bluuebunny/crossref_metadata_2025 huggingface dataset:
Determining salmon provenance with automated otolith reading
Authors: Kemp Chandler E , Doherty Susan K
Published: October 2021

Synthetic otolith marks are used at hundreds of hatcheries throughout the Pacific Rim to record the release location of salmon. Each year, human readers examine tens of thousands of otolith samples to identify the marks in salmon that are caught. The data inform dynamic management practices that maximize allowable catch while preserving populations, and guide hatchery investments. However, the method is limited by the time required to process otoliths, the inability to distinguish between wild and un-marked hatchery fish, and in some cases classification processes are limited by the subjective decisions of human readers. Automated otolith reading using computer vision has the potential to improve on all three of these limitations. Our work advances the field of automated otolith reading through a novel otolith classification algorithm that uses two neural networks trained with an adversarial algorithm to achieve 93% classification accuracy between four hatchery marks and unmarked otoliths. The algorithm relies on hemisection images of the otolith exclusively: no additional biological data are needed. Our work demonstrates a novel technique with modest training requirements that achieves unprecedented accuracy. The method can be easily adopted in existing otolith labs, scaled to accommodate additional marks, and does not require tracking additional information about the fish that the otolith was retrieved from.

Author summary

Many fish harvested in commercial fisheries have a bone-like structure in their inner ear called an otolith. Otoliths are useful because as they grow changes in the fish’s environment create unique patterns that can be interpreted years later—similar to the way tree rings can be used to determine a tree’s age and rate of growth in different seasons. Hatcheries use this phenomenon to create unique patterns in the otoliths of fish they release that identify their origin. Trained otolith “readers” examine tens of thousands of otolith samples as part of commercial fishery management every year. The data help resource managers protect returns to wild streams and help hatcheries track the survival rates of their releases. However, human reading is time consuming, limited in the types of patterns that can be identified and can be subjective. Applying modern machine learning techniques to otolith reading has the potential to improve on all of these challenges. We developed a computational method that identifies hatchery marks in digital images of salmon otoliths without human input. In a test with otoliths containing one of four hatchery marks and unmarked otoliths, the method accurately classified 93% of otoliths. The method can be adopted in otolith labs and can be further improved by expanding the sample size used to train and test the method.
Golgi structural defect impairs glycosaminoglycan synthesis, sulfation, and secretion
Authors: Ahat Erpan , Song Yuefan , Xia Ke , Reid Whitney , Li Jie , Bui Sarah , Zhang Fuming , Linhardt Robert J , Wang Yanzhuang
Published: October 2021

Synthesis of glycosaminoglycans such as heparan sulfate (HS) and chondroitin sulfate (CS) occurs in the lumen of the Golgi but the relationship between Golgi structural integrity and glycosaminoglycan synthesis is not clear. In this study, we disrupted the Golgi structure by knocking out GRASP55 and GRASP65 and determined its effect on the synthesis, sulfation, and secretion of HS and CS. We found that GRASP depletion increased HS synthesis while decreasing CS synthesis in cells, altered HS and CS sulfation, and reduced both HS and CS secretion. Using proteomics, RNA-seq and biochemical approaches, we identified EXTL3, a key enzyme in the HS synthesis pathway, whose level is upregulated in GRASP knockout cells; while GalNacT1, an essential CS synthesis enzyme, is robustly reduced. In addition, we found that GRASP depletion decreased HS sulfation via the reduction of PAPSS2, a bifunctional enzyme in HS sulfation. Our study provides the first evidence that Golgi structural defect may significantly alter the synthesis and secretion of glycosaminoglycans.
Interferon-gamma Induces Melanogenesis Via Post-Translational Modification of Tyrosinase
Authors: Mo Xuan , Kazmi Hasan Raza , Preston-Alp Sarah , Zhou Bo , Zaidi M. Raza
Published: October 2021

Melanogenesis (melanin pigment production) in melanocytes is canonically stimulated by the alpha-melanocyte stimulating hormone (αMSH), which activates the cyclic-AMP-mediated expression of the melanocyte inducing transcription factor (MITF) and its downstream melanogenic genes, including the principal rate-limiting melanogenic enzyme tyrosinase (Tyr). Here we report that interferon-gamma (IFNG; type II interferon), but not IFN-alpha (a type I interferon), induces a noncanonical melanogenic pathway. Inhibition of IFNG pathway by the JAK inhibitor ruxolitinib or knocking out Stat1 abrogated the IFNG-induced melanogenesis. Interestingly, IFNG-induced melanogenesis was independent of MITF. IFNG markedly increased the Tyr protein expression but did not affect the mRNA expression, suggesting a post-translational regulatory mechanism. In contrast, IFNG had no effect on the expression of other melanogenesis-related proteins, e.g. tyrosinase-related protein 1 (Tyrp1) and dopachrome tautomerase (Dct). Glycosidase digestion assays revealed that IFNG treatment increased the mature glycosylated form of Tyr, but not its de novo synthesis. Moreover, cycloheximide chase assay showed that degradation of Tyr was decreased in IFNG-treated cells. These results suggest that the IFNG-STAT1 pathway regulates melanogenesis via modulation of the post-translational processing and protein stability of Tyr.

