bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative single cell and spatial transcriptomic analysis reveal reciprocal microglia-plasma cell crosstalk in the mouse brain during chronicTrypanosoma bruceiinfection
Authors: Quintana Juan F. , Chandrasegaran Praveena , Sinton Matthew C. , Briggs Emma , Otto Thomas D. , Heslop Rhiannon , Bentley-Abbot Calum , Loney Colin , de Lecea Luis , Mabbott Neil A. , MacLeod Annette 
Published: March 2022

AbstractHuman African trypanosomiasis, or sleeping sickness, is caused by the protozoan parasiteTrypanosoma bruceiand induces profound reactivity of glial cells and neuroinflammation when the parasites colonise the central nervous system. However, the transcriptional and functional responses of the brain to chronicT. bruceiinfection remain poorly understood. By integrating single cell and spatial transcriptomics of the mouse brain, we identified that glial responses triggered by infection are readily detected in the proximity to the circumventricular organs, including the lateral and 3rdventricle. This coincides with the spatial localisation of both slender and stumpy forms ofT. brucei. Furthermore,in silicopredictions and functional validations led us to identify a previously unknown crosstalk between homeostaticCx3cr1+microglia andCd138+plasma cells mediated by IL-10 and B cell activating factor (BAFF) signalling. This study provides important insights and resources to improve understanding of the molecular and cellular responses in the brain during infection with African trypanosomes.
Cuticle and cuticular sensilla in Agnostina
Authors: Naimark Elena B. , Chaika Stanislav Yu. 
Published: March 2022

AbstractThe microstructure of the cuticle of several Agnostina species is described. For the first time, it has been shown that their cuticle consists of three layers: thick outer and transitional layers and a thin inner layer. The layers are made up of stacks of laminae: the laminae in the outer layer are thicker than in the transitional and inner ones. The evolution of the agnostoid cuticle proceeded, apparently, in the direction of decreasing the thickness of the inner layer which in contrast to all other arthropods, is thinner than the outer layer. Apparently, the inner layer was mineralized to a lesser extent than the outer one. In the structure of the cuticle, Agnostina are close to horseshoe crabs and trilobites. On the outer and inner layers, a set of sensilla was revealed; they can be attributed to trichoid, campaniform, and digitiform sensilla (with mechanoreceptor function) and celoconic sensilla (with chemoreceptor function). Also, unique sensorial ensembles were found on cephalons and pygidia; the function of the former is probably mechanosensorial, and the purpose of the latter cannot be assumed on this material.
CHA1: A New Combinatorial Therapy That Reciprocally Regulates Wnt and JAK/STAT/Interferon Signaling to Re-program Breast Tumors and the Tumor-Resident Landscape
Authors: Alamoudi Mariam K. , Chipman Mollie , Deieso-Frechette Francesca , Bogis Ahlam Mukhtar , Alqurashi Roaya S. , Li Kaiqi , Zhang Rui , Castañer Maricel , Triafallou George , Herbosa Christopher G. , Carland Corinne , Lee AJ. Jaehoon , Gillani Kyle , Paulson K. Eric , Yee Amy S. 
Published: March 2022

ABSTRACTTriple negative breast cancers (TNBC) pose exceptional challenges with fatal brain metastases as a clear and unmet need. Immune checkpoint inhibitors (ICIs) are promising therapeutic strategies, but most TNBC are resistant, or “cold” tumors, due to lack of tumor-resident immune engagement. No FDA-approved therapies exist which promote a “cold-to-hot” transition or induce the important biomarker PD-L1, often used for ICI clinical decision-making. Maximal ICI susceptibility, or a full “cold-to-hot” transition, requires reciprocal Wnt signaling inhibition and Jak/STAT/interferon signaling activation. We report a new compound combination (CHA1) that fits the above criteria. CHA1 is comprised of EGCG (epigallocatechin-3-gallate; green-tea compound) and decitabine (DNA-methyltransferase (DNMT1) inhibitor; 5’deaza-cytidine; FDA-approved for hematologic malignancies). We used immune-compromised and syngeneic TNBC pre-clinical models to investigate tumor-intrinsic and tumor-resident T-cell effects, respectively. All results required CHA1 (but not EGCG or decitabine alone) and utilized attainable human dose equivalences with manageable safety profiles. CHA1 triggered efficient Wnt signaling inhibition by elevating Wnt pathway inhibitors (HBP1 and SFRP1) and traversed the blood-brain barrier to reduce both tumor and brain metastatic growth. Transcriptomic and expression analyses revealed that CHA1 treatment effectuated a robust tumor-intrinsic JAK/STAT/IFN response 1) to induce PDL1 and 2) to induce antigen presentation and processing genes, including MHC-1, MHC-2 and numerous genes attributed to professional antigen-presenting cells; 3) to induce CD8+-T-cell infiltration and activation. Additionally, CHA1 pre-treatment improved anti-PDL1 efficacy in a syngeneic setting. Lastly, we derived a composite gene signature emblematic of CHA1 treatment and of a favorable clinical prognosis in-silico. Together, our work supports a model in which CHA1 influences epigenetics, Wnt and Jak/STAT/IFN signaling mechanisms—all to reprogram an epithelial-mesenchymal TNBC tumor to express antigen-presenting properties and to recruit and activate tumor-resident CD8+-T-cells. We discuss our findings in the context of cancer biology and immunity with implications for improving ICI susceptibility for TNBC.
Combinatorial interactions of Hox genes establish appendage diversity of the amphipod crustacean Parhyale hawaiensis
Authors: Alberstat Erin Jarvis , Chung Kevin , Sun Dennis A , Ray Shagnik , Patel Nipam H. 
Published: March 2022

