bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying nonlinear Functional Connectivity with EEG/MEG using Nonlinear Time-Lagged Multidimensional Pattern Connectivity (nTL-MDPC)
Authors: Rahimi Setareh , Jackson Rebecca , Hauk Olaf 
Published: January 2023

AbstractInvestigating task- and stimulus-dependent connectivity is key to understanding how brain regions interact to perform complex cognitive processes. Most existing connectivity analysis methods reduce activity within brain regions to unidimensional measures, resulting in a loss of information. While recent studies have introduced new functional connectivity methods that exploit multidimensional information, i.e., pattern-to-pattern relationships across regions, they have so far mostly been applied to fMRI data and therefore lack temporal information. We recently developed Time-Lagged Multidimensional Pattern Connectivity for EEG/MEG data, which detects linear dependencies between patterns for pairs of brain regions and latencies in event-related experimental designs (Rahimi et al., 2022b). Due to the linearity of this method, it may miss important nonlinear relationships between activity patterns. Thus, we here introduce nonlinear Time-Lagged Multidimensional Pattern Connectivity (nTL-MDPC) as a novel bivariate functional connectivity metric for event-related EEG/MEG applications. nTL-MDPC describes how well patterns in ROIXat time pointtxcan predict patterns of ROIYat time pointtyusing artificial neural networks (ANNs). We evaluated this method on simulated data as well as on an existing EEG/MEG dataset of semantic word processing, and compared it to its linear counterpart (TL-MDPC). We found that nTL-MDPC indeed detected nonlinear relationships more reliably than TL-MDPC in simulations with moderate to high numbers of trials. However, in real brain data the differences were subtle, with identification of some connections over greater time lags but no change in the connections identified. The simulations and EEG/MEG results demonstrate that differences between the two methods are not dramatic, i.e. the linear method can approximate linear and nonlinear dependencies well.HighlightsnTL-MDPC is a bivariate functional connectivity method for event-related EEG/MEGnTL-MDPC detects linear and nonlinear connectivity at zero and non-zero lagsnTL-MDPC revealed connectivity between ATL hub and semantic control regionsDifferences between linear and nonlinear TL-MDPC were small
Confidence is predicted by pre- and post-choice decision signal dynamics
Authors: Grogan John P. , Rys Wouter , Kelly Simon P. , O’Connell Redmond G. 
Published: January 2023

AbstractIt is well established that one’s confidence in a choice can be influenced by new evidence encountered after commitment has been reached, but the processes through which post-choice evidence is sampled remain unclear. To investigate this, we traced the pre- and post-choice dynamics of electrophysiological signatures of evidence accumulation (Centro-parietal Positivity, CPP) and motor preparation (mu/beta band) to determine their sensitivity to participants’ confidence in their perceptual discriminations. Pre-choice CPP amplitudes scaled with confidence both when confidence was reported simultaneously with choice, or when reported 1-second after the initial direction decision. When additional evidence was presented during the post-choice delay period, the CPP continued to evolve after the initial choice, with a more prolonged build-up on trials with lower confidence in the alternative that was finally endorsed, irrespective of whether this entailed a change-of-mind. Further investigation established that this pattern was accompanied by earlier post-choice CPP peak latency, earlier lateralisation of motor preparation signals toward the ultimately chosen response, and faster confidence reports when participants indicated high certainty that they had made a correct or incorrect initial choice. These observations are consistent with confidence-dependent stopping theories according to which post-choice evidence accumulation ceases when a criterion level of confidence in a choice alternative has been reached. Our findings have implications for current models of choice confidence, and predictions they may make about EEG signatures.
Mental search of concepts is supported by egocentric vector representations and restructured grid maps
Authors: Viganò Simone , Bayramova Rena , Doeller Christian F. , Bottini Roberto 
Published: January 2023