SIGNIFICANCE

The canonical pathway that controls melanogenesis in melanocytes is activated by the alpha melanocyte stimulating hormone (αMSH) via its receptor MC1R, which activates the cyclic-AMP-mediated expression of the melanocyte master regulator MITF and its downstream target genes involved in the melanogenic process. Here we report a novel non-canonical melanogenic pathway that is mediated via the Interferon-gamma cytokine signaling. We show that this non-canonical pathway is independent of MITF-mediated gene expression, but rather functions via post-translational modification of the principal melanogenic enzyme Tyrosinase.
Phosphatases are predicted to govern prolactin-mediated JAK-STAT signaling in pancreatic beta cells
Authors: Simoni Ariella , Huber Holly , Georgia Senta K. , Finley Stacey D.
Published: October 2021

Patients with diabetes are unable to produce a sufficient amount of insulin to properly regulate their blood-glucose levels. One potential method of treating diabetes is to increase the number of insulin-secreting beta cells in the pancreas to enhance insulin secretion. It is known that during pregnancy, pancreatic beta cells proliferate in response to the pregnancy hormone, prolactin. Leveraging this proliferative response to prolactin may be a strategy to restore endogenous insulin production for patients with diabetes. To investigate this potential treatment, we previously developed a computational model to represent the prolactin-mediated JAK-STAT signaling pathway in pancreatic beta cells. However, this model does not account for variability in protein expression that naturally occurs between cells. Here, we applied the model to understand how heterogeneity affects the dynamics of JAK-STAT signaling. We simulated a sample of 10,000 heterogeneous cells with varying initial protein concentrations responding to prolactin stimulation. We used partial least squares regression to analyze the significance and role of each of the varied protein concentrations in producing the response of the cell. Our regression models predict that the concentrations of the cytosolic and nuclear phosphatases strongly influence the response of the cell. The model also predicts that increasing prolactin receptor strengthens negative feedback mediated by the inhibitor SOCS. These findings reveal biological targets that can potentially be used to modulate the proliferation of pancreatic beta cells to enhance insulin secretion and beta cell regeneration in the context of diabetes.
Characterization of pyridomycin B reveals the formation of functional groups in antimycobacterial pyridomycin
Authors: Huang Tingting , Zhou Zihua , Wei Maolong , Chen Lin , Xiao Zhihong , DENG Zixin , Lin Shuangjun
Published: October 2021

Pyridomycin, a cyclodepsipeptide with potent antimycobacterial activity, specifically inhibits the InhA enoyl reductase of Mycobacteria tuberculosis. Structure-activity relationship studies indicated that the enolic acid moiety in pyridomycin core system is an important pharmacophoric group and the natural configuration of the C-10 hydroxyl contributes to the bioactivity of pyridomycin. The ring structure of pyridomycin was generated by the nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) hybrid system (PyrE-F-G). Bioinformatics analysis reveals that SDR family protein Pyr2 functions as a 3-oxoacyl ACP reductase in the pyridomycin pathway. Inactivation of pyr2 resulted in accumulation of pyridomycin B, a new pyridomycin analogue featured with enol moiety in pyridyl alanine moiety and a saturated 3-methylvaleric acid group. The elucidated structure of pyridomycin B suggests that rather than functioning as a post-tailoring enzyme, Pyr2 catalyzes ketoreduction to form the C-10 hydroxyl group in pyridyl alanine moiety and the double bond formation of the enolic acid moiety derived from isoleucine when the intermediate assembled by PKS-NRPS machinery is still tethered to the last NRPS module, in a special energy-saving manner. Ser-His-Lys residues constitute the active site of Pyr2, which is different from the typically conserved Tyr based catalytic triad in the majority of SDRs. Site-directed mutation identified that His154 in the active site is a critical residue for pyridomycin B production. These findings will improve our understanding of the pyridomycin biosynthetic logic, identify the missing link for the double bound formation of enol ester in pyridomycin and enable creating chemical diversity of pyridomycin derivatives.
Assessing HD-EEG functional connectivity states using a human brain computational model
Authors: Tabbal Judie , Kabbara Aya , Yochum Maxime , Khalil Mohamad , Hassan Mahmoud , Benquet Pascal
Published: October 2021

Objective

Electro/Magnetoencephalography (EEG/MEG) source-space network analysis is increasingly recognized as a powerful tool for tracking fast electrophysiological brain dynamics. However, an objective and quantitative evaluation of pipeline steps is challenging due to the lack of realistic ‘controlled’ data. Here, our aim is two-folded: 1) provide a quantitative assessment of the advantages and limitations of the analyzed techniques and 2) introduce (and share) a complete framework that can be used to optimize the entire pipeline of EEG/MEG source connectivity.

Approach

We used a human brain computational model containing both physiologically based cellular GABAergic and Glutamatergic circuits coupled through Diffusion Tensor Imaging, to generate high-density EEG recordings. We designed a scenario of successive gamma-band oscillations in distinct cortical areas to emulate a virtual picture-naming task. We identified fast time-varying network states and quantified the performance of the key steps involved in the pipeline: 1) inverse models to reconstruct cortical-level sources, 2) functional connectivity measures to compute statistical interdependency between regional signals, and 3) dimensionality reduction methods to derive dominant brain network states (BNS).

