bluuebunny/crossref_metadata_2025_split huggingface dataset:
Matrix stiffness controls ciliogenesis and centriole position
Authors: Williantarra Ivanna , Leung Sophia , Choi Yu Suk , Channa Ashika , McGlashan Sue R 
Published: August 2021

AbstractMechanical stress and the stiffness of the extracellular matrix are key drivers of tissue development and homeostasis. Aberrant mechanosensation is associated with a wide range of pathologies, including diseases such as osteoarthritis. Substrate stiffness is one of the well-known mechanical properties of the matrix that enabled establishing the central dogma of an integrin-mediated mechanotransduction using stem cells. However, how specific cells ‘feel’ or sense substrate stiffness requires further study. The primary cilium is an essential cellular organelle that senses and integrates mechanical and chemical signals from the extracellular environment. We hypothesised that the primary cilium dynamically alters its length and position to fine-tune cell mechanosignalling based on substrate stiffness alone. We used a hydrogel system of varying substrate stiffness to examine the role of substrate stiffness on cilia frequency, length and centriole position as well as cell and nuclei area over time. Contrary to other cell types, we show that chondrocyte primary cilia shorten on softer substrates demonstrating tissue-specific mechanosensing which is aligned with the tissue stiffness the cells originate from. We further show that stiffness alone determines centriole positioning to either the basal or apical membrane during attachment and spreading, with centriole positioned towards the basal membrane on stiffer substrates. These phenomena are mediated by force generation actin-myosin stress fibres in a time-dependent manner. Based on these findings, we propose that substrate stiffness plays a central role in cilia positioning, regulating cellular response to external forces, and may be a key driver of mechanosignalling-associated diseases.Significance StatementThe primary cilium has been thrust into the limelight owing to its role as a cellular sensor in embryonic development and adult tissue maintenance. How the primary cilium interacts with the mechanical environment still remains unclear. We show that substrate stiffness dynamically regulates primary cilium length and position through integrin-mediated traction forces, the cilia are a key determinant of cell shape on certain stiffnesses. Our data support the promising potential of primary cilia as a novel target in mechanotherapy for improved clinical outcomes in cartilage pathobiology.
Limitations of composability of cis-regulatory elements in messenger RNA
Authors: Haynes Samuel , Auxillos Jamie , Danecka Weronika , Jain Abhishek , Alibert Clemence , Wallace Edward 
Published: August 2021

ABSTRACTGenes are commonly abstracted into a coding sequence and cis-regulatory elements (CREs), such as promoters and terminators, and short sequence motifs within these regions. Modern cloning techniques allow easy assembly of synthetic genetic constructs from discrete cis-regulatory modules. However, it is unclear how much the contributions of CREs to gene expression depend on other CREs in the host gene. Using budding yeast, we probe the extent of composability, or independent effects, of distinct CREs. We confirm that the quantitative effect of a terminator on gene expression depends on both promoter and coding sequence. We then explore whether individual cisregulatory motifs within terminator regions display similar context dependence, using transcriptomewide datasets of mRNA decay. To test the extent of composability, we construct reporter genes consisting of combinations of motifs within various terminator contexts, paired with different promoters. Our results show that the effect of a motif on RNA abundance depends both on its host terminator, and also on the associated promoter sequence. This emphasises the need for improved motif inference that includes both local and global context effects, which in turn could aid in the accurate use of CREs for the engineering of synthetic genetic constructs.
Peripheral sTREM2-related inflammatory activity alterations in early stage Alzheimer’s disease
Authors: Weber Grace E. , Khrestian Maria , Tuason Elizabeth D. , Shao Yvonne , Pillai Jagan , Rao Stephen , Feng Hao , Zhou Yadi , Cheng Feixiong , DeSilva Tara M. , Stauffer Shaun , Leverenz James B. , Bekris Lynn M. 
Published: August 2021

