Ian , Martini Leonardo , Silverman Edwin K. , Weiss Scott T. , Glass Kimberly R. 
Published: October 2022

AbstractThe versatility of cellular response arises from the communication, or crosstalk, of signaling pathways in a complex network of signaling and transcriptional regulatory interactions. Understanding the various mechanisms underlying crosstalk on a global scale requires untargeted computational approaches. We present a network-based statistical approach, MuXTalk, that uses high-dimensional edges called multilinks to model the unique ways in which signaling and regulatory interactions can interface. We demonstrate that the signaling-regulatory interface is located primarily in the intermediary region between signaling pathways where crosstalk occurs, and that multilinks can differentiate between distinct signaling-transcriptional mechanisms. Using statistically over-represented multilinks as proxies of crosstalk, we predict crosstalk among 60 signaling pathways, expanding currently available crosstalk databases by more than five-fold. MuXTalk surpasses existing methods in terms of prediction performance, identifies additions to manual curation efforts, and pinpoints potential mediators of crosstalk for each prediction. Moreover, it accommodates the inherent context-dependence of crosstalk, allowing future applications to cell type- and disease-specific crosstalk.
Targeting Fusobacterium nucleatum through Chemical Modifications of Host-Derived Transfer RNA Fragments
Authors: Yang Mengdi , Dong Pu-Ting , Cen Lujia , Shi Wenyuan , He Xuesong , Li Jiahe 
Published: October 2022

ABSTRACTHost mucosal barriers possess an arsenal of defense molecules to maintain mucosal health. In addition to well-established defense molecules such as antimicrobial peptides and immunoglobulins, a subset of extracellular host-derived small RNAs (sRNAs) also exhibits antimicrobial functions in a cross-kingdom fashion. We recently uncovered the sRNA-mediated crosstalk between human normal oral keratinocytes and Fusobacterium nucleatum (Fn), an opportunistic oral pathobiont with increasing implications in extra-oral diseases. Notably, when challenged with Fn, oral keratinocytes released Fn-targeting tRNA-derived sRNAs (tsRNAs), an emerging class of noncoding sRNAs with diverse functions in gene regulation. Additionally, synthetic mimics of the Fn-targeting tsRNAs exhibited highly selective antimicrobial activity against Fn. However, excess synthetic tsRNAs (in the micromolar range) were required to achieve growth inhibition, which limits their potential as antimicrobials. Here, we chemically modify nucleotides of the anti-Fn tsRNAs, termed MOD-tsRNAs, and demonstrate their species- and sequence-specific inhibition in the nanomolar range in various Fn type strains and clinical tumor isolates. In contrast, the same MOD-tsRNAs do not inhibit two representative oral bacteria, Porphoromonas gingivalis (Pg) and Streptococcus mitis (Sm). Additionally, MOD-tsRNAs are internalized by different Fn strains while exhibiting minimal uptake by Pg and Sm. Further RNA sequencing and affinity pull-down assays implicate MOD-tsRNAs as potential ribosome-targeting antimicrobials against Fn. Taken together, our work provides a framework to target opportunistic pathobionts through co-opting host-derived extracellular tsRNAs, whose potential applications may have been limited by their intrinsic instability as well as our limited understanding of the inhibition mechanism.
Attentional inhibition ability predicts neural representation during challenging auditory streaming
Authors: Belo Joan , Clerc Maureen , Schön Daniele 
Published: October 2022

