bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial tumour gene signature discriminates neoplastic from non-neoplastic compartments in colon cancer: unravelling predictive biomarkers for relapse
Authors: Sallinger Katja , Gruber Michael , Müller Christin-Therese , Bonstingl Lilli , Pritz Elisabeth , Pankratz Karin , Gerger Armin , Smolle Maria Anna , Aigelsreiter Ariane , Surova Olga , Svedlund Jessica , Nilsson Mats , Kroneis Thomas , El-Heliebi Amin 
Published: September 2022

AbstractBackgroundTherapeutic management of stage II colon cancer remains difficult regarding the decision whether adjuvant chemotherapy should be administered or not. Low rates of recurrence are opposed to chemotherapy induced toxicity and current clinical features are limited in predicting disease relapse. Predictive biomarkers are urgently needed and we hypothesise that the spatial tissue composition of relapsed and non-relapsed colon cancer stage II patients reveals relevant biomarkers.MethodsThe spatial tissue composition of stage II colon cancer patients was examined by in situ sequencing technology with sub-cellular resolution. A panel of 175 genes was designed investigating specific cancer-associated processes and components of the tumour microenvironment. We identified a tumour gene signature to subclassify tissue into neoplastic and non-neoplastic tissue compartments based on spatial expression patterns generated by in situ sequencing (GTC-tool – Genes-To-Count).ResultsThe GTC-tool automatically identified tissue compartments that were used to quantify gene expression of biological processes upregulated within the neoplastic tissue in comparison to non-neoplastic tissue and within relapsed versus non-relapsed stage II colon patients. Three differentially expressed genes (FGFR2, MMP11 and OTOP2) in the neoplastic tissue compartments of relapsed patients in comparison to non-relapsed patients were identified predicting recurrence in stage II colon cancer.ConclusionsIn depth spatial in situ sequencing revealed novel potential predictive biomarkers for disease relapse in colon cancer stage II patients. Our developed open-access GTC-tool allows to accurately capture the tumour compartment and quantify spatial gene expression in colon cancer tissue.
miR-28 plus ibrutinib as a novel combination therapy for Diffuse Large B Cell Lymphoma
Authors: Fuertes Teresa , Álvarez-Corrales Emigdio , Ubieto-Capella Patricia , Serrano-Navarro Álvaro , Gómez-Escolar Carmen , de Molina Antonio , Méndez Juan , Ramiro Almudena R. , de Yébenes Virginia G. 
Published: September 2022

ABSTRACTDiffuse large B cell lymphoma (DLBCL) is the most common aggressive B cell lymphoma and accounts for nearly 40% of cases of B cell non-Hodgkin lymphoma. DLBCL is generally treated with R-CHOP chemotherapy, but many patients do not respond or relapse after treatment. Here, we analyzed the therapeutic potential of the tumor suppressor microRNA-28 (miR-28) for DLBCL, alone and in combination with the Bruton’s tyrosine kinase inhibitor ibrutinib. Combination therapy with miR-28 plus ibrutinib potentiated the anti-tumor effects of monotherapy with either agent by inducing a specific transcriptional cell-cycle arrest program that impairs DNA replication. Moreover, we found that downregulation of the miR-28-plus-ibrutinib gene signature correlates with better survival of ABC-DLBCL patients. These results provide evidence for the effectiveness of a new miRNA-based ibrutinib combination therapy for DLBCL and unveil the miR-28-plus-ibrutinib gene signature as a new predictor of outcome in ABC-DLBCL patients.STATEMENT OF SIGNIFICANCEThis study demonstrates that a miRNA-based combination therapy with ibrutinib is superior to both monotherapies in DLBCL. miR-28 plus ibrutinib combined therapy inhibits DLBCL growth through the induction of a transcriptional program that impairs DNA replication. Our results provide a new gene signature with prognostic value for ABC-DLBCL.
Analysis of noisy transient signals based on Gaussian process regression
Authors: Baglaeva I. , Iaparov B. , Zahradník I. , Zahradníková A. 
Published: September 2022