AbstractHox genes establish regional identity along the anterior-posterior axis in diverse animals. Changes in Hox expression can induce striking homeotic transformations, where one region of the body is transformed into another. Previous work in Drosophila has demonstrated that Hox cross-regulatory interactions are crucial for maintaining proper Hox expression. One major mechanism is the phenomenon of “posterior prevalence”, wherein anterior Hox genes are repressed by more posterior Hox genes. Loss of posterior Hox expression under this model would predict posterior-to-anterior transformations, as is frequently observed in Drosophila. While posterior prevalence is thought to occur in many animals, studies of such Hox cross-regulation have focused on a limited number of organisms. In this paper, we examine the cross-regulatory interactions of three Hox genes, Ultrabithorax (Ubx), abdominal-A (abd-A), and Abdominal-B (Abd-B) in patterning thoracic and abdominal appendages in the amphipod crustacean Parhyale hawaiensis. Studies of Hox function in Parhyale have previously revealed two striking phenotypes which differed markedly from what a “posterior prevalence” model would predict, including non-contiguous and anterior-to-posterior transformations. We probe the logic of Parhyale Hox cross-regulation by using CRISPR/Cas9 to systematically examine all combinations of Ubx, abd-A, and Abd-B loss of function in Parhyale. By analyzing homeotic phenotypes and examining the expression of additional Hox genes, we reveal Hox cross-regulatory interactions in Parhyale. From these data, we also demonstrate that some Parhyale Hox genes function combinatorially to specify posterior limb identity, rather than abiding by a posterior prevalence mechanism. These results provide evidence that combinatorial Hox interactions may be responsible for the tremendous body plan diversity of crustaceans.Graphical Abstract
Mobile elements in human population-specific genome and phenotype divergence
Authors: Kojima Shohei , Koyama Satoshi , Ka Mirei , Saito Yuka , Parrish Erica H. , Endo Mikiko , Takata Sadaaki , Mizukoshi Misaki , Hikino Keiko , Takeda Atsushi , Gelinas Asami F. , Heaton Steven M. , Koide Rie , Kamada Anselmo J. , Noguchi Michiya , Hamada Michiaki ,   Biobank Japan Project Consortium, Kamatani Yoichiro , Murakawa Yasuhiro , Ishigaki Kazuyoshi , Nakamura Yukio , Ito Kaoru , Terao Chikashi , Momozawa Yukihide , Parrish Nicholas F. 
Published: March 2022

AbstractMobile genetic elements (MEs) are heritable mutagens that contribute to divergence between lineages by recursively generating structural variants. ME variants (MEVs) are difficult to genotype, obscuring their impact on recent genome and trait diversification. We developed a tool that uses short-read sequence data to accurately genotype MEVs, enabling us to study them using statistical genetics methods in global human genomes. We observe population-specific differences in the distribution of Alu insertions that distinguish Japanese from other populations. We integrated MEVs with epigenomic and expression quantitative trait loci (eQTL) maps to determine how they impact traits. This reveals coherent patterns by which specific MEs regulate tissue-specific gene expression, including creating or attenuating enhancers and recruiting post-transcriptional regulators. We pinpoint MEVs as genetic causes of disease risk, including a LINE-1 insertion linked to keloid and other diseases of fibroblast inflammation, by introducing MEVs into the genome-wide association study (GWAS) framework. In addition to nominating previously-hidden MEVs as causes of human diseases, this work highlights MEs as accelerators of human population divergence and begins to decipher the semantics of MEs.
DiSiR: a software framework to identify ligand-receptor interactions at subunit level from single-cell RNA-sequencing data
Authors: Vahid Milad R. , Kurlovs Andre , Auge Franck , Olfati-Saber Reza , de Rinaldis Emanuele , Rapaport Franck , Savova Virginia 
Published: March 2022