AbstractFocusing on a single source within a complex auditory scene is challenging. M/EEG-based auditory attention detection allows to detect which stream, within a set of multiple concurrent streams, an individual is attending to. The high inter-individual variability in the AAD performance is most often attributed to physiological factors and signal to noise ratio of neural data. Here we address the hypothesis that cognitive factors and in particular sustained attention, WM and attentional inhibition, may also partly explain the variability in AAD performance, because they support the cognitive processes required when listening to complex auditory scenes. Here, we chose a particularly challenging auditory scene, by presenting dichotically polyphonic classical piano excerpts lasting one minute each. Two different excerpts were presented simultaneously in each ear. Forty-one participants, with different degrees of musical expertise, listened to these complex auditory scenes focussing on one ear while we recorded the EEG. Participants also completed several tasks assessing executive functions. As expected, attended stimuli were better decoded than unattended stimuli. Importantly, attentional inhibition ability did explain around 10% of the reconstruction accuracy and around 8% of the classification accuracy. No other cognitive function was a significant predictor of reconstruction or of classification accuracies. No clear effect of musical expertise was found on reconstruction and classification performances. In conclusion, cognitive factors seem to impact the robustness of the auditory representation and hence the performance of neural based decoding approaches. Taking advantage of this relation could be useful to improve next-generation hearing aids.
Butyrate decreases Campylobacter jejuni motility and attachment partially through influence on LysR expression
Authors: Gunther Nereus W. , Nunez Alberto , Bagi Lori , Abdul-Wakeel Aisha , Ream Amy , Liu Yanhong , Uhlich Gaylen 
Published: October 2022

AbstractThe food pathogen Campylobacter jejuni both colonizes the lower intestines of poultry and infects the lower intestines of humans. The lower intestines of both poultry and humans are also home to a wide range of commensal organisms which compete with an organism like C. jejuni for space and resources. The commensal organisms are believed to protect humans against infection by pathogens of the digestive tract like C. jejuni. The short chain fatty acid (SCFA) butyrate is a metabolite commonly produced by commensal organisms within both the poultry and human digestive tract. We investigated the affect that physiologically relevant concentrations of butyrate have on C. jejnui. Butyrate at concentrations of 5 and 20 mM negatively impacted C. jejuni motility and attachment. These two traits are believed important for C. jejuni’s ability to infect the lower intestines of humans. Additionally, 20 mM butyrate concentrations were observed to influence the expression of a range of different Campylobacter proteins. Constitutive expression of one of these proteins, LysR, within a C. jejuni strain partially lessened the negative influence butyrate had on the bacteria’s motility.ImportanceResearch studies on the short chain fatty acid, butyrate, have produced evidence for it both negatively and positively impacting Campylobacter jejuni’s colonization of poultry or infection of the human intestinal tract. There is significant value in clarifying if butyrate has potential as an intervention agent capable of interfering in the virulence process of C. jejuni. The results presented, show that butyrate, at physiological levels, negatively impacts C. jejuni motility and attachment, two important factors in the virulence process. Additionally, a proteomic analysis of butyrate’s influence on C. jejuni, identified that the expression of the transcriptional factor, LysR, was repressed in the presence of butyrate. Overexpression of the lysR gene restored some motility in the presence of butyrate suggesting this factor had a positive influence on the flagella necessary for C. jejuni’s movement.
Biomass generation and heterologous isoprenoid milking from engineered microalgae grown in anaerobic membrane bioreactor effluent
Authors: de Freitas Bárbara Bastos , Overmans Sebastian , Medina Julie Sanchez , Hong Pei-Ying , Lauersen Kyle J. 
Published: October 2022

1.AbstractWastewater (WW) treatment in anaerobic membrane bioreactors (AnMBR) is considered more sustainable than in their aerobic counterparts. However, outputs from AnMBR are mixed methane and carbon dioxide gas streams as well as ammonium- (N) and phosphate- (P) containing waters. Using AnMBR outputs as inputs for photoautotrophic algal cultivation can strip the CO2 and remove N and P from effluent which feed algal biomass generation. Recent advances in algal engineering have generated strains for concomitant high-value side product generation in addition to biomass, although only shown in heavily domesticated, lab-adapted strains. Here, investigated whether such a strain of Chlamydomonas reinhardtii could be grown directly in AnMBR effluent with CO2 at concentrations found in its off-gas. The domesticated strain was found to proliferate over bacteria in the non-sterile effluent, consume N and P to levels that meet general discharge or reuse limits, and tolerate cultivation in modelled (extreme) outdoor environmental conditions prevalent along the central Red Sea coast. High-value co-product milking was then demonstrated, up to 837 μg L−1 culture in 96 h, in addition to algal biomass production, ∼2.4 g CDW L−1 in 96 h, directly in effluents. This is the first demonstration of a combined bio-process that employs a heavily engineered algal strain to enhance the product generation potentials from AnMBR effluent treatment. This study shows it is possible to convert waste into value through use of engineered algae while also improve wastewater treatment economics through co-product generation.Abstract Figure
Molecular view of ER membrane remodeling by the Sec61/TRAP translocon
Authors: Karki Sudeep , Javanainen Matti , Tranter Dale , Rehan Shahid , Huiskonen Juha T. , Happonen Lotta , Paavilainen Ville O. 
Published: October 2022

