bluuebunny/crossref_metadata_2025_split huggingface dataset:
Androgen Receptor driven gene score identifies tumors with Epithelial to Mesenchymal Transition features in triple negative breast cancer
Authors: Rajarajan Savitha , Snijesh VP , Anupama CE , Nair Madhumathy G , Apoorva D , Chandrakala M , Patil Sharada , Nimbalkar Vidya P , Alexander Annie , Pillai Maalavika , Jolly Mohit Kumar , Sabarinathan Radhakrishnan , Ramesh Rakesh S , Srinath BS , Prabhu Jyothi S 
Published: February 2023

AbstractBackgroundAndrogen receptor (AR) is considered marker associated with better prognosis within hormone receptor positive tumors. Its role in triple negative tumors however is controversial showing both better and worse prognosis and different methods are used for identification of AR driven tumors. Conflicting results could be due to intrinsic molecular differences or scoring method for AR positivity. We attempted to develop an AR driven gene score and examined its utility in subtypes of breast cancer (BC).MethodsA bioinformatic pipeline was constructed and applied on publicly available microarray data sets obtained from AR positive BC cell lines treated with dihydrotestosterone (DHT). Expression levels of genes identified through the pipeline along with set of epithelial mesenchymal transition (EMT) markers, proliferation associated genes and enzymes involved in intracrinal androgen metabolism was evaluated in a cohort of Indian Breast cancer patients. Tumors were divided into AR high and low based on the gene score and association with clinical parameters, circulating androgens, disease free survival, proliferation and EMT markers were examined, all results were further validated in external public datasets.ResultsAR driven gene score was calculated as average expression of the 6 genes selected through bioinformatic analysis. 53% (133/249) tumors were classified as AR high by the gene score and had significantly better clinical parameters such as higher age, smaller tumor size, lower grade and lower proliferation. Tumors with high AR driven gene score had significantly better disease-free survival (mean survival time of 86.13 vs 72.69 months, log rank p=0.032) when compared to the AR low tumors. A subset analysis within TNBC (N=66) showed 36% (24/66) were AR high and had significantly higher expression of EMT markers (p=0.024). Though circulating levels of total testosterone was not different between the groups, intratumoral levels of 5 alfa reductase (SRD5A1) was significantly high in tumors with high AR driven score.ConclusionRole of AR in breast cancer is debatable and difficult to decipher with protein detection alone. Our results support the context dependent function of AR in driving better prognosis, while identifying its role in driving EMT within TNBC tumors.
Immunostimulatory effects ofBacillus coagulansSANK70258
Authors: Ikeda Yuki , Ito Naoto , Yamashita Niya , Minamikawa Natsuki , Nagata Kazuki , Yashiro Takuya , Aida Masanori , Yamada Ryouichi , Hachisu Masakazu , Nishiyama Chiharu 
Published: February 2023

AbstractSpecific intestinal bacteria modulate immunoresponses through various pathways, and several probiotic bacteria have been identified as immunostimulants by screening. In the present study, we evaluated the immunomodulating effects ofBacillus coagulansSANK70258 (B. coagulansSANK70258), a spore-forming and lactic acid-producing bacterium usable as food supplement for human and animals. We found that treatment of mouse splenocytes with γ-ray irradiatedB. coagulansSANK70258 induced high amount of IFN-γ in comparison with 7 kinds of typical lactic acid bacteria. Further analyses using splenocytes revealed that NK cell is a major source of IFN-γ, andB.coagulansSANK70258-induced IFN-γ production was inhibited by neutralization of IL-12 or IL-23, depletion of CD11c+cells, and inhibition of NFκB.B. coagulansSANK70258 also induced release of IFN-γ from activated CD8+T cells, and increased expression of chemokine receptors in CD8+T cells.B. coagulansSANK70258-treatment induced production of cytokines from bone marrow-derived dendritic cells, which is reduced by knockdown ofTlr2andNod2. B. coagulansSANK70258-treatment also induced IgA production from Peyer’s patch cells with high level among tested lactic bacteria. The oral intake of γ-ray irradiatedB. coagulansSANK70258 significantly increased intestinal IgA levels and IgA-expressing B cells in the Peyer’s patch of mice. Taken together, we conclude thatB. coagulansSANK70258 possesses high activity as immunostimulant inducing production of IFN-γ and IgA.
Increased cortical inhibition immediately following brief motor memory reactivation supports reconsolidation and overnight offline learning gains
Authors: Eisenstein Tamir , Furman-Haran Edna , Tal Assaf 
Published: February 2023