Main Results

Using a systematic evaluation of the different decomposition techniques, results show significant variability among tested algorithms in terms of spatial and temporal accuracy. We outlined the spatial precision, the temporal sensitivity, and the global accuracy of the extracted BNS relative to each method. Our findings suggest a good performance of wMNE/PLV combination to elucidate the appropriate functional networks and ICA techniques to derive relevant dynamic brain network states.

Significance

We suggest using such brain models to go further in the evaluation of the different steps and parameters involved in the EEG/MEG source-space network analysis. This can reduce the empirical selection of inverse model, connectivity measure, and dimensionality reduction method as some of the methods can have a considerable impact on the results and interpretation.
Clustered PHD domains in KMT2/MLL proteins are attracted by H3K4me3 and H3 acetylation-rich active promoters and enhancers
Authors: Stroynowska-Czerwinska Anna Maria , Klimczak Magdalena , Pastor Michal , Kazrani Asgar Abbas , Misztal Katarzyna , Bochtler Matthias
Published: October 2021

Histone lysine-specfic methyltransferase 2 (KMT2A-D) proteins, alternatively called mixed lineage leukaemia (MLL1-4) proteins, mediate positive transcriptional memory. As the catalytic subunits of human COMPASS-like complexes, they methylate H3K4 at promoters and enhancers. KMT2A-D contain understudied highly conserved triplets and a quartet of plant homeodomains (PHDs). Here, we show that all clustered PHDs localise to the well-defined loci of H3K4me3 and H3 acetylation-rich active promoters and enhancers. Surprisingly, we observe little difference in binding pattern between PHDs from promoter-specific KMT2A-B and enhancer-specific KMT2C-D. Fusion of the KMT2A CXXC domain to the PHDs drastically enhances their preference for promoters over enhancers. Hence, the presence of CXXC domains in KMT2A-B, but not KMT2C-D, may explain the promoter/enhancer preferences of the full-length proteins. Importantly, targets of PHDs overlap with KMT2A targets and are enriched in genes involved in the cancer pathways. We also observe that PHDs of KMT2A-D are mutated in cancer, especially within conserved folding motifs (Cys4HisCys2Cys/His), which cause a domain loss-of-function. Taken together, our data suggests that PHDs of KMT2A-D guide the full-length proteins to active promoters and enhancers, and thus play a role in positive transcriptional memory.

GRAPHICAL ABSTRACT
Identifying tumor cells at the single cell level
Authors: Dohmen Jan , Baranovskii Artem , Ronen Jonathan , Uyar Bora , Franke Vedran , Akalin Altuna
Published: October 2021

Tumors are highly complex tissues composed of cancerous cells, surrounded by a heterogeneous cellular microenvironment. Tumor response to treatments is governed by an interaction of cancer cell intrinsic factors with external influences of the tumor microenvironment. Disentangling the heterogeneity within a tumor is a crucial step in developing and utilization of effective cancer therapies. The single cell sequencing technology enables an effective molecular characterization of single cells within the tumor. This technology can help deconvolute heterogeneous tumor samples and thus revolutionize personalized medicine. However, a governing challenge in cancer single cell analysis is cell annotation, the assignment of a particular cell type or a cell state to each sequenced cell. One of the critical cell type annotation challenges is identification of tumor cells within single cell or spatial sequencing experiments.This is a critical limiting step for a multitude of research, clinical, and commercial applications. A reliable method addressing that challenge is a prerequisite for automatic annotation of histopathological data, profiled using multichannel immunofluorescence or spatial sequencing. Here, we propose Ikarus, a machine learning pipeline aimed at distinguishing tumor cells from normal cells at the single cell level. We have tested ikarus on multiple single cell datasets to ascertain that it achieves high sensitivity and specificity in multiple experimental contexts.
Competition for water and species coexistence in phenologically structured annual plant communities
Authors: Levine Jacob I. , Levine Jonathan M. , Gibbs Theo , Pacala Stephen W.
Published: October 2021

Both competition for water and phenological variation are important determinants of plant community structure, but ecologists lack a synthetic theory for how they affect coexistence outcomes. We developed an analytically tractable model of water competition for Mediterranean annual communities and demonstrate that variation in phenology alone can maintain high diversity in spatially homogenous assemblages of water-limited plants. We modeled a system where all water arrives early in the season and species vary in their ability to grow under drying conditions. As a consequence, species differ in growing season length, and compete by shortening the growing season of their competitors. This model replicates and offers mechanistic explanations for qualitative patterns observed in prior empirical studies of how phenology influences coexistence among Mediterranean annuals. Additionally, we found that a decreasing, concave-up tradeoff between growth rate and access to water can theoretically maintain infinite diversity under simple but realistic assumptions. High diversity is possible because: 1) later plants escape competition after their earlier-season competitors have gone to seed and 2) early-season species are more than compensated for their shortened growing season by a growth-rate advantage. Together, these mechanisms provide an explanation for how annual plant species might coexist when competing only for water.
Kernel-based Nonlinear Manifold Learning for EEG Channel Selection with Application to Alzheimer’s Disease
Authors: Gunawardena Rajintha , Sarrigiannis Ptolemaios G. , Blackburn Daniel J. , He Fei
Published: October 2021