AbstractProtein translocation across the endoplasmic reticulum (ER) membrane is an essential initial step in protein entry into the secretory pathway. The conserved Sec61 protein translocon facilitates polypeptide translocation and coordinates cotranslational polypeptide processing events. In cells, the majority of Sec61 is stably associated with a heterotetrameric membrane protein complex, the translocon associated protein complex (TRAP), yet the mechanism by which TRAP assists in polypeptide translocation or cotranslational modifications such as N-glycosylation remains unknown. Here, we demonstrate the structure of the core Sec61/TRAP complex bound to a mammalian ribosome by Cryo-EM. The interactions with ribosome anchor the Sec61/TRAP complex in a conformation that renders the ER membrane locally thinner by significantly curving its the lumenal leaflet. We propose a model for how TRAP stabilizes the ribosome exit tunnel to assist nascent polypeptide insertion through Sec61 and provides a ratcheting mechanism into the ER lumen by direct polypeptide interactions.
Interpretable brain decoding from sensations to cognition to action: graph neural networks reveal the representational hierarchy of human cognition
Authors: Zhang Yu , Fan Lingzhong , Jiang Tianzi , Dagher Alain , Bellec Pierre 
Published: October 2022

AbstractInter-subject modeling of cognitive processes has been a challenging task due to large individual variability in brain structure and function. Graph neural networks (GNNs) provide a potential way to project subject-specific neural responses onto a common representational space by effectively combining local and distributed brain activity through connectome-based constraints. Here we provide in-depth interpretations of biologically-constrained GNNs (BGNNs) that reach state-of-the-art performance in several decoding tasks and reveal inter-subject aligned neural representations underpinning cognitive processes. Specifically, the model not only segregates brain responses at different stages of cognitive tasks, e.g. motor preparation and motor execution, but also uncovers functional gradients in neural representations, e.g. a gradual progression of visual working memory (VWM) from sensory processing to cognitive control and towards behavioral abstraction. Moreover, the multilevel representations of VWM exhibit better inter-subject alignment in brain responses, higher decoding of cognitive states, and strong phenotypic and genetic correlations with individual behavioral performance. Our work demonstrates that biologically constrained deep-learning models have the potential towards both cognitive and biological fidelity in cognitive modeling, and open new avenues to interpretable functional gradients of brain cognition in a wide range of cognitive neuroscience questions.HighlightsBGNN improves inter-subject alignment in task-evoked responses and promotes brain decodingBGNN captures functional gradients of brain cognition, transforming from sensory processing to cognition to representational abstraction.BGNNs with diffusion or functional connectome constraints better predict human behaviors compared to other graph architecturesGraphic AbstractMultilevel representational learning of cognitive processes using BGNN
Neural representations of the content and production of human vocalization
Authors: Voigtlaender Vera A. , Sandhaeger Florian , Hawellek David J. , Hage Steffen R. , Siegel Markus 
Published: October 2022