AbstractAlzheimer’s disease (AD) has been linked to multiple immune system genetic variants, implicating potential broad alterations in inflammatory profiles in the disease. Triggering receptor expressed on myeloid cells 2 (TREM2) genetic variants are risk factors for AD and other neurodegenerative diseases. A soluble TREM2 isoform (sTREM2) is elevated in cerebrospinal fluid in the early stages of AD suggesting it may be a biomarker of progressive alterations in immune response to AD-related pathology. Multiple studies have reported an altered peripheral immune response in AD. However, less is known about the relationship between plasma sTREM2 and the altered peripheral immune response in AD. The objective of this exploratory study was to examine the relationship between sTREM2 and inflammatory activity in human participants defined by clinically characterized cognitive symptoms and groups defined by the cerebrospinal fluid biomarkersamyloid beta, phosphorylatedtau, andneurodegeneration (NIA-AA Research Framework: “ATN continuum”.) The hypothesis of this exploratory study was that sTREM2 related inflammatory activity differs by AD stage. We observed different patterns of inflammatory activity across disease groups and ATN categories that implicates peripheral sTREM2 related inflammatory activity as altered in the early stages of AD. Notably, fractalkine showed a significant relationship with sTREM2 across different analyses in the control groups that was lost as disease progressed, and fractalkine, IL-5 and IL-17A were decreased in AD. These preliminary data provide important support to the hypothesis that sTREM2-related inflammatory activity is a stage-specific biomarker of AD progression, providing the groundwork for future studies and therapeutic strategies.
Sciviewer enables interactive visual interrogation of single-cell RNA-Seq data from the Python programming environment
Authors: Kotliar Dylan , Colubri Andres 
Published: August 2021

AbstractSummaryVisualizing two-dimensional (2D) embeddings (e.g. UMAP or tSNE) is a key step in interrogating single-cell RNA sequencing (scRNA-Seq) data. Subsequently, users typically iterate between programmatic analyses (e.g. clustering and differential expression) and visual exploration (e.g. coloring cells by interesting features) to uncover biological signals in the data. Interactive tools exist to facilitate visual exploration of embeddings such as performing differential expression on user-selected cells. However, the practical utility of these tools is limited because they don’t support rapid movement of data and results to and from the programming environments where the bulk of data analysis takes place, interrupting the iterative process. Here, we present the Single-cell Interactive Viewer (Sciviewer), a tool that overcomes this limitation by allowing interactive visual interrogation of embeddings from within Python. Beyond differential expression analysis of user-selected cells, Sciviewer implements a novel method to identify genes varying locally along any user-specified direction on the embedding. Sciviewer enables rapid and flexible iteration between interactive and programmatic modes of scRNA-Seq exploration, illustrating a useful approach for analyzing high-dimensional data.Availability and implementationCode and examples are provided at https://github.com/colabobio/sciviewer
Next generation restoration metrics: Using soil eDNA bacterial community data to measure trajectories towards rehabilitation targets
Authors: Liddicoat Craig , Krauss Siegfried L. , Bissett Andrew , Borrett Ryan J. , Ducki Luisa C. , Peddle Shawn D. , Bullock Paul , Dobrowolski Mark P. , Grigg Andrew , Tibbett Mark , Breed Martin F. 
Published: August 2021

AbstractIn post-mining rehabilitation, successful mine closure planning requires specific, measurable, achievable, relevant and time-bound (SMART) completion criteria, such as returning ecological communities to match a target level of similarity to reference sites. Soil microbiota are fundamentally linked to the restoration of degraded ecosystems, helping to underpin ecological functions and plant communities. High-throughput sequencing of soil eDNA to characterise these communities offers promise to help monitor and predict ecological progress towards reference states. Here we demonstrate a novel methodology for monitoring and evaluating ecological restoration using three long-term (> 25 year) case study post-mining rehabilitation soil eDNA-based bacterial community datasets. Specifically, we developed rehabilitation trajectory assessments based on similarity to reference data from restoration chronosequence datasets. Recognising that many alternative options for microbiota data processing have potential to influence these assessments, we comprehensively examined the influence of standard versus compositional data analyses, different ecological distance measures, sequence grouping approaches, eliminating rare taxa, and the potential for excessive spatial autocorrelation to impact on results. Our approach reduces the complexity of information that often overwhelms ecologically-relevant patterns in microbiota studies, and enables prediction of recovery time, with explicit inclusion of uncertainty in assessments. We offer a step change in the development of quantitative microbiota-based SMART metrics for measuring rehabilitation success. Our approach may also have wider applications where restorative processes facilitate the shift of microbiota towards reference states.
Autophagy cargo receptors are secreted via extracellular vesicles and particles in response to endolysosomal inhibition or impaired autophagosome maturation
Authors: Solvik Tina A. , Nguyen Tan A. , Lin Yu-Hsiu Tony , Marsh Timothy , Huang Eric J. , Wiita Arun P. , Debnath Jayanta , Leidal Andrew M. 
Published: August 2021

