bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spaces of phylogenetic diversity indices: combinatorial and geometric properties
Authors: Manson Kerry , Steel Mike 
Published: February 2023

AbstractBiodiversity is a concept most naturally quantified and measured across sets of species. However, for some applications, such as prioritising species for conservation efforts, a species-by-species approach is desirable. Phylogenetic diversity indices are functions that apportion the total biodiversity value of a set of species across its constituent members. As such, they aim to measure each species’ individual contribution to, and embodiment of, the diversity present in that set. However, no clear definition exists that encompasses the diversity indices in current use. This paper presents conditions that define diversity indices arising from the phylogenetic diversity measure on rooted phylogenetic trees. In this context, the diversity index ‘score’ given to a species represents a measure of its unique and shared evolutionary history as displayed in the underlying phylogenetic tree. Our definition generalises the diversity index notion beyond the popular Fair Proportion and Equal-Splits indices. These particular indices may now be seen as two points in a convex space of possible diversity indices, for which the boundary conditions are determined by the underlying shape of each phylogenetic tree. We calculated the dimension of the convex space associated with each tree shape and described the extremal points.
Rural selection drives the evolution of an urban-rural cline in coat color in gray squirrels
Authors: Cosentino Bradley J. , Vanek John P. , Gibbs James P. 
Published: February 2023

AbstractPhenotypic differences between urban and rural populations are well-documented, but the evolutionary processes driving trait variation along urbanization gradients are often unclear. We combined spatial data on abundance, trait variation, and measurements of fitness to understand cline structure and test for natural selection on heritable coat color morphs (melanic, gray) of eastern gray squirrels (Sciurus carolinensis) along an urbanization gradient. Population surveys using remote cameras and visual counts at 76 sites along the urbanization gradient revealed a significant cline in melanism, decreasing from 48% in the city center to <5% in rural woodlands. Among 76 translocated squirrels to test for phenotypic selection, survival was lower for the melanic than gray morph in rural woodlands, whereas there was no difference in survival between color morphs in the city. These results suggest the urban-rural cline in melanism is explained by natural selection favoring the gray morph in rural woodlands combined with relaxed selection in the city. Our study illustrates how trait variation between urban and rural populations can emerge from selection primarily in rural populations rather than adaptation to novel features of the urban environment.
In vivophotopharmacology with light-activated opioid drugs
Authors: McClain Shannan P. , Ma Xiang , Johnson Desiree A. , Johnson Caroline A. , Layden Aryanna E. , Yung Jean C. , Lubejko Susan T. , Livrizzi Giulia , Jenny He X. , Zhou Jingjing , Ventriglia Emilya , Rizzo Arianna , Levinstein Marjorie , Gomez Juan L. , Bonaventura Jordi , Michaelides Michael , Banghart Matthew R. 
Published: February 2023

SummaryTraditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate the feasibility and experimental advantages ofin vivophotopharmacology using “caged” opioid drugs that are activated in the brain with light after systemic administration in an inactive form. To enable bidirectional manipulations of endogenous opioid receptorsin vivo, we developed PhOX and PhNX, photoactivatable variants of the mu opioid receptor agonist oxymorphone and the antagonist naloxone. Photoactivation of PhOX in multiple brain areas produced local changes in receptor occupancy, brain metabolic activity, neuronal calcium activity, neurochemical signaling, and multiple pain- and reward-related behaviors. Combining PhOX photoactivation with optical recording of extracellular dopamine revealed adaptations in the opioid sensitivity of mesolimbic dopamine circuitry during chronic morphine administration. This work establishes a general experimental framework for usingin vivophotopharmacology to study the neural basis of drug action.HighlightsA photoactivatable opioid agonist (PhOX) and antagonist (PhNX) forin vivophotopharmacology.Systemic pro-drug delivery followed by local photoactivation in the brain.In vivophotopharmacology produces behavioral changes within seconds of photostimulation.In vivophotopharmacology enables all-optical pharmacology and physiology.
The double-drift illusion biases the marmoset oculomotor system
Authors: Dotson Nicholas M. , Davis Zachary W. , Salisbury Jared M. , Palmer Stephanie E. , Cavanagh Patrick , Reynolds John H. 
Published: February 2023