AbstractSpeech, as the spoken form of language, is fundamental for human communication. The phenomenon of covert inner speech implies a functional independence of speech content and motor production. However, it remains unclear how a flexible mapping between speech content and production is achieved on the neural level. To address this, we recorded magnetoencephalography (MEG) in humans performing a rule-based vocalization task. On each trial, vocalization content (one of two vowels) and production form (overt or covert) were instructed independently. Using multivariate pattern analysis, we found robust neural information about vocalization content and production, mostly originating from speech areas of the left hemisphere. Production signals dynamically transformed upon presentation of the content cue, whereas content signals remained largely stable throughout the trial. In sum, our results show dissociable neural representations of vocalization content and production in the human brain and provide new insights into the neural dynamics underlying human vocalization.
Transcriptionally active nitrogen fixation and biosynthesis of diverse secondary metabolites by Dolichospermum and Aphanizominom-like Cyanobacteria in western Lake Erie Microcystis blooms
Authors: Yancey Colleen E. , Mathiesen Olivia , Dick Gregory J. 
Published: October 2022

AbstractCyanobacterial harmful algal blooms (cyanoHABs) in the western basin of Lake Erie are dominated by microcystin producing Microcystis spp., but other cyanobacterial taxa that coexist in these communities may play important roles in production of toxins and shaping bloom dynamics and community function. In this study, we used metagenomic and metatranscriptomic data from the 2014 western Lake Erie cyanoHAB to explore the genetic diversity and biosynthetic potential of cyanobacteria belonging to the Anabaena, Dolichospermum, Aphanizomenon (ADA) clade. We reconstructed two near-complete metagenome-assembled genomes from two distinct ADA clade species, each containing biosynthetic gene clusters that encode novel and known secondary metabolites that were transcriptionally active. These taxa also appear to have varying nutrient acquisition strategies, and their ability to fix N may be important for synthesizing N rich metabolites as well as supporting bloom persistence. Although not the dominant organism in this system, these results suggest that ADA may be important community members in western Lake Erie cyanoHABs that have the potential to produce unmonitored toxins.HighlightsThrough metagenomic approaches, we generated two near-complete metagenome assembled genomes from two distinct species that are dispersed across the ADA clade of cyanobacteria.These ADA cyanobacteria have the potential to produce a variety of known and novel secondary metabolites, and use different nitrogen fixation strategies as observed through differential transcript abundanceThis works highlights the diversity of cyanobacteria in western Lake Erie blooms despite their continued dominance by Microcystis, and that these less abundant cyanobacteria may produce unmonitored toxins and shape bloom dynamics through N-fixation.
Posttranscriptional regulation of cell wall integrity in budding yeast
Authors: Bresson Stefan , Shchepachev Vadim , Tollervey David 
Published: October 2022

ABSTRACTThe fungal cell wall provides protection and structure, and is an important target for antifungal compounds. A MAP kinase cascade termed the cell wall integrity (CWI) pathway regulates transcriptional responses to cell wall damage. Here we describe a posttranscriptional pathway that plays an important complementary role. We discovered that the RNA-binding proteins (RBPs) Mrn1 and Nab6 specifically target the 3’ UTRs of a largely overlapping set of cell wall-related mRNAs. These mRNAs are downregulated in the absence of Nab6, indicating a function in target mRNA stabilization. Nab6 acts in parallel to CWI signaling to maintain appropriate expression of cell wall genes during stress. Cells lacking both pathways are hypersensitive to antifungal compounds targeting the cell wall. Deletion of MRN1 partially alleviates growth defects associated with Δnab6 and Mrn1 has an opposing function in mRNA destabilization. Our results uncover a novel posttranscriptional pathway which mediates cellular resistance to antifungal compounds.
Telomere Position Effect Over Long Distance acts as a genome-wide epigenetic regulator through a commoncis- element
Authors: Chevalier Raphaël , Pienkwoski Victor Murcia , Jullien Nicolas , Caron Leslie , Magdinier Frédérique , Robin Jérôme D. 
Published: October 2022