AbstractThe endosome-lysosome (endolysosome) system plays central roles in both autophagic degradation and secretory pathways, including the exocytic release of extracellular vesicles and particles (EVPs). Although previous work has revealed important interconnections between autophagy and EVP-mediated secretion, our molecular understanding of these secretory events during endolysosome inhibition remains incomplete. Here, we delineate a secretory autophagy pathway upregulated in response to endolysosomal inhibition that mediates the EVP-associated extracellular release of autophagic cargo receptors, including p62/SQSTM1. This extracellular secretion is highly regulated and critically dependent on multiple ATGs required for the progressive steps of early autophagosome formation as well as Rab27a-dependent exocytosis. Furthermore, the disruption of autophagosome maturation, either due to genetic inhibition of the autophagosome-to-autolyosome fusion machinery or blockade via the SARS-CoV2 viral protein ORF3a, is sufficient to induce robust EVP-associated secretion of autophagy cargo receptors. Finally, we demonstrate that this ATG-dependent, EVP-mediated secretion pathway buffers against the intracellular accumulation of autophagy cargo receptors when classical autophagic degradation is impaired. Based on these results, we propose that secretory autophagy via EVPs functions as an alternate route to clear sequestered material and maintain proteostasis in response to endolysosomal dysfunction or impaired autophagosome maturation.
Escaping from multiple visual threats: Modulation of escape responses in Pacific staghorn sculpin (Leptocottus armatus)
Authors: Kimura Hibiki , Pfalzgraff Tilo , Levet Marie , Kawabata Yuuki , Steffensen John F. , Johansen Jacob L. , Domenici Paolo 
Published: August 2021

ABSTRACTFish perform rapid escape responses to avoid sudden predatory attacks. During escape responses, fish bend their bodies into a C-shape and quickly turn away from the predator and accelerate. The escape trajectory is determined by the initial turn (Stage 1) and a contralateral bend (Stage 2). Previous studies have used a single threat or model predator as a stimulus. In nature, however, multiple predators may attack from different directions simultaneously or in close succession. It is unknown whether fish are able to change the course of their escape response when startled by multiple stimuli at various time intervals. Pacific staghorn sculpin (Leptocottus armatus) were startled with a left and right visual stimulus in close succession. By varying the timing of the second stimulus, we were able to determine when and how a second stimulus could affect the escape response direction. Four treatments were used: a single visual stimulus (control); or two stimuli coming from opposite sides separated by a 0 ms (simultaneous treatment); a 33 ms; or a 83 ms time interval. The 33 ms and 83 ms time intervals were chosen to occur shortly before and after a predicted 60 ms visual escape latency (i.e. during Stage 1). The 0 ms and 33 ms treatments influenced both the escape trajectory and the Stage 1 turning angle, compared to a single stimulation, whereas the 83 ms treatment had no effect on the escape response. We conclude that Pacific staghorn sculpin can modulate their escape response only between stimulation and the onset of the response, but that escape responses are ballistic after the body motion has started.SUMMARY STATEMENTUsing double stimulation from opposite sides at different time intervals to simulate coordinated predatory attacks, Pacific staghorn sculpin escape away from the first stimulus, but were unable to turn away from the second stimulus while the escape response was in progress.
Sleep spindles, ripples, and interictal epileptiform discharges in the human anterior and mediodorsal thalamus
Authors: Szalárdy Orsolya , Simor Péter , Ujma Péter , Jordán Zsófia , Halász László , Erőss Loránd , Fabó Dániel , Bódizs Róbert 
Published: August 2021