AbstractThe double-drift illusion has two unique characteristics: the error between the perceived and physical position of the stimulus grows over time, and saccades to the moving target land much closer to the physical than the perceived location. These results suggest that the perceptual and saccade targeting systems integrate visual information over different timescales. Functional imaging studies in humans have revealed several potential cortical areas of interest, including the prefrontal cortex. However, we currently lack an animal model to study the neural mechanisms of location perception that underlie the double-drift illusion. To fill this gap, we trained two marmoset monkeys to fixate and then saccade to the double drift stimulus. In line with human observers for radial double-drift trajectories, we find that saccade endpoints do show a significant bias that is, as it is in humans, smaller than that seen in perception. This bias is modulated by changes in the external and internal speeds of the stimulus. These results demonstrate that the saccade targeting system of the marmoset monkey is influenced by the double-drift illusion.
Dynamics of brain-muscle networks reveal effects of age and somatosensory function on gait
Authors: Roeder Luisa , Breakspear Michael , Kerr Graham K. , Boonstra Tjeerd W. 
Published: February 2023

AbstractWalking is a complex motor activity that requires coordinated interactions between sensory and motor systems. We used mobile EEG and EMG to investigate the brain-muscle networks involved in gait control during overground walking in young, older and individuals with Parkinson’s Disease. Dynamic interactions between the sensorimotor cortices and eight leg muscles within a gait cycle were assessed using multivariate analysis. We identified three distinct brain-muscle networks during a gait cycle. These networks include a bilateral network, a left-lateralised network activated during the left swing phase, and a right-lateralised network active during right swing. The trajectories of these networks are contracted in older adults, indicating a reduction in neuromuscular connectivity with age. Individuals with impaired tactile sensitivity of the foot showed a selective enhancement of the bilateral network, possibly reflecting a compensation strategy to maintain gait stability. These findings provide a parsimonious description of interindividual differences in neuromuscular connectivity during gait.TeaserDynamic network analysis shows how brain-muscle connectivity during gait varies with age and somatosensory function.
Optotracers to study biofilms in host-relevant systems and non-conventional treatments usingStaphylococcus aureuswound biofilms as a case study
Authors: Shaikh Nijamuddin , Kaushik Karishma S 
Published: February 2023

AbstractOptotracers have a wide-range of applications in the detection, visualization, and characterization of biofilms. More recently, optotracers have been used in antibiotic susceptibility assays for biofilms and for the detection of biomarkers in clinical biofilm infections. This is particularly important, given that the field is increasingly focused on the evaluation of novel anti-biofilm agents and the study of biofilms in host-relevant systems. Given this, the possibility of using optotracers for an expanded set of biofilm focus areas is important to explore. In this study, we examine the application of the optotracer EbbaBiolight 680 to study biofilms in a host-relevant system and for the evaluation of a non-conventional anti-biofilm remedy. UsingStaphylococcus aureuswound biofilms as a case study, we leverage a previously builtin vitro4-D wound microenvironment platform and a plant-based wound remedy. We find that EbbaBiolight 680 can be used to visualizeS. aureusbiofilms, likely detecting both bacterial cells and bacterial EPS components. Further, the optotracer can be used to evaluate and quantify the effects of the plant-based wound remedy onS. aureusbiomass formation. However, in the 4-D wound microenvironment, EbbaBiolight 680 detected host cellular and matrix elements, which confounded the detection of biofilms. Taken together, this study opens the possibility of using optotracers as screening tools for the identification of novel anti-biofilm treatments and underscores the need for modifications for their use in host-relevant systems.
Leptin antagonism improves Rett syndrome phenotype in symptomatic maleMecp2-nullmice
Authors: Belaïdouni Yasmine , Diabira Diabe , Brosset-Heckel Mélanie , Valsamides Victoria , Graziano Jean-Charles , Santos Catarina , Menuet Clément , Wayman Gary A. , Gaiarsa Jean-Luc 
Published: February 2023