AbstractDynamic systems such as cells or tissues generate, either spontaneously or in response to stimuli, transient signals that carry information about the system. Characterization of recorded transients is often hampered by a low signal-to-noise ratio (SNR). Reduction of the noise by filtering has limited use due to partial signal distortion. Occasionally, transients can be approximated by a mathematical function, but such a function may not hold correctly if recording conditions change. We introduce here the model-independent approximation method for general noisy transient signals based on the Gaussian process regression (GPR). The method was implemented in the software TransientAnalyzer, which detects transients in a record, finds their best approximation by the Gaussian process, constructs a surrogate spline function, and estimates specified signal parameters. The method and software were tested on a cellular model of the calcium concentration transient corrupted by various SNR levels and recorded at a low sampling frequency. Statistical analysis of the model data sets provided the error of estimation <7.5% and the coefficient of variation of estimates <17% for peak SNR=5. The performance of GPR on signals of diverse experimental origin was even better than fitting by a function. The software and its description are available on GitHub.Statement of SignificanceTransient signals convey information on the state and function of the studied system. However, the estimation of their characteristic parameters is complicated by the noise present in the recordings. Methods used for noise reduction have various disadvantages, such as distortion of the time course by filtering, the difficult superposition of many transients for accurate averaging, or a lack of a model for data fitting. In this work, we present a general method for the automatic analysis of noisy transient signals based on Gaussian process regression and its implementation in Python. The method can analyze recorded transients reliably at peak SNR ≥ 2 with a precision equivalent to the model-fitting methods.
The clone wars: the Japanese knotweed (Fallopia japonica) vs the black vine weevil (Otiorhynchus sulcatus) – characterization of a potential herbivory
Authors: Teulier Loic , Puijalon Sara , Boisselet Christelle , Piola Florence 
Published: September 2022

AbstractThe Japanese knotweed (Fallopia japonica) is considered as highly invasive in Europe and is largely widespread in France, without any established predator. This short study first characterized the herbivory of Fallopia by the black vine weevil (Otiorhynchus sulcatus), a commonly encountered coleopteran in France. Through an experimental design of leaf choices, between Fragaria spp. and Fallopia spp., our results show that the insects prefer Fallopia, even if it is presented for the first time. Even if this simple observation may appear as trivial, it highlights a novel plant-insect interaction and may start new insight in plant control or invasion management.
Inferring sparse structure in genotype-phenotype maps
Authors: Petti Samantha , Reddy Gautam , Desai Michael M. 
Published: September 2022

AbstractCorrelation among multiple phenotypes across related individuals may reflect some pattern of shared genetic architecture: individual genetic loci affect multiple phenotypes (an effect known as pleiotropy), creating observable relationships between phenotypes. A natural hypothesis is that pleiotropic effects reflect a relatively small set of common “core” cellular processes: each genetic locus affects one or a few core processes, and these core processes in turn determine the observed phenotypes. Here, we propose a method to infer such structure in genotype-phenotype data. Our approach,sparse structure discovery(SSD) is based on a penalized matrix decomposition designed to identify latent structure that is low-dimensional (many fewer core processes than phenotypes and genetic loci), locus-sparse (each locus affects few core processes) and/or phenotype-sparse (each phenotype is influenced by few core processes). Our use of sparsity as a guide in the matrix decomposition is motivated by the results of a novel empirical test indicating evidence of sparse structure in several recent genotype-phenotype data sets. First, we use synthetic data to show that our SSD approach can accurately recover core processes if each genetic locus affects few core processes or if each phenotype is affected by few core processes. Next, we apply the method to three datasets spanning adaptive mutations in yeast, genotoxin robustness assay in human cell lines, and genetic loci identified from a yeast cross, and evaluate the biological plausibility of the core process identified. More generally, we propose sparsity as a guiding prior for resolving latent structure in empirical genotype-phenotype maps.
Learning the sound inventory of a complex vocal skill via an intrinsic reward
Authors: Toutounji Hazem , Zai Anja T. , Tchernichovski Ofer , Hahnloser Richard H.R. , Lipkind Dina 
Published: September 2022