For the characterisation and diagnosis of neurological disorders, dynamical, causal and crossfrequency coupling analysis using the EEG has gained considerable attention. Due to high computational costs in implementing some of these methods, the selection of important EEG channels is crucial. The channel selection method should be able to accommodate non-linear and spatiotemporal interactions among EEG channels. In neuroscience, different measures of (dis)similarity are used to quantify functional connectivity between EEG channels. Brain regions functionally connected under one measure do not necessarily imply the same with another measure, as they could even be disconnected. Therefore, developing a generic measure of (dis)similarity is important in channel selection. In this paper, learning of spatial and temporal structures within the data is achieved by using kernel-based nonlinear manifold learning, where the positive semi-definite kernel is a generalisation of various (dis)similarity measures. We introduce a novel EEG channel selection method to determine which channel interrelationships are more important for the in-depth neural dynamical analysis, such as understanding the effect of neurodegeneration, e.g. Alzheimer’s disease (AD), on global and local brain dynamics. The proposed channel selection methodology uses kernel-based nonlinear manifold learning via Isomap and Gaussian Process Latent Variable Model (Isomap-GPLVM). The Isomap-GPLVM method is employed to learn the spatial and temporal local similarities and global dissimilarities present within the EEG data structures. The resulting kernel (dis)similarity matrix is used as a measure of synchrony, i.e. linear and nonlinear functional connectivity, between EEG channels. Based on this information, linear Support Vector Machine (SVM) classification with Monte-Carlo cross-validation is then used to determine the most important spatio-temporal channel inter-relationships that can well distinguish a group of patients from a cohort of age-matched healthy controls (HC). In this work, the analysis of EEG data from HC and patients with mild to moderate AD is presented as a case study. Considering all pairwise EEG channel combinations, our analysis shows that functional connectivity between bipolar channels within temporal, parietal and occipital regions can distinguish well between mild to moderate AD and HC groups. Furthermore, while only considering connectivity with respect to each EEG channel. Our results indicate that connectivity of EEG channels along the fronto-parietal with other channels are important in diagnosing mild to moderate AD.
Integrated analysis of single-cell and transcriptome based RNA-seq multilayer network and WGCNA for construction and validation of an immune cell-related prognostic model in clear cell renal cell carcinoma
Authors: Wu Guanlin , Guo Weiming , Zhu Shuai , Fan Gang
Published: October 2021

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer (RCC). The increasing incidence and poor prognosis of ccRCC after tumour metastasis makes the study of its pathogenesis extremely important. Traditional studies mostly focus on the regulation of ccRCC by single gene, while ignoring the impact of tumour heterogeneity on disease progression. The purpose of this study is to construct a prognostic risk model for ccRCC by analysing the differential marker genes related to immune cells in the single-cell database for providing help in clinical diagnosis and targeted therapy. Single-cell data and ligand-receptor relationship pair data were downloaded from related publications, and ccRCC phenotype and expression profile data were downloaded from TCGA and CPTAC. The DEGs and marker genes of the immune cell were combined and then intersected with the ligand-receptor gene data, and the 981 ligand-receptor relationship pairs obtained were intersected with the target gene of the transcription factor afterwards; 7,987 immune cell multilayer network relationship pairs were finally observed. Then, the genes in the network and the genes in TCGA were intersected to obtain 966 genes for constructing a co-expression network. Subsequently, 53 genes in black and magenta modules related to prognosis were screened by WGCNA for subsequent analysis. Whereafter, using the data of TCGA, 28 genes with significant prognostic differences were screened out through univariate Cox regression analysis. After that, LASSO regression analysis of these genes was performed to obtain a prognostic risk scoring model containing 16 genes, and CPTAC data showed that the effectiveness of this model was good. The results of correlation analysis between the risk score and other clinical factors showed that age, grade, M, T, stage and risk score were all significantly different (p < 0.05), and the results of prognostic accuracy also reached the threshold of qualification. Combined with clinical information, univariate and multivariate Cox regression analyses verified that risk score was an independent prognostic factor (p < 0.05). A nomogram constructed based on a predictive model for predicting the overall survival was established, and internal validation performed well. Our findings suggest that the predictive model built based on the immune cells scRNA-seq will enable us to judge the prognosis of patients with ccRCC and provide more accurate directions for basic relevant research and clinical practice.
Speed fluctuations of bacterial replisomes
Authors: Bhat Deepak , Hauf Samuel , Plessy Charles , Yokobayashi Yohei , Pigolotti Simone
Published: October 2021