AbstractPracticing motor skills stabilizes and strengthens motor memories by repeatedly reactivating and reconsolidating them. The conventional view, by which a repetitive practice is required for substantially improving skill performance, has been recently challenged by behavioral experiments, in which even brief reactivations of the motor memory have led to significant improvements in skill performance. However, the mechanisms which facilitate brief reactivation-induce skill improvements remain elusive. While initial memory consolidation has been repeatedly associated with increased neural excitation and dis-inhibition, reconsolidation has been shown to involve a poorly-understood mixture of both excitatory and inhibitory alterations.Here, we followed a three-day reactivation-reconsolidation framework, to examine whether the excitatory/inhibitory mechanisms which underlie brief reactivation and repetitive practice differ. Healthy volunteers practiced a motor sequence learning task using either brief reactivation or repetitive practice and were assessed using ultra-high field (7T) magnetic resonance spectroscopy at the primary motor cortex (M1). We found that increased inhibition (GABA concentrations) and decreased excitation/inhibition (glutamate/GABA ratios) immediately following the brief reactivation were associated with overnight offline performance gains. These gains were on-par with those exhibited following repetitive practice, where no correlations with inhibitory or excitatory changes were observed. Our findings suggest that brief reactivation and repetitive practice depend on fundamentally different neural mechanisms, and that early inhibition – and not excitation – is particularly important in supporting the learning gains exhibited by brief reactivation.
Design, evaluation and implementation of synthetic isopentyldiol pathways inEscherichia coli
Authors: Liu Yongfei , Chen Lin , Liu Pi , Yuan Qianqian , Ma Chengwei , Wang Wei , Zhang Chijian , Ma Hongwu , Zeng An-Ping 
Published: February 2023

AbstractIsopentyldiol (IPDO) is an important raw material in cosmetic industry. So far IPDO is exclusively produced through chemical synthesis. Growing interest in natural personal care products has inspired the quest to develop a bio-based process. We previously reported a biosynthetic route that produces IPDO via extending leucine catabolism (route A), the efficiency of which, however, is not satisfactory. To address this issue, we computational designed a novel non-natural IPDO synthesis pathway (Route B) using RetroPath RL, the state of art tool for bio-retrosynthesis based on Artificial Intelligence methods. We compared this new pathway with route A and another two intuitively designed routes for IPDO biosynthesis from various aspects. Route B, which exhibits the highest thermodynamic driving force, least non-native reaction steps and lowest energy requirements appeared to hold the greatest potential for IPDO production. All three newly designed routes were then implemented inE. coliBL21(DE3) strain. Results show that the computationally designed route B can produce 2.2 mg/L IPDO from glucose, whereas no IPDO production from routes C and D. These results highlight the importance and usefulness ofin silicodesign and comprehensive evaluation of the potential efficiencies of candidate pathways in constructing novel non-natural pathways for the production of biochemicals.
Exploratory mass cytometry analysis reveals immunophenotypes of cancer treatment-related pneumonitis
Authors: Yanagihara Toyoshi , Hata Kentaro , Matsubara Keisuke , Kunimura Kazufumi , Suzuki Kunihiro , Tsubouchi Kazuya , Ikegame Satoshi , Baba Yoshihiro , Fukui Yoshinori , Okamoto Isamu 
Published: February 2023

AbstractAnti-cancer treatments can result in various adverse effects, including infections due to immune suppression/dysregulation and drug-induced toxicity in the lung. One of the major opportunistic infections isPneumocystis jiroveciipneumonia (PCP), which can cause severe respiratory complications and high mortality rates. Cytotoxic drugs and immune-checkpoint inhibitors (ICIs) can induce interstitial lung diseases (ILDs). Nonetheless, the differentiation of these diseases can be difficult, and the pathogenic mechanisms of such diseases are not yet fully understood. To better comprehend the immunophenotypes, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid from patients with PCP, cytotoxic drug-induced ILD (DI-ILD), and ICI-associated ILD (ICI-ILD) using two panels containing 64 markers. In PCP, we observed an expansion of the CD16+T cell population, with the highest CD16+T proportion in a fatal case. In ICI-ILD, we found an increase in CD57+CD8+T cells expressing immune checkpoints (TIGIT+LAG3+TIM-3+PD-1+), FCRL5+B cells, and CCR2+CCR5+CD14+monocytes. These findings uncover the diverse immunophenotypes and possible pathomechanisms of cancer treatment-related pneumonitis.
Generative machine learning produces kinetic models that accurately characterize intracellular metabolic states
Authors: Choudhury Subham , Narayanan Bharath , Moret Michael , Hatzimanikatis Vassily , Miskovic Ljubisa 
Published: February 2023