SummaryReinforcement learning (RL) is thought to underlie the acquisition of vocal skills like birdsong and speech, where sounding like one’s “tutor” is rewarding. Yet, we find that the standard actor-critic RL model of birdsong learning fails to account for juvenile zebra finches’ efficient learning of an inventory of multiple syllables. But when we replace a single actor with multiple independent actors that jointly maximize a common intrinsic reward, then birds’ empirical learning trajectories are accurately reproduced. Importantly, the influence of each actor (syllable) on the magnitude of global reward is competitively determined by its acoustic similarity to target syllables. This leads to each actor matching the target it is closest to, and occasionally, to the competitive exclusion of an actor from the learning process (i.e., the learned song). We propose that a competitive-cooperative multi-actor (MARL) algorithm is key for the efficient learning of the action inventory of a complex skill.
The ubiquitin conjugase Rad6 mediates ribosome pausing during oxidative stress
Authors: Meydan Sezen , Barros Géssica C. , Simões Vanessa , Harley Lana , Cizubu Blanche K. , Guydosh Nicholas R. , Silva Gustavo M. 
Published: September 2022

SUMMARYOxidative stress causes K63-linked ubiquitination of ribosomes by the E2 ubiquitin conjugase, Rad6. How Rad6-mediated ubiquitination of ribosomes affects global translation, however, is unclear. We therefore performed Ribo-seq and Disome-seq in Saccharomyces cerevisiae, and found that oxidative stress caused ribosome pausing at specific amino acid motifs, and this also led to ribosome collisions. However, these redox pausing signatures were lost in the absence of Rad6 but did not depend on the ribosome-associated quality control (RQC) pathway. We also found that Rad6 is needed to inhibit overall translation in response to oxidative stress and its deletion leads to increased expression of antioxidant genes. Finally, we observed that the lack of Rad6 leads to changes during translation initiation that affect activation of the integrated stress response (ISR) pathway. Our results provide a high-resolution picture of the gene expression changes during oxidative stress and unravel an additional stress response pathway affecting translation elongation.HIGHLIGHTSRad6 is required for sequence-specific ribosome pausing under oxidative stress.Rad6 affects translation independently of the RQC pathway.Cells lacking Rad6 show dysregulated translational repression upon oxidative stress.Loss of Rad6 leads to altered activation of the ISR pathway.
Nanoscale infrared spectroscopy identifies parallel to antiparallel beta sheet transformation of Aβ fibrils
Authors: Banerjee Siddhartha , Baghel Divya , Hasan-ul-Iqbal Md. , Ghosh Ayanjeet 
Published: September 2022

AbstractSpontaneous aggregation of amyloid beta (Aβ) proteins leading to the formation of oligomers and eventually into fibrils has been identified as a key pathological signature of Alzheimer’s disease. Structure of late stage aggregates have been studied in depth by conventional structural biology techniques including Nuclear Magnetic Resonance, X-ray crystallography and Infrared Spectroscopy; however the structure of early-stage aggregates is less known due to their transient nature. As a result, the structural evolution of amyloid aggregates from its early oligomers to mature fibril is still not fully understood. Here we have applied AFM-IR nanospectroscopy to investigate the aggregation of Aβ 16-22, which spans the amyloidogenic core of the amyloid beta peptide. Our results demonstrate that Aβ 16-22 involves a structural transition from oligomers with parallel beta sheets to antiparallel fibrils through disordered and possibly helical intermediate fibril structures, contrary to the known aggregation pathway of full-length Aβ.
The TaxUMAP atlas: efficient display of large clinical microbiome data reveals ecological competition involved in protection against bacteremia
Authors: Schluter Jonas , Djukovic Ana , Taylor Bradford P. , Yan Jinyuan , Duan Caichen , Hussey Grant A. , Liao Chen , Sharma Sneh , Fontana Emily , Amoretti Luigi A. , Wright Roberta J. , Dai Anqi , Peled Jonathan U. , Taur Ying , Perales Miguel-Angel , Siranosian Benjamin A. , Bhatt Ami S. , van den Brink Marcel R.M. , Pamer Eric G. , Xavier Joao B. 
Published: September 2022