AbstractThe human hippocampal-entorhinal system is known to represent both spatial locations and abstract concepts in memory in the form of allocentric cognitive maps. Using fMRI, we show that the human parietal cortex evokes complementary egocentric-like vector representations in conceptual spaces during goal-directed mental search, akin to those observable during physical navigation to determine where a goal is located relative to oneself. Concurrently, grid-like representations, a neural signature of allocentric cognitive maps in entorhinal, prefrontal, and parietal cortices, are restructured as a function of conceptual goal proximity, akin to rodent grid cells firing around reward locations during spatial exploration. These brain mechanisms might support flexible and parallel readout of where target conceptual information is stored in memory, capitalizing on complementary reference frames.
FLInt: Single Shot Safe Harbor Transgene Integration viaFluorescentLandmarkInterference
Authors: Malaiwong Nawaphat , Porta-de-la-Riva Montserrat , Krieg Michael 
Published: January 2023

AbstractThe stable incorporation of transgenes and recombinant DNA material into the host genome is a bottleneck in many bioengineering applications. Due to the low efficiency, identifying the transgenic animals is often a needle in the haystack. Thus, optimal conditions require efficient screening procedures, but also known and safe landing sites that do not interfere with host expression, low input material and strong expression from the new locus. Here, we leverage an existing library of≈300 different loci coding for fluorescent markers that are distributed over all 6 chromosomes inCaenorhabditis elegansas safe harbors for versatile transgene integration sites using CRISPR/Cas9. We demonstrated that a single crRNA was sufficient for cleavage of the target region and integration of the transgene of interest, which can be easily followed by loss of the fluorescent marker. The same loci can also be used for extrachromosomal landing sites and as co-CRISPR markers without affecting body morphology or animal behavior. Thus, our method overcomes the uncertainty of transgene location during random mutagenesis, facilitates easy screening through fluorescence interference and can be used as co-CRISPR markers without further influence in phenotypes.
Elucidating the combined toxicity of aflatoxin B1 and fumonisin B1 on HepG2 cells based on respirometry and transcriptome analyses
Authors: Chen Xiangrong , Abdallah Mohamed F. , Grootaert Charlotte , Van Nieuwerburgh Filip , Rajkovic Andreja 
Published: January 2023

AbstractAflatoxin B1 (AFB1) and fumonisin B1 (FB1) are two toxic mycotoxins widely found in food contaminants, and known for their hepatotoxicity in human. However, their combined toxicity still needs to be deeply investigated especially for their harmful effect. Therefore, the current work aimed at investigating the (combined) effect of AFB1 and FB1 on mitochondrial and glycolytic activity of HepG2 cell line, a well-recognizedin vitromodel system to study liver cell function. In our previous work, we studied the impact of a short term exposure to different doses of AFB1, FB1, and their binary mixture (MIX) on the bioenergetic status of HepG2 cells. Seahorse respirometry analysis revealed that the co-exposure, especially at high doses (8 µg/mL for AFB1 and 160 µg/mL for FB1), is more toxic as a result of more inhibition of all parameters of mitochondrial respiration. RNA transcriptome sequencing showed that the p53 signaling pathway, which is a major orchestrator of mitochondrial apoptosis, was differentially expressed. Moreover, the co-exposure has significantly downregulated Cx I, Cx II, Cx III, and Cx IV genes, which represent the onset of the suppressed mitochondrial respiration in HepG2 cells. It was found that FB1 is contributed more to the MIX effects than AFB1.⍰Environmental ImplicationAflatoxin B1 (AFB1) and fumonisin B1 (FB1) are two main mycotoxins that frequently (co-)contaminate maize and maize-based ingredients in several parts of the world. Both toxins are well-known for their hepatotoxicity in humans as the liver is their main target organ. However, the combined toxicity of AFB1 and FB1 still needs to be deeply investigated especially for their effect on cellular respiration. In this study, we proved that a binary mixture of AFB1 and FB1 is more toxic on mitochondrial respiration, and disrupted the p53 signaling pathway to induce apoptosis, which promised a novel insight of hazardous materials-induced hepatic damage.
Characterization of 3D organotypic epithelial tissues reveals tonsil-specific differences in tonic interferon signaling
Authors: Jackson Robert , Rajadhyaksha Esha V , Loeffler Reid S , Flores Caitlyn E , Van Doorslaer Koenraad 
Published: January 2023