Replisomes are multi-protein complexes that replicate genomes with remarkable speed and accuracy. Despite their importance, their dynamics is poorly characterized, especially in vivo. In this paper, we present an approach to infer the replisome dynamics from the DNA abundance distribution measured in a growing bacterial population. Our method is sensitive enough to detect subtle variations of the replisome speed along the genome. As an application, we experimentally measured the DNA abundance distribution in Escherichia coli populations growing at different temperatures using deep sequencing. We find that the average replisome speed increases nearly five-fold between 17°C and 37°C. Further, we observe wave-like variations of the replisome speed along the genome. These variations correlate with previously observed variations of the mutation rate. We interpret this correlation as a speed–error trade-off in DNA replication. Our approach has the potential to elucidate replication dynamics in E. coli mutants and in other bacterial species.
Discovery of small molecule inhibitors of the PTK7/β-catenin inter-action targeting the Wnt signaling pathway in colorectal cancer
Authors: Ganier Laetitia , Betzi Stéphane , Derviaux Carine , Roche Philippe , Muller Christophe , Hoffer Laurent , Morelli Xavier , Borg Jean-Paul
Published: October 2021

Second cause of death due to cancer worldwide, colorectal cancer (CRC) is a major public health issue. The discovery of new therapeutic targets is thus essential. The pseudokinase PTK7 intervenes in the regulation of the Wnt/β-catenin pathway signaling, in part, through a kinase-domain dependent interaction with the β-catenin protein. PTK7 is overexpressed in CRC; an event associated with metastatic development and reduced survival of non-metastatic patient. In addition, numerous alterations have been identified in CRC inducing constitutive activation of Wnt/β-catenin pathway signaling through β-catenin accumulation. Thus, we thought that targeting PTK7/β-catenin interaction could be of interest for future drug development. In this study, we have developed a NanoBRET™ screening assay recapitulating the interaction between PTK7 and β-catenin to identify compounds able to disrupt this protein-protein interaction. A high-throughput screening allowed us to identify small molecule inhibitors targeting the Wnt pathway signaling and inducing anti-proliferative effect in vitro in CRC cells harboring β-catenin or APC mutations downstream of PTK7. Thus, inhibition of the PTK7/β-catenin interaction could represent, in the future, a new therapeutic strategy to inhibit cell growth dependent on Wnt signaling pathway. Moreover, despite a lack of enzymatic activity of its tyrosine kinase domain, targeting the PTK7 kinase domain-dependent functions appears to be of interest for further therapeutic development.
SustainedRanavirusoutbreak causes mass-mortality and morbidity in imperiled amphibians
Authors: Hartmann Arik M. , Maddox Max L. , Ossiboff Robert J. , Longo Ana V.
Published: October 2021

A persistent two-month long outbreak ofRanavirusin a natural community of amphibians contributed to a mass die-off of gopher frog tadpoles(Lithobates capito)and severe disease in striped newts(Notophthalmus perstriatus)in Florida. Ongoing mortality inL. capitoand signs inN. perstriatuscontinued for five weeks after the first observation. Hemorrhagic disease and necrosis were diagnosed from pathological examination ofL. capitotadpoles. We confirmed detection of a Frog Virus 3 (FV3)-likeRanavirusvia quantitative PCR in all species. Our findings highlight the susceptibility of these species toRvand the need for long-term disease surveillance during epizootics.
Association of ocean macroplastic debris with stranded sea turtles in the Central Gulf of Thailand
Authors: Prampramote Jindarha , Boonhoh Worakan , Intongead Sutsiree , Sakornwimol Watchara , Prachamkhai Pimchanok , Sansamur Chalutwan , Hayakijkosol Orachun , Wongtawan Tuempong
Published: October 2021

The impact of macroplastic debris (> 5 mm in size) on marine life is a global concern but is rarely investigated in Thailand. Our objective was to investigate the relationship between stranded sea turtles and macroplastics found in the Central Gulf of Thailand. The turtle (n = 388) stranding record between 2017-2020 was analysed retrospectively to determine their size, species, and interaction with macroplastics. Thereafter, between 2019-2020, macroplastics were collected, from the gastrointestinal (GI) tract of dead turtles and from the beaches where stranded turtles were found. A stereomicroscope was used to visually categorise the macroplastics, and the plastic composition was analysed using a Fourier-transform infrared (FTIR) spectrometer. Green sea turtles (Chelonia mydas) were found to account for the majority of stranded turtles (74%, n = 251), and macroplastics were discovered in 74% of cases of entanglement and ingestion. At the juvenile stage, the stranded turtle was strongly related to macroplastics. Immature turtles were more likely to become entangled than adult turtles. Entangled turtles had a greater survival rate than turtles that had consumed plastic. The plastic fibres were the majority of macroplastics found in the GI tracts (62%, n = 152/244) and on the beach (64%, n = 74/115). Most fibres from GI tracts (83%, n = 126/152) and the beaches (93%, n = 68/74) were identified as the fishing net comprised of polyethylene or polypropylene. We concluded that fishing nets made of polyethylene or polypropylene might be one of the significant causes of sea turtle stranding in the Central Gulf of Thailand, and this issue requires immediate resolution.
Synchronous seasonality in the gut microbiota of wild wood mouse populations
Authors: Marsh K.J. , Raulo A.M. , Brouard M. , Troitsky T. , English H. M. , Allen B. , Raval R. , Webster J.P. , Knowles S. C. L.
Published: October 2021

The gut microbiome performs many important functions in mammalian hosts, with community composition shaping its functional role. However, what factors drive individual microbiota variation in wild animals and to what extent these are predictable or idiosyncratic across populations remains poorly understood.