ABSTRACTRett syndrome (RTT) is a severe neurodevelopmental disorder that arise fromde novomutations in the X-linked geneMECP2(methyl-CpG-binding protein 2). Circulating levels of the adipocyte hormone leptin are elevated in RTT patients and rodent models of the disease. Leptin targets a large number of brain structures and regulates a wide range of developmental and physiological functions which are altered in RTT. We hypothesized that elevated leptin levels might contribute to RTT pathogenesis. Accordingly, we show that pharmacological antagonism of leptin or genetic reduction of leptin production prevents the degradation of health status, weight loss and the progression of breathing and locomotor deficits. At the neuronal level, the anti-leptin strategies rescue the hippocampal excitatory/inhibitory imbalance and synaptic plasticity impairment. Targeting leptin might therefore represent a new approach for RTT treatment.
Novel diversity of polar Cyanobacteria revealed by genome-resolved metagenomics
Authors: Pessi Igor S. , Popin Rafael Vicentini , Durieu Benoit , Lara Yannick , Savaglia Valentina , Roncero-Ramos Beatriz , Hultman Jenni , Verleyen Elie , Vyverman Wim , Wilmotte Annick 
Published: February 2023

AbstractBenthic microbial mats dominated by Cyanobacteria are important features of polar lakes. Although culture-independent studies have provided important insights into their diversity, only a handful of genomes of polar Cyanobacteria have been sequenced to date. Here, we applied a genome-resolved metagenomics approach to data obtained from Arctic, sub-Antarctic, and Antarctic microbial mats. We recovered 22 unique metagenome-assembled genomes (MAGs) of Cyanobacteria, most of which are only distantly related to genomes that have been sequenced so far. These include i) lineages that are common in polar microbial mats such as the filamentous taxaPseudanabaena, Leptolyngbya, Microcoleus/Tychonema, andPhormidium; ii) the less common taxaCrinaliumandChamaesiphon; iii) an enigmatic Chroococcales lineage only distantly related toMicrocystis; and iv) an early branching lineage in the order Gloeobacterales that is almost exclusively restricted to the cold biosphere, for which we propose the nameCandidatusSivonenia alaskensis. Our results show that genome-resolved metagenomics is a powerful tool for expanding our understanding of the diversity of Cyanobacteria, especially in understudied remote and extreme environments.Data summaryThe sequencing data generated in this study have been submitted to the European Nucleotide Archive (ENA) under the BioProject PRJEB59431. Individual accession numbers for raw reads and genomic bins are listed inTable S1andTable S3, respectively. Genomic bins can also be downloaded from doi.org/10.6084/m9.figshare.22003967. The commands used throughout this study are available ingithub.com/igorspp/polar-cyanobacteria-MAGs.Impact statementCyanobacteria are photosynthetic microorganisms that play important roles in polar lacustrine ecosystems. Many Cyanobacteria are difficult to grow in the laboratory, particularly in isolation from other organisms, which makes it challenging to sequence their genomes. As such, considerably fewer genomes of Cyanobacteria have been sequenced so far compared to other bacteria. In this study, we used a metagenomics approach to recover novel genomes of Cyanobacteria from Arctic and Antarctic microbial mats without the need to isolate the organisms. The community DNA was extracted and sequenced, and the genomes of individual populations were separated using bioinformatics tools. We recovered 22 different genomes of Cyanobacteria, many of which have not been sequenced before. We describe in more detail an interesting lineage of ancestral Cyanobacteria in the order Gloeobacterales, for which we propose the nameCandidatusSivonenia alaskensis. Our study shows that genome-resolved metagenomics is a valuable approach for obtaining novel genomes of Cyanobacteria, which are needed to improve our understanding of life in the polar regions and the planet at large.
Experiment-based Computational Model Predicts that IL-6 Trans-Signaling Plays a Dominant Role in IL-6 mediated signaling in Endothelial Cells
Authors: Song Min , Wang Youli , Annex Brian H. , Popel Aleksander S. 
Published: February 2023