ABSTRACTThree-dimensional (3D) culturing techniques can recapitulate the stratified nature of multicellular epithelial tissues. Organotypic 3D epithelial tissue culture methods have several applications, including the study of tissue development and function, drug discovery and toxicity testing, host-pathogen interactions, and the development of tissue-engineered constructs for use in regenerative medicine. We grew 3D organotypic epithelial tissues from foreskin, cervix, and tonsil-derived primary cells and characterized the transcriptome of thesein vitrotissue equivalents. Using the same 3D culturing method, all three tissues yielded stratified squamous epithelium, validated histologically using basal and superficial epithelial cell markers. The goal of this study was to use RNA-seq to compare gene expression patterns in these three types of epithelial tissues to gain a better understanding of the molecular mechanisms underlying their function and identify potential therapeutic targets for various diseases. Functional profiling by over-representation and gene set enrichment analysis revealed tissue-specific differences:i.e., cutaneous homeostasis and lipid metabolism in foreskin, extracellular matrix remodeling in cervix, and baseline innate immune differences in tonsil. Specifically, tonsillar epithelia may play an active role in shaping the immune microenvironment of the tonsil balancing inflammation and immune responses in the face of constant exposure to microbial insults. Overall, these data serve as a resource, with gene sets made available for the research community to explore, and as a foundation for understanding the epithelial heterogeneity and how it may impact theirin vitrouse. An online resource is available to investigate these data (https://viz.datascience.arizona.edu/3DEpiEx/).
Hospital and urban wastewaters shape the structure and active resistome of environmental biofilms
Authors: Buelow Elena , Dauga Catherine , Carrion Claire , Mathé-Hubert Hugo , Achaibou Sophia , Gaschet Margaux , Jové Thomas , Chesneau Olivier , Kennedy Sean P. , Ploy Marie-Cecile , Da Re Sandra , Dagot Christophe 
Published: January 2023

AbstractBackgroundDemonstration of the transfer, dynamics, and regulation of antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs) in a complex environmental matrix is yet experimentally challenging, with many essential open questions such as how and where transfer and dissemination of ARGs happens in nature. The extent and conditions of MGEs transfer that carry ARGs is still largely unexplored in natural environments and microbial communities. Biofilms are structures that include high density multi-species bacterial communities embedded in self-produced extracellular polymeric substances (EPS) constituting a matrix that facilitates gene transfer and where bacteria exhibit high tolerance to stress and to antibiotics. In this study we implemented a sampling and analysis approach that allows phenotypic and genomic analyses ofin situand reconstitutedin vitrohospital and urban wastewater (WW) biofilms. To assess the potential of hospital and urban WW biofilms to efficiently disseminate ARGs in the WW system, we explored the EPS within the biofilm matrix and assessed the expression of the resistome (ARGs) and mobilome (MGEs) by metatranscriptomics.ResultsWe first showed that a) the composition of EPS differs depending on their growth environment (in situandin vitro) and their sampling origin (hospital vs urban WW) and that b) a low amount of ciprofloxacin impacted the composition of the EPS. Next, the metatranscriptomic approach showed that a) expression of ARGs and MGEs increase upon adding a low amount of ciprofloxacin for biofilms from hospital WW but not for those from urban WW and b) that expression of specific plasmids that carry individual or multiple ARGs varies depending on the WW origins of the biofilms. When the same plasmids were expressed in both, urban and hospital WW biofilms, they carried and expressed different ARGs.ConclusionWe show that hospital and urban wastewaters shape the structure and active resistome of environmental biofilms, and we confirmed that hospital WW is an important hot spot for the dissemination and selection of AMR. The different responses to antibiotic pressure in hospitalvsurban biofilms, coupled with differences in biofilm structure helps delineate distinct characteristics of hospital and urban WW biofilms highlighting the relationships between the resistome and its expression in environmental biofilms and their surrounding ecosystems.
Comprehensive longitudinal study of home-cage activity, including climbing, reveals new complex phenotypic profile in the N171-82Q HD mouse model with implications for refined preclinical studies
Authors: Bains Rasneer S. , Forrest Hamish , Sillito Rowland R. , Armstrong J. Douglas , Stewart Michelle , Nolan Patrick M. , Wells Sara E. 
Published: January 2023