Here, we use a multi-population dataset from a common rodent species (the wood mouse,Apodemus sylvaticus), to test whether a consistent set of ‘core’ gut microbes is identifiable in this species, and to what extent the predictors of microbiota variation are consistent across populations.

Between 2014 and 2018 we used capture-mark-recapture and 16S rRNA profiling to intensively monitor two wild UK mouse populations and their gut microbiota, as well as characterising the microbiota from a laboratory-housed colony of the same species.

Although broadly similar at high taxonomic levels and despite being only 50km apart, the two wild populations did not share a single bacterial amplicon sequence variant (ASV). Meanwhile, the laboratory-housed colony shared many ASVs with one of the wild populations from which it is thought to have been founded decades ago. Despite strong taxonomic divergence in the microbiota, the factors predicting compositional variation in each wild population were remarkably similar. We identified a strong and consistent pattern of seasonal microbiota restructuring that occurred at both sites, in all years, and within individual mice. While the microbiota was highly individualised, seasonal convergence in the gut microbiota among individuals occurred in late winter/early spring.

These findings reveal highly repeatable seasonal gut microbiota dynamics across distinct populations of this species, despite divergent taxa being involved. Providing a platform for future work to understand the drivers and functional implications of such predictable seasonal microbiome restructuring, including whether it might provide the host with adaptive seasonal phenotypic plasticity.
Food or physics: plankton communities structured across Gulf of Alaska eddies
Authors: Kroeger Caitlin , Gentemann Chelle , García-Reyes Marisol , Batten Sonia , Sydeman William
Published: October 2021

Oceanic features, such as mesoscale eddies that entrap and transport water masses, create heterogeneous seascapes to which biological communities may respond. To date, however, our understanding of how internal eddy dynamics influence plankton community structuring is limited by sparse sampling of eddies and their associated biotic communities. In this paper, we used 10 years of archived Continuous Plankton Recorder (CPR) data (2002-2013) associated with 9 mesoscale eddies in the Northeast Pacific/Gulf of Alaska to test the hypothesis that eddy origin and rotational direction determines the structure and dynamics of entrained plankton communities. Using generalized additive models and accounting for confounding factors (e.g., timing of sampling), we found peak diatom abundance within both cyclonic and anticyclonic eddies near the eddy edge. Zooplankton abundances, however, varied with distance to the eddy center/edge by rotational type and eddy life stage, and differed by taxonomic group. For example, the greatest abundance of small copepods was found near the center of anticyclonic eddies during eddy maturation and decay, but near the edge of cyclonic eddies during eddy formation and intensification. Distributions of copepod abundances across eddy surfaces were not mediated by phytoplankton distribution. Our results therefore suggest that physical mechanisms such as internal eddy dynamics exert a direct impact on the structure of zooplankton communities rather than indirect mechanisms involving potential food resources.
Accounting for animal movement improves vaccination strategies against wildlife disease in heterogeneous landscapes
Authors: McClure Katherine M. , Bastille-Rousseau Guillaume , Davis Amy J. , Stengel Carolyn A. , Nelson Kathleen , Chipman Richard B. , Wittemyer George , Abdo Zaid , Gilbert Amy T. , Pepin Kim M.
Published: October 2021

Oral baiting is used to deliver vaccines to wildlife to prevent, control, and eliminate infectious diseases. A central challenge is how to spatially distribute baits to maximize encounters by target animal populations, particularly in urban and suburban areas where wildlife like raccoons (Procyon lotor) are abundant and baits are delivered along roads. Methods from movement ecology that quantify movement and habitat selection could help to optimize baiting strategies by more effectively targeting wildlife populations across space. We developed a spatially explicit, individual-based model of raccoon movement and oral rabies vaccine seroconversion to examine whether and when baiting strategies that match raccoon movement patterns perform better than currently employed baiting strategies in an oral rabies vaccination zone in greater Burlington, Vermont, USA. Habitat selection patterns estimated from locally radio-collared raccoons were used to parameterize movement simulations. We then used our simulations to estimate raccoon population rabies seroprevalence under currently used baiting strategies (actual baiting) relative to habitat selection-based baiting strategies (habitat baiting). We conducted simulations on the Burlington landscape and artificial landscapes that varied in heterogeneity relative to Burlington in the proportion and patch size of preferred habitats. We found that the benefits of habitat baiting strongly depended on the magnitude and variability of raccoon habitat selection and the degree of landscape heterogeneity within the baiting area. Habitat baiting improved seroprevalence over actual baiting for raccoons characterized as habitat specialists but not for raccoons that displayed weak habitat selection similar to radio-collared individuals—except when baits were delivered off roads where preferred habitat coverage and complexity was more pronounced. In contrast, in artificial landscapes with either more strongly juxtaposed favored habitats and/or higher proportions of favored habitats, habitat baiting performed better than actual baiting, even when raccoons displayed weak habitat preferences and where baiting was constrained to roads. Our results suggest that habitat selection-based baiting could increase raccoon population seroprevalence in urban-suburban areas, where practical, given the heterogeneity and availability of preferred habitat types in those areas. Our novel simulation approach provides a flexible framework to test alternative baiting strategies in multiclass landscapes to optimize bait distribution strategies.
TargetedTshz3deletion in corticostriatal circuit components segregates core autistic behaviors
Authors: Caubit Xavier , Gubellini Paolo , Roubertoux Pierre L. , Carlier Michèle , Molitor Jordan , Chabbert Dorian , Metwaly Mehdi , Salin Pascal , Fatmi Ahmed , Belaidouni Yasmine , Brosse Lucie , Goff Lydia Kerkerian-Le , Fasano Laurent
Published: October 2021