AbstractSleep spindles are major oscillatory components of Non-Rapid Eye Movement (NREM) sleep, reflecting hyperpolarization-rebound sequences of thalamocortical neurons, the inhibition of which is caused by the NREM-dependent activation of GABAergic neurons in the reticular thalamic nucleus. Reports suggest a link between sleep spindles and several forms of interictal epileptic discharges (IEDs) which are considered as expressions of pathological off-line neural plasticity in the central nervous system. Here we investigated the relationship between thalamic sleep spindles, IEDs and ripples in the anterior and mediodorsal nuclei (ANT and MD) of epilepsy patients. Whole-night LFP from the ANT and MD were co-registered with scalp EEG/polysomnography by using externalized leads in 15 epilepsy patients undergoing Deep Brain Stimulation protocol. Slow (∼12 Hz) and fast (∼14 Hz) sleep spindles were present in the human ANT and MD. Roughly, one third of thalamic sleep spindles were associated with IEDs or ripples. Both IED- and ripple-associated spindles were longer than pure spindles. IED-associated thalamic sleep spindles were characterized by broadband increase in thalamic and cortical activity, both below and above the spindle frequency range, whereas ripple-associated thalamic spindles exceeded pure spindles in terms of 80–200 Hz thalamic, but not cortical activity as indicated by time-frequency analysis. These result show that thalamic spindles coupled with IEDs are reflected at the scalp slow and beta-gamma oscillation as well. IED density during sleep spindles in the MD, but not in the ANT was identified as correlates of years spent with epilepsy, whereas no signs of pathological processes were correlated with measures of ripple and spindle association. Furthermore, the density of ripple-associated sleep spindles in the ANT showed a positive correlation with general intelligence. Our findings indicate the complex and multifaceted role of the human thalamus in sleep spindle-related physiological and pathological neural plasticity.
Efficient identification of trait-associated loss-of-function variants in the UK Biobank cohort by exome-sequencing based genotype imputation
Authors: Zhang Lei , Yan Shan-Shan , Ni Jing-Jing , Pei Yu-Fang 
Published: August 2021

AbstractThe large-scale open access whole-exome sequencing (WES) data of the UK Biobank ~200,000 participants is accelerating a new wave of genetic association studies aiming to identify rare and functional loss-of-function (LoF) variants associated with a broad range of complex traits and diseases, however the community is in short of stringent replication of new associations. In this study, we proposed to merge the WES genotypes and the genome-wide genotyping (GWAS) genotypes of 167,000 UKB Caucasian participants into a combined reference panel, and then to impute 241,911 UKB Caucasian participants who had the GWAS genotypes only. We then proposed to use the imputed data to replicate association identified in the discovery WES sample. Using a leave-100-out imputation strategy in the reference panel, we showed that average imputation accuracy measure r2is modest to high at LoF variants of all minor allele frequency (MAF) intervals including ultra-rare ones: 0.942 at MAF interval [1%, 50%], 0.807 at [0.1%, 1.0%), 0.805 at [0.01%, 0.1%), 0.664 at [0.001%, 0.01%) and 0.410 at (0, 0.001%). As applications, we studied single variant level and gene level associations of LoF variants with estimated heel BMD (eBMD) and 4 lipid traits: high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), triglycerides (TG) and total cholesterol (TC). In addition to replicating dozens of previously reported genes such asMEPEfor eBMD andPCSK9for more than one lipid trait, the results also identified 2 novel gene-level associations:PLIN1(cumulative MAF=0.10%, discovery BETA=0.38, P=1.20×10−13; replication BETA=0.25, P=1.03×10−6) andANGPTL3(cumulative MAF=0.10%, discovery BETA=−0.36, P=4.70×10−11; replication BETA=−0.30, P=6.60×10−11) for HDL-C, as well as one novel single variant level association (11:14843853:C:T, MAF=0.11%, discovery BETA=−0.31, P=2.70×10−9; replication BETA=−0.31, P=8.80×10−14,PDE3B) for TG. Our results highlighted the strength of WES based genotype imputation as well as provided useful imputed data within the UKB cohort.
Microtubule deacetylation reduces cell stiffness to allow the onset of collective cell migrationin vivo
Authors: Marchant CL , Malmi-Kakkada AN , Espina JA , Barriga EH 
Published: August 2021