AbstractMonitoring the activity of mice within their home cage is proving to be a powerful tool for revealing subtle and early-onset phenotypes in mouse models. Video tracking, in particular, lends itself to automated machine-learning technologies that have the potential to improve the manual annotations carried out by humans. This type of recording and analysis is particularly powerful in objective phenotyping, monitoring behaviors with no experimenter intervention. In this study, we focus on non-evoked voluntary behaviors, which do not require any contact with the animal or exposure to specialist equipment. We show that the monitoring of climbing on the wire cage lid of a standard individually ventilated cage (IVC) yields reproducible data reflecting complex phenotypes of individual mouse inbred strains and of a widely used mouse model of neurodegeneration. In addition, performing such measurements in the home-cage environment, over several 24-hour periods, allows for the collection of comprehensive behavioral and activity data, which reveals prolific sexual dimorphism and biphasic changes in locomotor activity. Here we present data from home-cage analysis, which reveals the complexity of unprovoked behavior in both wild-type and mutant mice. This has the potential to greatly enhance the characterization of mouse strains, detect early and subtle signs of disease and increase reproducibility in preclinical studies.
Mycobacterium tuberculosisresides in lysosome-poor monocyte-derived lung cells during chronic infection
Authors: Zheng Weihao , Chang I-Chang , Limberis Jason , Budzik Jonathan M. , Zha B. Shoshana , Howard Zach , Chen Lucas , Ernst Joel D. 
Published: January 2023

ABSTRACTMycobacterium tuberculosis(Mtb) infects cells in multiple lung myeloid cell subsets and causes chronic infection despite innate and adaptive immune responses. However, the mechanisms allowing Mtb to evade elimination are not fully understood. Here, using new methods, we determined that after T cell responses have developed, CD11clomonocyte-derived lung cells termed MNC1 (mononuclear cell subset 1), harbor more live Mtb compared to alveolar macrophages (AM), neutrophils, and less permissive CD11chiMNC2. Bulk RNA sequencing of sorted cells revealed that the lysosome biogenesis pathway is underexpressed in MNC1. Functional assays confirmed that Mtb-permissive MNC1 have less lysosome content, acidification, and proteolytic activity than AM, and less nuclear TFEB, a master regulator of lysosome biogenesis. Mtb infection does not drive lysosome deficiency in MNC1 in vivo. Instead, Mtb recruits MNC1 and MNC2 to the lungs for its spread from AM to these cell subsets as a virulence mechanism that requires the Mtb ESX-1 secretion system. The c-Abl tyrosine kinase inhibitor nilotinib activates TFEB and enhances lysosome function of primary macrophages in vitro and MNC1 and MNC2 in vivo, improving control of Mtb infection. Our results indicate that Mtb exploits lysosome-poor monocyte-derived cells for in vivo persistence, suggesting a potential target for host-directed tuberculosis therapy.One Sentence SummaryVirulent Mtb recruits and exploits intrinsically lysosome-deficient lung mononuclear cell subsets to resist elimination during chronic infection.
Structural insights into regulation of TRPM7 divalent cation uptake by the small GTPase ARL15
Authors: Mahbub Luba , Kozlov Guennadi , Zong Pengyu , Tetteh Sandra , Nethramangalath Thushara , Knorn Caroline , Jiang Jianning , Shahsavan Ashkan , Lee Emma , Yue Lixia , Runnels Loren W. , Gehring Kalle 
Published: January 2023