We previously linkedTSHZ3haploinsufficiency to autism spectrum disorder (ASD) and showed that embryonic or postnatalTshz3deletion in mice results in behavioral traits relevant to the two core domains of ASD, namely social interaction deficits and repetitive behaviors. Here, we provide evidence that cortical projection neurons (CPNs) and striatal cholinergic interneurons (SCINs) are two main and complementary players in the TSHZ3-linked ASD syndrome. We show that in the cerebral cortex, TSHZ3 is expressed in CPNs and in a proportion of GABA interneurons, while not in cholinergic interneurons or glial cells. TSHZ3-expressing cells, which are predominantly SCINs in the striatum, represent a low proportion of neurons in the ascending cholinergic projection system. We then characterized two new conditional knockout (cKO) models generated by crossingTshz3flox/floxwithEmx1-Cre(Emx1-cKO) orChat-Cre(Chat-cKO) mice to decipher the respective role of CPNs and SCINs.Emx1-cKOmice show altered excitatory synaptic transmission onto CPNs and plasticity at corticostriatal synapses, with neither cortical neuron loss nor impaired layer distribution. These animals present social interaction deficits but no repetitive patterns of behavior.Chat-cKOmice exhibit no loss of SCINs but changes in the electrophysiological properties of these interneurons, associated with repetitive patterns of behavior without social interaction deficits. Therefore, dysfunction in either CPNs or SCINs segregates with a distinct ASD behavioral trait. These findings provide novel insights onto the implication of the corticostriatal circuitry in ASD by revealing an unexpected neuronal dichotomy in the biological background of the two core behavioral domains of this disorder.
Enhanced mismatch negativity in harmonic compared to inharmonic sounds
Authors: Quiroga-Martinez D. R. , Basiński K. , Nasielski J. , Tillmann B. , Brattico E. , Cholvy F. , Fornoni L. , Vuust P. , Caclin A
Published: October 2021

Many natural sounds have frequency spectra composed of integer multiples of a fundamental frequency. This property, known as harmonicity, plays an important role in auditory information processing. However, the extent to which harmonicity influences the processing of sound features beyond pitch is still unclear. This is interesting because harmonic sounds have lower information entropy than inharmonic sounds. According to predictive processing accounts of perception, this property could produce more salient neural responses due to the brain’s weighting of sensory signals according to their uncertainty. In the present study, we used electroencephalography to investigate brain responses to harmonic and inharmonic sounds commonly occurring in music: piano tones and hi-hat cymbal sounds. In a multi-feature oddball paradigm, we measured mismatch negativity (MMN) and P3a responses to timbre, intensity, and location deviants in listeners with and without congenital amusia—an impairment of pitch processing. As hypothesized, we observed larger amplitudes and earlier latencies (for both MMN and P3a) in harmonic compared to inharmonic sounds. These harmonicity effects were modulated by sound feature. Moreover, the difference in P3a latency between harmonic and inharmonic sounds was larger for controls than amusics. We propose an explanation of these results based on predictive coding and discuss the relationship between harmonicity, information entropy, and precision weighting of prediction errors.
Functional screen of Inflammatory bowel disease genes reveals key epithelial functions
Authors: Ntunzwenimana Jessy Carol , Boucher Gabrielle , Paquette Jean , Gosselin Hugues , Alikashani Azadeh , Morin Nicolas , Beauchamp Claudine , Thauvette Louise , Rivard Marie-Ève , Dupuis Frédérique , Deschenes Sonia , Foisy Sylvain , Latour Frédéric , Lavallée Geneviève , Daly Mark J. , Xavier Ramnik J. ,   the iGenoMed Consortium, Charron Guy , Goyette Philippe , Rioux John D.
Published: October 2021

Background

Genetic studies have been tremendously successful in identifying genomic regions associated with a wide variety of phenotypes, although the success of these studies in identifying causal genes, their variants, and their functional impacts have been more limited.

Methods

We identified 145 genes from IBD-associated genomic loci having endogenous expression within the intestinal epithelial cell compartment. We evaluated the impact of lentiviral transfer of the open reading frame (ORF) of these IBD genes into the HT-29 intestinal epithelial cell line via transcriptomic analyses. Comparing the genes whose expression was modulated by each ORF, as well as the functions enriched within these gene lists, identified ORFs with shared impacts and their putative disease-relevant biological functions.