AbstractMost of cell-cell interactions and crosstalks are mediated by ligand-receptor interactions. The advent of single-cell RNA-sequencing (scRNA-seq) techniques has enabled characterizing tissue heterogeneity at single-cell level. Over the past recent years, several methods have been developed to study ligand-receptor interactions at cell type level using scRNA-seq data. However, there is still no easy way to query the activity of a specific user-defined signaling pathway in a targeted way or map the interactions of the same subunit with different ligands as part of different receptor complexes. Here, we present DiSiR, a fast and easy-to-use permutation-based software framework to investigate how individual cells are interacting with each other by analyzing signaling pathways of multi-subunit ligand-activated receptors from scRNA-seq data, not only for available curated databases of ligand-receptor interactions, but also for interactions that are not listed in these databases. We show that, when utilized to infer melanoma disease map on a gold-standard dataset, DiSiR outperforms other well-known permutation-based methods, e.g., CellPhoneDB and ICELLNET. To demonstrate DiSiR’s utility in exploring data and generating biologically relevant hypotheses, we apply it to COVID lung and rheumatoid arthritis (RA) synovium scRNA-seq data and highlight potential differences between inflammatory pathways at cell type level for control vs. disease samples.
Synthetic torpor triggers a neuroprotective and regulated mechanism in the rat brain, favoring the reversibility of Tau protein hyperphosphorylation
Authors: Squarcio Fabio , Hitrec Timna , Piscitiello Emiliana , Cerri Matteo , Giovannini Catia , Martelli Davide , Occhinegro Alessandra , Taddei Ludovico , Tupone Domenico , Amici Roberto , Luppi Marco 
Published: March 2022

AbstractHyperphosphorylated Tau protein (PPTau) is the hallmark of tauopathic neurodegeneration. During “synthetic torpor” (ST), a transient hypothermic state which can be induced in rats by the local pharmacological inhibition of the Raphe Pallidus, a reversible brain Tau hyperphosphorylation occurs. The aim of the present study was to elucidate the – as yet unknown – molecular mechanisms underlying this process, at both a cellular and systemic level. Different phosphorylated forms of Tau and the main cellular factors involved in Tau phospho-regulation were assessed by western blot in the parietal cortex and hippocampus of rats induced in ST, at either the hypothermic nadir or after the recovery of euthermia. Pro- and anti-apoptotic markers, as well as different systemic factors which are involved in natural torpor, were also assessed. Finally, the degree of microglia activation was determined through morphometry. Overall, the results show that ST triggers a regulated biochemical process which can counteract PPTau formation starting, unexpectedly even for a non-hibernator, from the hypothermic nadir. In particular, at the nadir, the glycogen synthase kinase-β was largely inhibited in both regions, the antiapoptotic factor AKT was significantly activated in the hippocampus, and melatonin plasma levels were significantly increased, while a transient neuroinflammation was observed during the recovery period. Together, the present data suggest that ST can trigger a previously undescribed latent and regulated physiological process, that is able to cope with brain PPTau formation.Graphical abstract
qad: An R-package to detect asymmetric and directed dependence in bivariate samples
Authors: Griessenberger Florian , Trutschnig Wolfgang , Junker Robert R. 
Published: March 2022