AbstractCystathionine-β-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) are an evolutionarily conserved family of magnesium transporters. They promote efflux of Mg2+ions on their own or uptake of divalent cations when coupled to the transient receptor potential ion channel subfamily M member 7 (TRPM7). Recently, ADP-ribosylation factor-like GTPase 15 (ARL15) has been identified as CNNM binding partner and an inhibitor of divalent cation influx by TRPM7. Here, we characterize ARL15 as a GTP-binding protein and demonstrate that it binds the CNNM CBS-pair domain with low micromolar affinity. The crystal structure of the complex between ARL15 GTPase domain and CNNM2 CBS-pair domain reveals the molecular determinants of the interaction and allowed the identification of mutations in ARL15 and CNNM2 mutations that abrogate binding. Loss of CNNM binding prevented ARL15 suppression of TRPM7 channel activity in support of previous reports that the proteins function as a ternary complex. Binding experiments with phosphatase of regenerating liver 2 (PRL2 or PTP4A2) revealed that ARL15 and PRLs compete for binding CNNM, suggesting antagonistic regulation of divalent cation transport by the two proteins.
Alanine replacements in the structured C-terminal domain of the prion protein reveal conformationally variable regions as major determinants for prion propagation
Authors: Bhamra Savroop K. , Arora Parineeta , Hosszu Laszlo L. P. , Bieschke Jan , Clarke Anthony R. , Collinge John , Jat Parmjit S. 
Published: January 2023

AbstractMutational analysis of the cellular prion protein (PrPC) has revealed various regions of the protein that modulate prion propagation. However, most approaches involve deletions, insertions, or replacements in the presence of the wild-type cellular protein, which may mask the true phenotype. Here, site-directed alanine mutagenesis of PrPCwas conducted to identify sites particularly a ‘surface patch’ of the protein pertinent to prion propagation in the absence of the wild-type prion protein. Mutations were targeted to the helical, sheet and loop regions of PrPC, or a combination thereof and the mutated proteins expressed in PK1 cells in which endogenous PrPChad been silenced. PK1 cells are a clone of mouse neuroblastoma cells that are highly susceptible to Rocky Mountain Laboratory mouse prions. Using the scrapie cell assay, a highly sensitive cell culture-based bioassay for quantifying infectious titres of mouse prions, we found that all mutations within the structured 121-230 domain, irrespective of secondary structure, severely reduced prion propagation. The reduction was most pronounced for mutations within conformationally variable regions of the protein (G123A.L124A.G125A and V188A.T191A.T192A) and those neighbouring or within helix 1 (S134A.R135A.M153A and H139A.G141A.D146A). While mutations G123A and G125A would likely disrupt the structure of the prion fibril, the other mutations are unlikely to cause disruption. Our data therefore suggests that conformationally variable regions within the structured domain of PrPCare the major determinants of prion propagation efficacy.
PanPA: generation and alignment of panproteome graphs
Authors: Dabbaghie Fawaz , Srikakulam Sanjay K. , Marschall Tobias , Kalinina Olga V. 
Published: January 2023

AbstractMotivationCompared to eukaryotes, prokaryote genomes are more diverse through different mechanisms, including a higher mutation rate and horizontal gene transfer. Therefore, using a linear representative reference can cause a reference bias. Graph-based pangenome methods have been developed to tackle this problem. However, comparisons in DNA space is still challenging due to this high diversity. In contrast, amino acids have higher similarity due to evolutionary constraints, resulting in conserved amino acids that, however, may be encoded by several synonymous codons. Coding regions cover the majority of the genome in prokaryotes. Thus, building panproteomes leverages the high sequence similarity while not losing much of the genome in non-coding regions.ResultsWe presentPanPA, a method that takes a set of multiple sequence alignments (MSAs) of proteins or protein clusters, indexes them, and builds a graph for each MSA. In the querying step, it can align DNA or amino acid sequences back to these graphs. We first showcase thatPanPAgenerates correct alignments on a panproteome from 1,350E. coli. To demonstrate that panproteomes allow longer phylogenetic distance comparison, we compare DNA and protein alignments from 1,073S. entericaassemblies againstE. colireference genome, pangenome, and panproteome usingBWA,GraphAligner, andPanPArespectively, wherePanPAwas able to produce around 22% more alignments. We also aligned DNA short-reads WGS sample fromS. entericaagainst theE. colireference withBWAand the panproteome withPanPA, wherePanPAwas able to find alignment for 69% of the reads compared to 5% withBWAAvailabilityPanPAis available athttps://github.com/fawaz-dabbaghieh/PanPAContactfawaz@hhu.de,olga.kalinina@helmholtz-hzi.deSupplementary informationSupplementary data are available atBioinformaticsonline.