AbstractInflammatory cytokine mediated responses are important in the development of many diseases that are associated with angiogenesis. Targeting angiogenesis as a prominent strategy has shown limited effects in many contexts such as peripheral arterial disease (PAD) and cancer. One potential reason for the unsuccessful outcome is the mutual dependent role between inflammation and angiogenesis. Inflammation-based therapies primarily target inflammatory cytokines such as interleukin-6 (IL-6) in T cells, macrophages, cancer cells, muscle cells, and there is a limited understanding of how these cytokines act on endothelial cells. Thus, we focus on one of the major inflammatory cytokines, IL-6, mediated intracellular signaling in endothelial cells by developing a detailed computational model. Our model quantitatively characterized the effects of IL-6 classic and trans-signaling in activating the signal transducer and activator of transcription 3 (STAT3), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinase (MAPK) signaling to phosphorylate STAT3, extracellular regulated kinase (ERK) and Akt, respectively. We applied the trained and validated experiment-based computational model to characterize the dynamics of phosphorylated STAT3 (pSTAT3), Akt (pAkt), and extracellular regulated kinase (pERK) in response to IL-6 classic and/or trans-signaling. The model predicts that IL-6 classic and trans-signaling induced responses are IL-6 and soluble IL-6 receptor (sIL-6R) dose-dependent. Also, IL-6 trans-signaling induces stronger downstream signaling and plays a dominant role in the overall effects from IL-6. In addition, both IL-6 and sIL-6R levels regulate signaling strength. Moreover, our model identifies the influential species and kinetic parameters that specifically modulate the pSTAT3, pAkt, and pERK responses, which represent potential targets for inflammatory cytokine mediated signaling and angiogenesis-based therapies. Overall, the model predicts the effects of IL-6 classic and/or trans-signaling stimulation quantitatively and provides a framework for analyzing and integrating experimental data. More broadly, this model can be utilized to identify targets that influence inflammatory cytokine mediated signaling in endothelial cells and to study the effects of angiogenesis- and inflammation-based therapies.
LDLR-mediated targeting and productive uptake of siRNA-peptide ligand conjugatesin vitroandin vivo
Authors: B. Broc , K. Varini , R. Sonnette , B. Pecqueux , F. Benoist , M. Thomas , M. Masse , Y. Mechioukhi , G. Ferracci , M. David , J. Temsamani , M. Khrestchatisky , G. Jacquot , P. Lécorché 
Published: February 2023

ABSTRACTsiRNAs have become one of the most promising therapeutic agents because of their specificity and their potential to modulate the expression of gene-related diseases. Any gene of interest can be potentially up or down-regulated, making RNA-based technology the healthcare breakthrough of our era. However, the functional and specific delivery of siRNAs into tissues of interest and into the cytosol of target cells remains highly challenging, mainly due to the lack of efficient and selective delivery systems. Among the variety of carriers for siRNA delivery, peptides have become essential candidates because of their high selectivity, stability and conjugation versatility. Here, we describe the development of molecules encompassing siRNAs againstSOD1, conjugated to peptides that target the LDLR, and their biological evaluation bothin vitroandin vivo.Abstract FigureGRAPHICAL ABSTRACT
Structure of the ceramide-bound SPOTS complex
Authors: Schäfer Jan-Hannes , Körner Carolin , Esch Bianca M. , Limar Sergej , Parey Kristian , Walter Stefan , Januliene Dovile , Moeller Arne , Fröhlich Florian 
Published: February 2023

AbstractSphingolipids are structural membrane components that also function in cellular stress responses. The serine palmitoyl-transferase (SPT) catalyzes the rate limiting step in sphingolipid biogenesis. Its activity is tightly regulated through multiple binding partners, including Tsc3, Orm proteins, ceramides, and the phosphatidylinositol-4-phosphate (PI4P) phosphatase Sac1. The structural organization and regulatory mechanisms of this complex are not yet understood.Here, we report the high-resolution cryo-EM structures of the yeast SPT in complex with Tsc3 and Orm1 (SPOT) as dimers and monomers and a monomeric complex further carrying Sac1 (SPOTS). In all complexes, the tight interaction of the downstream metabolite ceramide and Orm1 reveals the ceramide dependent inhibition. Additionally, observation of ceramide and ergosterol binding suggests a co-regulation of sphingolipid biogenesis and sterol metabolism within the SPOTS complex.
Verification of nucleotide sequence reagent identities in original publications in high impact factor cancer research journals
Authors: Pathmendra Pranujan , Park Yasunori , Enguita Francisco J. , Byrne Jennifer A. 
Published: February 2023