SUMMARYThe microbiome is associated with health and disease, but causal effects are hard to quantify— especially in humans where controlled experiments are nearly impossible. Akin to natural experiments, closely monitored patients offer an alternative to characterize microbiome effects. We present TaxUMAP, a taxonomically-informed visualization method to effectively display diverse microbiome states. TaxUMAP charts a microbiome atlas from 1,870 cancer patients as they progress through therapy-induced perturbations, and quantifies the microbiome contribution to patients’ risk for life-threatening bacteremia. We find that the lowest diversity states (gut dominations) that follow antibiotic treatments are stable, and that diverse communities harbor more diverse antimicrobial resistance genes than dominations. We reveal that certain Klebsiella species are associated with reduced risk for bacteremia, an effect driven by bacterial competition that we validate experimentally in vitro and in vivo. TaxUMAP effectively maps longitudinal microbiome data that can facilitate research into causal microbiome effects on human health.HIGHLIGHTSTaxUMAP charts an atlas of patients’ microbiome states and their clinical context to reveal new causal effects.Antibiotics deplete the biodiversity and reduce the number of different antimicrobial resistance genes in the gut microbiome.Certain Klebsiella species are associated with lower risk of bacteremia by other gut-borne pathogens.These Klebsiella outcompete other gram-negative pathogens in vivo.
Rising novelty and homogenization of breeding bird communities in the U.S.
Authors: Latimer C. E. , Graves R. A. , Pidgeon A. M. , Gorzo J. M. , Henschell M. , Schilke P. R. , Hobi M. L. , Olah A. , Kennedy C.M. , Zuckerberg B. , Radeloff V. C. 
Published: September 2022

AbstractAimHuman modification has profound effects on the diversity of ecological communities. Yet, surprisingly little is known about how abiotic novelty due to human modification relates to biological novelty as measured by shifts in species composition from historical baselines. Using space-for-time substitution, we ask a) whether high human modification results in biotic homogenization or heterogenization across different spatial scales; b) if high modification results in the formation of novel, “no-analog” communities; and c) whether changes in bird community composition varies in response to proxies of historical land-use and duration-of-exposure to anthropogenic disturbances.LocationConterminous United States.Time Period2012 – 2016.Major taxa studiedPasseriformes.MethodsWe analyzed continent-wide avian biodiversity data from an online checklist program, eBird, to examine how shifts in breeding bird species composition have been impacted by human modification at regional and continental scales and tested four hypotheses related to how abiotic novelty resulting from human modification generates biological novelty.ResultsAt regional scales, bird communities in highly human-modified areas exhibited similar levels of β-diversity as those in the least modified areas. However, at the continental scale, spatial turnover in community composition was lower in human-modified areas, suggesting that anthropogenic disturbance has a strong homogenizing effect on bird communities at that scale. Lastly, human modification contributed more to community composition in regions where natural disturbance was infrequent and Euro-American settlement occurred later, consistent with the hypothesis that exposure to historical disturbances can shape how contemporary bird communities respond to human modification.Main conclusionsThe observed patterns of increased biotic novelty and homogenization in regions with less frequent disturbances and a longer history of human modification suggests that future extensive human modification could result in further homogenization of bird communities, particularly in the western U.S. We argue that current human-modified environments hold great potential for biodiversity conservation.
Commensal-specific CD4 T cells promote inflammation in the central nervous system via molecular mimicry
Authors: White Zachary , Cabrera Ivan , Ochoa-Raya Andrea , Kapustka Isabel , Koster Kevin P. , Matsuo Takashi , Jayawardena Dulari , Kageyama Takahiro , Dudeja Pradeep K , Lutz Sarah E. , Yoshii Akira , Sano Teruyuki 
Published: September 2022