AbstractCorrelations belong to the standard repertoire of ecologists for quantifying the strength of dependence between two random variables. Classical dependence measures are usually not capable of detecting non-monotonic or non-functional dependencies. Furthermore, they completely fail to detect asymmetry and direction in dependence, which exist in many situations and should not be ignored. In this paper, we present qad (short for quantification of asymmetric dependence), a non-parametric statistical method to quantify directed and asymmetric dependence of bivariate samples. qad is applicable in general situations, is sensitive to noise in data, exhibits a good small sample performance, detects asymmetry in dependence, shows high power in testing for independence, requires no assumptions regarding the underlying distribution of the data, and reliably quantifies the information gain/predictability of quantity Y given knowledge of quantity X, and vice versa (i.e. q(X,Y) ≠ q(Y, X)). Here, we briefly recall the methodology underlying qad, introduce the functions of the R-package qad, which returns estimates for the measures q(X, Y) denoting the directed dependence of Y on X (or, equivalently, the influence of X on Y), q(Y, X) the directed dependence of X on Y, a(X, Y) ≔ q(X, Y) − q(Y, X) the asymmetry in dependence. Furthermore, qad can be used to predict Y given knowledge of X, and vice versa. Additionally, we compare empirical performance of qad with that of seven other well established measures and demonstrate the applicability of qad on ecological datasets. We illustrate that direction and asymmetry in dependence are universal properties of bivariate associations. qad thus provides additional information gain and the avoidance of model bias and will therefore advance and facilitate the understanding of ecological systems.
Subjective cognitive decline predicts lower cingulo-opercular network functional connectivity in individuals with lower neurite density in the forceps minor
Authors: Ruiz-Rizzo Adriana L. , Viviano Raymond P. , Daugherty Ana M. , Finke Kathrin , Müller Hermann J. , Damoiseaux Jessica S. 
Published: March 2022

AbstractCognitive complaints of attention/concentration problems are highly frequent in older adults with subjective cognitive decline (SCD). Functional connectivity in the cingulo-opercular network (CON-FC) supports cognitive control, tonic alertness, and visual processing speed. Thus, those complaints in SCD may reflect a decrease in CON-FC. Frontal white-matter tracts such as the forceps minor exhibit age- and SCD-related alterations and, therefore, might influence the CON-FC decrease in SCD. Here, we aimed to determine whether SCD predicts an impairment in CON-FC and whether neurite density in the forceps minor modulates that effect. To do so, we integrated cross-sectional and longitudinal analyses of multimodal data in a latent growth curve modeling approach. Sixty-nine healthy older adults (13 males; 68.33 ± 7.95 years old) underwent resting-state functional and diffusion-weighted magnetic resonance imaging, and the degree of SCD was assessed at baseline with the memory functioning questionnaire (greater score indicating more SCD). Forty-nine of the participants were further enrolled in two follow-ups, each about 18 months apart. Baseline SCD did not predict CON-FC after three years or its rate of change (p-values > 0.092). Notably, however, the forceps minor neurite density did modulate the relation between SCD and CON-FC (intercept; b = 0.21, 95% confidence interval, CI, [0.03, 0.39], p = 0.021), so that SCD predicted a greater CON-FC decrease in older adults with relatively lower neurite density in the forceps minor. The neurite density of the forceps minor, in turn, negatively correlated with age. These results suggest that CON-FC alterations in SCD are dependent upon the forceps minor neurite density. Accordingly, these results imply modifiable age-related factors that could help delay or mitigate both age and SCD-related effects on brain connectivity.
Spatiotemporal variations in retrovirus-host interactions among Darwin’s finches
Authors: Hill Jason , Lillie Mette , Pettersson Mats E , Rubin Carl-Johan , Grant B Rosemary , Grant Peter R , Andersson Leif , Jern Patric 
Published: March 2022

AbstractEndogenous retroviruses (ERVs) are inherited remnants of past retroviruses that colonized host germline over millions of years, providing a sampling of retroviral diversity across time. The utility of ERVs as markers of host genome evolution is augmented by their ability to reveal historic retrovirus-host interactions, given that ERVs are examples of active retroviruses at the time of germline invasion. Here, we utilize the strength of Darwin’s finches, a system synonymous with evolutionary studies, for investigating ERV history, revealing recent retrovirus-host interactions in natural populations. By mapping ERV variation across all species of Darwin’s finches and comparing with outgroup species, we highlight geographical and historical patterns of retrovirus-host occurrence, utilizing the system as a natural model for evaluating the extent and timing of retroviral activity in hosts undergoing adaptive radiation and colonization of new environments. We found shared ERVs among all samples indicating retrovirus-host associations pre-dating host speciation, as well as considerable ERV variation across populations of the entire Darwin’s finches’ radiation. Unexpected ERV variation in finch species on different islands suggest historical changes in gene flow and selection. Non-random distribution of ERVs along and between chromosomes, as well as across finch species, suggests association between ERV accumulation and the rapid speciation of Darwin’s finches.
Ecological and evolutionary consequences of selective interspecific information use
Authors: Hämäläinen Reetta , Kajanus Mira H. , Forsman Jukka T. , Kivelä Sami M. , Seppänen Janne-Tuomas , Loukola Olli J. 
Published: March 2022