AbstractHuman gene research studies that describe wrongly identified nucleotide sequence reagents have been mostly identified in journals of low to moderate impact factor, where unreliable findings could be considered to have limited influence on future research. This study examined whether papers describing wrongly identified nucleotide sequences are also published in high impact factor cancer research journals. We manually verified nucleotide sequence identities in originalMolecular Cancerarticles published in 2014, 2016, 2018 and 2020, including nucleotide sequence reagents that were claimed to target circRNAs. Using keywords identified in problematic 2018 and 2020Molecular Cancerpapers, we also verified nucleotide sequence identities in 2020Oncogenepapers that studied miRNA(s) and/or circRNA(s). Overall, 3.8% (253/6,647) and 4.3% (50/1,165) nucleotide sequences that were verified inMolecular CancerandOncogenepapers, respectively, were found to be wrongly identified. These wrongly identified nucleotide sequences were distributed across 18% (92/500) originalMolecular Cancerpapers, including 38%Molecular Cancerpapers from 2020, and 40% (21/52) selectedOncogenepapers from 2020. Original papers with wrongly identified nucleotide sequences were therefore unexpectedly frequent in two high impact factor cancer research journals, highlighting the risks of employing journal impact factors or citations as proxies for research quality.
IDHwt glioblastomas can be stratified by their transcriptional response to standard treatment, with implications for targeted therapy
Authors: Tanner Georgette , Barrow Rhiannon , Finetti Martina , Ajaib Shoaib , Ahmed Nazia , Pollock Steven , Rippaus Nora , Bruns Alexander F. , Syed Khaja , Poulter James , Wilson Erica , Johnson Colin , Varn Frederick S. , Brüning-Richardson Anke , Hogg Catherine , Droop Alastair , Gusnanto Arief , Care Matthew A. , Cutillo Luisa , Westhead David , Short Susan C. , Jenkinson Michael D. , Brodbelt Andrew , Chakrabarty Aruna , Ismail Azzam , Verhaak Roel GW , Stead Lucy F. 
Published: February 2023

AbstractGlioblastoma (GBM) brain tumours lackingIDH1mutations (IDHwt) have the worst prognosis of all brain neoplasms. Patients receive surgery and chemoradiotherapy but tumours almost always fatally recur. Using RNAseq data from 107 pairs of pre- and post-standard treatment locally recurrent IDHwt GBM tumours, we identified two responder subtypes based on therapy-driven changes in gene expression. In two thirds of patients a specific subset of genes is up-regulated from primary to recurrence (Up responders) and in one third the same genes are down-regulated (Down responders). Characterisation of the responder subtypes indicates subtype-specific adaptive treatment resistance mechanisms. In Up responders treatment enriches for quiescent proneural GBM stem cells and differentiated neoplastic cells with increased neurotransmitter signalling, whereas Down responders commonly undergo therapy-driven mesenchymal transition. Stratifying GBM tumours by response subtype may lead to more effective treatment. In support of this, modulators of gamma aminobutyric acid (GABA) neurotransmitter signalling differentially sensitise Up and Down responder GBM models to standard treatmentin vitro.
An ULK1/2-PXN mechanotransduction complex suppresses breast cancer cell migration
Authors: Liang Peigang , Zhang Jiaqi , Wu Yuchen , Zheng Shanyuan , Xu Zhaopeng , Yang Shuo , Wang Jinfang , Ma Suibin , Xiao Li , Hu Tianhui , Jiang Wenxue , Xing Qiong , Kundu Mondira , Wang Bo 
Published: February 2023

AbstractThe remodeling and stiffening of the extracellular matrix (ECM) associated with breast cancers is a well-recognized modulator of disease progression. However, how changes in the mechanical properties of the ECM are converted into biochemical signals that direct tumor cell migration and metastasis remains poorly characterized. Here, we describe a new role for the autophagy-inducing serine/threonine kinases ULK1 and ULK2 in mechanotransduction. We demonstrate that ULK1/2 activity inhibits the assembly of actin stress fibers and focal adhesions (FAs), and as a consequence impedes cell contraction and migration. Mechanistically, we identify PXN/paxillin, a key component of the mechanotransducing machinery, as a direct binding partner and substrate of ULK1/2. ULK-mediated phosphorylation of PXN at S32 and S119 weakens homotypic interactions and liquid-liquid phase separation of PXN, impairing FA assembly, which in turn impedes the mechanotransduction of breast cancer cells. ULK1/2 and the well characterized PXN regulator, FAK/Src, have opposing functions on mechanotransduction and compete for phosphorylation of adjacent serine and tyrosine residues. Thus, our study reveals ULK1/2 as important regulators of PXN-dependent mechanotransduction.HighlightsULK1/2 interact with PXN and phosphorylate PXN at S32 and S119 in response to mechanical stimuliULK1/2-mediated phosphorylation of PXN regulates mechanotransduction and migration of breast cancer cellsULK1/2 modulate the biomaterial properties of focal adhesions through PXN phosphorylationULK1/2 and FAK/Src act antagonistically in mechanotransduction through competitive phosphorylation of PXN