AbstractCommensal bacteria are critical regulators of both tissue homeostasis and the development and exacerbation of autoimmunity. However, it remains unclear how the intestinal microbiota contributes to inflammation in tissues such as the central nervous system (CNS) where these microbes are typically absent and whether T cell receptor (TCR) specificity for commensal-derived antigens is important to the development of tissue inflammation-related outcomes. Here, we found that ileum- and cecum-colonizing segmented filamentous bacteria (SFB)-specific T cells (clone TCR7B8) can infiltrate the CNS wherein they can be reactivated and produce high levels of inflammatory cytokines including IFNγ, IL-17A, TNFα, and GM-CSF in the absence of regulatory T cells. In contrast, other SFB-specific T cells (clone TCR1A2) recognizing an epitope in which 8/9 amino acids overlap with those recognized by TCR7B8 failed to induce such neuroinflammation. Despite their similar SFB-derived peptide antigen targets, TCR7B8 was found to recognize peptides derived from host proteins including receptor tyrosine-protein kinase ErbB2, trophinin 1, and anaphase-promoting complex subunit 2 in vitro, whereas TCR1A2 did not, indicating that TCR7B8 induces CNS inflammation via molecular mimicry. Immune checkpoint blockade accelerated TCR7B8-mediated CNS inflammation, suggesting a potential cause of immune-related adverse events induced in cancer patients undergoing such treatment. Together, our findings reveal a potential mechanism whereby gut commensal-specific T cells are dysregulated and contribute to extraintestinal inflammation.
In vivoproximity ligation reveals endogenous candidate interactors of Neurexin’s intracellular domain
Authors: Profes Marcos Schaan , Tiroumalechetty Araven , Patel Neel , Lauar Stephanie S. , Sidoli Simone , Kurshan Peri T. 
Published: September 2022

AbstractNeurexins are highly-spliced transmembrane cell adhesion molecules that bind an array of partners via their extracellular domains. However, much less is known about the signaling pathways downstream of neurexin’s largely-invariant intracellular domain. C. elegans contains a single neurexin gene that we have previously shown is required for presynaptic assembly and stabilization. To gain insight into the signaling pathways mediating neurexin’s presynaptic functions, we employed a proximity ligation method, endogenously tagging neurexin’s intracellular domain with the promiscuous biotin ligase TurboID, allowing us to isolate adjacent biotinylated proteins by streptavidin pull-down and mass spectrometry. We compared our experimental strain to a control strain in which neurexin, endogenously tagged with TurboID, was dispersed from presynaptic active zones by the deletion of its C-terminal PDZ-binding motif. Using this approach we identified both known and novel intracellular interactors of neurexin, including active zone scaffolds, actin-binding proteins (including almost every member of the Arp2/3 complex), signaling molecules, and mediators of RNA trafficking, protein synthesis and degradation, among others. Characterization of mutants for candidate neurexin interactors revealed that they recapitulate aspects of thenrx-1mutant phenotype, suggesting they may be involved in neurexin signaling. Finally, to investigate a possible role for neurexin in local actin assembly, we endogenously tagged its intracellular domain with actin depolymerizing and sequestering peptides (DeActs), and found that this led to defects in active zone assembly.
Targeting the Hedgehog Signaling Pathway to Improve Tendon-to-Bone Integration
Authors: Kamalitdinov Timur B. , Fujino Keitaro , Lang Sinaia Keith , Jiang Xi , Madi Rashad , Evans Mary Kate , Zgonis Miltiadis H. , Kuntz Andrew F. , Dyment Nathaniel A. 
Published: September 2022

ABSTRACTObjectiveWhile the role of Hedgehog (Hh) signaling in promoting zonal fibrocartilage production during development is well-established, whether this pathway can be leveraged to improve tendon-to-bone repair in adults is unknown. Our objective was to genetically and pharmacologically stimulate the Hh pathway in cells that give rise to zonal fibrocartilaginous attachments to promote tendon-to-bone integration.DesignHh signaling was stimulated genetically, via constitutive Smo (SmoM2 construct) activation of activated bone marrow stromal cells, or pharmacologically, via systemic agonist delivery, to mice following anterior cruciate ligament reconstruction (ACLR). To assess tunnel integration, we measured mineralized fibrocartilage (MFC) formation in these mice 28 days post-surgery and performed tunnel pullout testing.ResultsHh pathway-related genes increased in cells forming the zonal attachments in WT mice. Both genetic and pharmacologic stimulation of the Hh pathway increased MFC formation and integration strength 28 days post-surgery. We next conducted studies to define the role of Hh in specific stages of the tunnel integration process. We found Hh agonist treatment increased proliferation of the progenitor pool in the first week post-surgery. Additionally, genetic stimulation led to continued MFC production in later stages of the integration process. These results indicate that Hh signaling plays an important biphasic role in cell proliferation and differentiation towards fibrochondrocytes following ACLR.ConclusionThis study reveals a biphasic role for Hh signaling during the tendon-to-bone integration process after ACLR. In addition, the Hh pathway is a promising therapeutic target to improve tendon-to-bone repair outcomes.