AbstractEmbryogenesis, tissue repair and cancer metastasis rely on collective cell migration (CCM).In vitrostudies propose that migrating cells are stiffer when exposed to stiff substrates, known to allow CCM, but softer when plated in compliant non-permissive surfaces. Here, by combiningin vivoatomic force microscopy (iAFM) and modelling we reveal that to collectively migratein vivo, cells require to dynamically decrease their stiffness in response to the temporal stiffening of their native substrate. Moreover, molecular and mechanical perturbations of embryonic tissues uncover that this unexpected cell mechanical response is achieved by a new mechanosensitive pathway involving Piezo1-mediated microtubule deacetylation. Finally, lowering microtubule acetylation and consequently cell stiffness was sufficient to allow CCM in soft non-permissive substrates, suggesting that a fixed value of substrate stiffness is not as essential for CCM as it is reaching an optimal cell-to-substrate stiffness value. Thesein vivoinsights on cell-to-substrate mechanical interplay have major implications to our re-interpretation of physiological and pathological contexts.
Virulence determinant, PTP7, controls vesicle budding from the Maurer’s clefts, adhesin protein trafficking and host cell remodeling inPlasmodium falciparum
Authors: Carmo Olivia M. S. , Shami Gerald J. , Cox Dezerae , Liu Boyin , Blanch Adam J. , Tiash Snigdha , Tilley Leann , Dixon Matthew W.A. 
Published: August 2021

AbstractPresentation of the variant antigen,Plasmodium falciparumerythrocyte membrane protein 1 (EMP1), at knob-like protrusions on the surface of infected red blood cells, underpinsP. falciparummalaria pathogenicity. Here we describe a protein PF3D7_0301700 (PTP7), that functions at the nexus between the intermediate trafficking organelle, the Maurer’s cleft, and the infected red blood cell surface. Genetic disruption of PTP7 leads to accumulation of vesicles at the Maurer’s clefts, grossly aberrant knob morphology, and failure to deliver EMP1 to the red blood cell surface. We show that an expanded low complexity sequence in the C-terminal region of PTP7, found only in theLaveraniaclade ofPlasmodium, is critical for efficient virulence protein trafficking.Author SummaryWe describe a malaria parasite protein involved in virulence factor trafficking (PTP7) that moves between different compartments in the host red blood cell cytoplasm in a stage-dependent manner. Upon disruption of the PTP7 locus, the Maurer’s cleft trafficking compartments become decorated with vesicles; the knobby protrusions on the host red blood cell surface are depleted and distorted; and trafficking of the virulence protein, EMP1, to the host red blood cell surface is ablated. We provide evidence that a region of PTP7 with low sequence complexity plays an important role in driving fission of vesicles from the Maurer’s clefts.
A practical framework RNMF for the potential mechanism of cancer progression with the analysis of genes cumulative contribution abundance
Authors: Li Zhenzhang , Liang Haihua , Zhang Shaoan , Luo Wen 
Published: August 2021

AbstractMutational signatures can reveal the mechanism of tumorigenesis. We developed theRNMFsoftware for mutational signatures analysis, including a key model of cumulative contribution abundance (CCA) which was designed to highlight the association between genes and mutational signatures. Applied it to 1073 esophageal squamous cell carcinoma (ESCC) and found that APOBEC signatures (SBS2* and SBS13*) mediated the occurrence ofPIK3CAE545k mutation. Furthermore, we found that age signature is strongly linked to theTP53R342* mutation. In addition, the CCA matrix image data of genes in the signatures New, SBS3* and SBS17b* were helpful for the preliminary evaluation of shortened survival outcome. In a word,RNMFcan successfully achieve the correlation analysis of genes and mutational signatures, proving a strong theoretical basis for the study of tumor occurrence and development mechanism and clinical adjuvant medicine.