AbstractAmong epigenetic modifiers, telomeres, represent attractive modulators of the genome in part through position effects. Telomere Position Effect – Over Long Distances (TPE-OLD) modulates genes expression by changes in telomere-dependent long-distance loops, with a reach of 10Mb from a telomere. However, TPE-OLD remains poorly defined. To gain further insights into the genome-wide impact of telomere length on genomic and epigenomic regulation through TPE-OLD, we used cells with controlled telomere length combined to a genome wide transcriptome and methylome analysis. By integrating omics data, we identified a commoncis-acting motif that behaves as an insulator or enhancer. Using reporter assays integrating this element, we uncovered thetranspartners regulating this activity. Further exploiting our cellular model, we observed the depletion of one candidate factor, RBPJ, at TPE-OLD associated loci upon telomere shortening. We concluded that, at the genome-wide level, TPE-OLD is relayed by RBPJ binding Alu-like elements to telomeres that acts as enhancers. In response to external stimuli (i.e., Aging), TPE-OLD might act by coordinating telomere length to the action of Alu newly evolved enhancers in association with RBPJ.
Estrogens dynamically regulate neurogenesis in the dentate gyrus of adult female rats
Authors: Yagi Shunya , Wen Yanhua , Burrowes Ariel A Batallán , Blankers Samantha A , Galea Liisa AM 
Published: October 2022

AbstractEstrone and estradiol differentially modulate neuroplasticity and cognition, but how they influence maturation pathways of new neurons in the adult hippocampus is not known. The present study assessed the effects of estrone and estradiol on various aspects of neurogenesis in the dentate gyrus (DG) of ovariectomized young adult Sprague-Dawley rats using daily subcutaneous injections of 17β-estradiol or estrone. Rats were injected with a DNA synthesis marker, 5-bromo-2-deoxyuridine (BrdU), and were perfused one, two, or three weeks after BrdU injection and treatment. Immunofluorescent labelling for GFAP/Sox2 was used to examine the density of neural stem/progenitor cells and Ki67 for cell proliferation. Double-immunofluorescent labelling of BrdU with doublecortin (DCX) or NeuN was used to examine the attrition and maturation of adult-born neurons over time. Length of time post ovariectomy was associated with a reduction in neural stem/progenitor cells in the DG. Estrogens had effects on different components of neurogenesis after one week of exposure but not after prolonged treatment. Estradiol enhanced, whereas estrone reduced, cell proliferation after one week but not after longer exposure to hormones. Both estrogens increased the density of BrdU/DCX-ir cells after one week of exposure but showed greater attrition of new neurons between one and two weeks after exposure, suggesting that the effects of estrogens on neurogenesis were not sustained. These results demonstrate that estrogens modulate several aspects of adult hippocampal neurogenesis differently in the short term, but may lose their ability to influence neurogenesis after long-term exposure.
“Helicase” Activity Promoted Through Dynamic Interactions Between a ssDNA Translocase and a Diffusing SSB Protein
Authors: Mersch Kacey , Sokoloski Joshua E. , Nguyen Binh , Galletto Roberto , Lohman Timothy M. 
Published: October 2022

AbstractReplication protein A (RPA) is a eukaryotic single stranded (ss) DNA binding (SSB) protein that is essential for all aspects of genome maintenance. RPA binds ssDNA with high affinity but can also diffuse along ssDNA. By itself, RPA is capable of transiently disrupting short regions of duplex DNA by diffusing from a ssDNA that flanks the duplex DNA. Using single molecule total internal reflection fluorescence and optical trapping combined with fluorescence approaches we show that S. cerevisiae Pif1 can use its ATP-dependent 5’ to 3’ translocase activity to chemo-mechanically push a single human RPA (hRPA) directionally along ssDNA at rates comparable to those of Pif1 translocation alone. We further show that using its translocation activity Pif1 can push hRPA from a ssDNA loading site into a duplex DNA causing stable disruption of at least 9 bp of duplex DNA. These results highlight the dynamic nature of hRPA enabling it to be readily reorganized even when bound tightly to ssDNA and demonstrate a new mechanism by which directional DNA unwinding can be achieved through the combined action of a ssDNA translocase that pushes an SSB protein.