Results

Analysis of the transcriptomic data for cell lines expressing the ORFs for known causal genes such as HNF4a, IFIH1 and SMAD3 identified functions consistent for what is known for these genes. These analyses also identified two major cluster of genes: Cluster 1 contained the known IBD causal genes IFIH1, SBNO2, NFKB1 and NOD2, as well as genes from other IBD loci (ZFP36L1, IRF1, GIGYF1, OTUD3, AIRE and PITX1), whereas Cluster 2 contained the known causal gene KSR1 and implicated DUSP16 from another IBD locus. Our analyses highlight how multiple IBD gene candidates impact on epithelial structure and function, including the protection of the mucosa from intestinal microbiota, and demonstrate that DUSP16, acts a regulator of MAPK activity and contributes to mucosal defense, in part via its regulation of the polymeric immunoglobulin receptor, involved in the protection of the intestinal mucosa from enteric microbiota.

Conclusions

This functional screen, based on expressing IBD genes within an appropriate cellular context, in this instance intestinal epithelial cells, resulted in changes to the cell’s transcriptome that are relevant to their endogenous biological function(s). This not only helped in identifying likely causal genes within genetic loci but also provided insight into their biological functions. Furthermore, this work has highlighted the central role of intestinal epithelial cells in IBD pathophysiology, providing a scientific rationale for a drug development strategy that targets epithelial functions in addition to the current therapies targeting immune functions.
Distinct and common features of numerical and structural chromosomal instability across different cancer types
Authors: Zhang Xiaoxiao , Kschischo Maik
Published: October 2021

A large proportion of tumours is characterised by numerical or structural chromosomal instability (CIN), defined as an increased rate of gaining or losing whole chromosomes (W-CIN) or of accumulating structural aberrations (S-CIN). Both W-CIN and S-CIN are associated with tumourigenesis, cancer progression, treatment resistance and clinical outcome. Although W-CIN and S-CIN can co-occur, they are initiated by different molecular events. By analysing tumour genomic data from 33 cancer types, we show that the majority of tumours with high levels of W-CIN underwent whole genome doubling, whereas S-CIN levels are strongly associated with homologous recombination deficiency. Both CIN phenotypes are prognostic in several cancer types. Most drugs are less efficient in high-CIN cell lines, but we also report compounds and drugs which should be investigated as targets for W-CIN or S-CIN. By analysing associations between CIN and bio-molecular entities with pathway and gene expression levels, we complement gene signatures of CIN and report that the drug resistance geneCKS1Bis strongly associated with S-CIN. Finally, we propose a potential copy number-dependent mechanism to activate thePI3Kpathway in high-S-CIN tumours.

1.

Simple summary

Many cancer cells are chromosomally unstable, a phenotype describing a tendency for accumulating chromosomal aberrations. Entire chromosomes tend to be gained or lost, which is called whole chromosome instability (W-CIN). Structural chromosomal instability (S-CIN) describes an increased rate of gaining, losing or translocating smaller parts of chromosomes. Here, we analyse data from 33 cancer types to find differences and commonalities between W-CIN and S-CIN. We find that W-CIN is strongly linked to whole genome doubling (WGD), whereas S-CIN is associated with a specific DNA damage repair pathway. Both W-CIN and S-CIN are difficult to target using currently available compounds and have distinct prognostic values. The activity of the drug resistance geneCKS1Bis associated with S-CIN, which merits further investigation. In addition, we identify a potential copy number-based mechanism promoting signalling of the importantPI3Kcancer pathway in high-S-CIN tumours.
Whole Organism Profiling of the Timp Gene Family
Authors: Peeney David , Fan Yu , Gurung Sadeechya , Lazaroff Carolyn , Ratnayake Shashikala , Warner Andrew , Karim Baktiar , Meerzaman Daoud , Stetler-Stevenson William G.
Published: October 2021

Tissue inhibitor of metalloproteinases (TIMPs/Timps) are an endogenous family of widely expressed matrisome-associated proteins that were initially identified as inhibitors of matrix metalloproteinase activity (Metzincin family proteases). Consequently, TIMPs are often considered simply as protease inhibitors by many investigators. However, an evolving list of new metalloproteinase-independent functions for TIMP family members suggests that this concept is outdated. These novel TIMP functions include direct agonism/antagonism of multiple transmembrane receptors, as well as functional interactions with matrisome targets. While the family was fully identified over two decades ago, there has yet to be an in-depth study describing the expression of TIMPs in normal tissues of adult mammals. An understanding of the tissues and cell-types that express TIMPs 1 through 4, in both normal and disease states are important to contextualize the growing functional capabilities of TIMP proteins, which are often dismissed as non-canonical. Using publicly available single cell RNA sequencing data from the Tabula Muris Consortium, we analyzed approximately 100,000 murine cells across eighteen tissues from non-diseased organs, representing seventy-three annotated cell types, to define the diversity in Timp gene expression across healthy tissues. We describe the unique expression profiles across tissues and organ-specific cell types that all four Timp genes display. Within annotated cell-types, we identify clear and discrete cluster-specific patterns of Timp expression, particularly in cells of stromal and endothelial origins. RNA in-situ hybridization across four organs expands on the scRNA sequencing analysis, revealing novel compartments associated with individual Timp expression. These analyses provide evidence of the biological significance of Timp expression in the identified cell sub-types, which are consistent with novel roles in normal tissue homeostasis and changing roles in disease progression. This understanding of the tissues, specific cell types and microenvironment conditions in which Timp genes are expressed adds important physiological context to the growing array of novel functions for TIMP proteins.