II.AbstactThe ecology of social information use has been studied in many intra- and interspecific contexts, while the evolutionary consequences of social information use remain less understood. Furthermore, selective social information use, where individuals are discriminative in their decision-making on how to use social information, has been overlooked in interspecific context. In particular, the intentional decision to reject a behavioural trait observed via social information, has gained less attention, although it has recently been shown to occur in various taxa. We develop an individual-based simulation model to explore in which circumstances social information use leads to different coevolutionary outcomes among populations of two species. The initial phenotypes and the balance between costs of competition and benefits of social information use determine whether selection leads to trait divergence, convergence or coevolutionary arms race between two species. Based on existing literature, we propose that selective decisions of individuals, including active rejection, may have far-reaching fitness consequences, potentially leading to similar evolutionary consequences among the populations of the information source and the user as predicted by our model. Overall, we argue that the eco-evolutionary consequences of selective interspecific social information use may be much more prevalent than thus far considered.
Metabolism of glucose activates TORC1 through multiple mechanisms in Saccharomyces cerevisiae
Authors: Alfatah Mohammad , Cui Liang , Hui Goh Corinna Jie , Wong Jin Huei , Lewis Jacqueline , Poh Wei Jie , Arumugam Prakash 
Published: March 2022

SummaryTarget of Rapamycin Complex 1 (TORC1) is a conserved eukaryotic protein complex that links the presence of nutrients with cell growth. In Saccharomyces cerevisiae, TORC1 activity is positively regulated by the presence of amino acids and glucose in the medium. However, mechanisms underlying nutrient-induced TORC1 activation remain poorly understood. By utilizing a TORC1 activation assay, we demonstrate that differential metabolism of glucose activates TORC1 through three distinct pathways in yeast. The first ‘canonical Rag GTPase-dependent pathway’ requires conversion of glucose to fructose 1,6-bisphosphate which activates TORC1 via the Rag GTPase heterodimer Gtr1GTP/Gtr2GDP. The second ‘non-canonical Rag GTPase-dependent pathway’ requires conversion of glucose to glucose 6-phosphate which activates TORC1 via Gtr1GTP/Gtr2GTP. The third ‘Rag GTPase-independent pathway’ requires complete glycolysis and vacuolar ATPase reassembly for TORC1 activation. Glucose-induced TORC1 activation can be uncoupled from glucose-induced AMPK inactivation. We have established a roadmap to deconstruct the link between glucose metabolism and TORC1 activation.
Paf1C denoises transcription and growth patterns to achieve organ shape reproducibility
Authors: Trinh Duy-Chi , Martin Marjolaine , Bald Lotte , Maizel Alexis , Trehin Christophe , Hamant Olivier 
Published: March 2022

SUMMARYIn multicellular systems, all cells exhibit transcriptional noise. However, its exact contribution to morphogenesis often remains unclear, especially in animals where cells can also move. Here we take advantage of walled plant cells, where transcriptional noise happens in tissues with a fixed topology. Using synchronously growing guard cells in stomata, we demonstrate that mutation in VIP3, a subunit of the conserved polymerase-associated factor 1 complex (Paf1C), increases transcriptional noise in Arabidopsis. This conclusion could be generalized to other group of cells at the shoot apex. Such noise translates into growth and shape defects. Indeed, in vip3 sepals, we measured higher growth heterogeneity between adjacent cells, with molecular evidence of increased local mechanical conflicts. This even culminated with the presence of negatively growing cells in specific growth conditions. Interestingly, such increased local noise makes the regional pattern of growth less clear-cut. Reduced regional conflicts lead to delay in organ growth arrest, ultimately making final organ shapes and sizes more variable. We propose that transcriptional noise is managed by Paf1C to ensure organ robustness by building up mechanical conflicts at the regional scale, instead of the local scale.HIGHLIGHTSPaf1C controls transcriptional noise in ArabidopsisPaf1C reduces growth heterogeneity and dampens local mechanical conflictsImpairing both Paf1C and microtubules can trigger negative growth in ArabidopsisScaling up local conflicts to regional ones with sharp boundaries contributes to organ shape robustness