AbstractGenerating large omics datasets has become routine practice to gain insights into cellular processes, yet deciphering such massive datasets and determining intracellular metabolic states remains challenging. Kinetic models of metabolism play a critical role in integrating omics data, as they provide explicit connections between metabolite concentrations, metabolic fluxes, and enzyme levels. Nevertheless, the challenges associated with determining the kinetic parameters that underlie cellular physiology pose significant obstacles to the broader acceptance and adoption of these models within the research community. Here, we present RENAISSANCE, a generative machine learning framework for efficiently parameterizing large-scale kinetic models with dynamic properties matching experimental observations. Through seamless integration and consolidation of diverse omics data and other relevant information, like extracellular medium composition, physicochemical data, and expertise of domain specialists, we show that the proposed framework accurately characterizes unknown intracellular metabolic states, including metabolic fluxes and metabolite concentrations inE. coli’s metabolic network. Moreover, we show that RENAISSANCE successfully estimates missing kinetic parameters and reconciles them with sparse and noisy experimental data, resulting in a substantial reduction in parameter uncertainty and a notable improvement in the accuracy and reliability of the parameter estimates. The proposed framework will be invaluable for researchers who seek to analyze metabolic variations involving changes in metabolite and enzyme levels and enzyme activity in health and biotechnological studies.
CD99 Promotes Self-renewal in Hematopoietic Stem Cells and Leukemia Stem Cells by Regulating Protein Synthesis
Authors: Huang Yi , Kapti Eda Gozel , Ji Yuanyuan , Thomas Toby , Dempsey Jebrail , Mims Karin , Berezniuk Iryna , Guo Liang , Kroger Benjamin , Hu Wenhuo , Park Christopher Y. , Chung Stephen S. 
Published: February 2023

SummaryBlood production is sustained by hematopoietic stem cells (HSCs), which are typically the only blood cells capable of long-term self-renewal. Acute myeloid leukemia (AML) is initiated by aberrantly self-renewing malignant stem cells termed leukemia stem cells (LSCs). HSCs exhibit and depend on low levels of protein synthesis to self-renew. However, the mechanisms by which HSCs regulate protein synthesis to maintain their capacity for self-renewal in the setting of proliferative stress and leukemogenesis remain unknown. Here we show CD99, a cell surface protein upregulated in LSCs, is required for self-renewal of proliferating HSCs and LSCs. We found that loss of CD99 in HSCs and LSCs leads to increased protein synthesis and that their self-renewal capacity can be restored by translation inhibition. These data demonstrate a functional role for CD99 in constraining protein synthesis, which may promote the clonal expansion of HSCs and LSCs that leads to AML. Furthermore, they show that similar to HSCs, LSCs depend on regulated protein synthesis.
Manipulating single-unit theta phase-locking with PhaSER: An open-source tool for real-time phase estimation and manipulation
Authors: Christenson Wick Zoé , Philipsberg Paul A , Lamsifer Sophia I , Kohler Cassidy , Katanov Elizabeth , Feng Yu , Humphrey Corin , Shuman Tristan 
Published: February 2023

ABSTRACTThe precise timing of neuronal spiking relative to the brain’s endogenous oscillations (i.e., phase-locking or spike-phase coupling) has long been hypothesized to coordinate cognitive processes and maintain excitatory-inhibitory homeostasis. Indeed, disruptions in theta phase-locking have been described in models of neurological diseases with associated cognitive deficits and seizures, such as Alzheimer’s disease, temporal lobe epilepsy, and autism spectrum disorders. However, due to technical limitations, determining if phase-locking causally contributes to these disease phenotypes has not been possible until recently. To fill this gap and allow for the flexible manipulation of single-unit phase-locking to on-going endogenous oscillations, we developed PhaSER, an open-source tool that allows for phase-specific manipulations. PhaSER can deliver optogenetic stimulation at defined phases of theta in order to shift the preferred firing phase of neurons relative to theta in real-time. Here, we describe and validate this tool in a subpopulation of inhibitory neurons that express somatostatin (SOM) in the CA1 and dentate gyrus (DG) regions of the dorsal hippocampus. We show that PhaSER is able to accurately deliver a photo-manipulation that activates opsin+ SOM neurons at specified phases of theta in real-time in awake, behaving mice. Further, we show that this manipulation is sufficient to alter the preferred firing phase of opsin+ SOM neurons without altering the referenced theta power or phase. All software and hardware requirements to implement real-time phase manipulations during behavior are available online (https://github.com/ShumanLab/PhaSER).
Beak morphometry and morphogenesis across avian radiations
Authors: Mosleh Salem , Choi Gary P. T. , Musser Grace M. , James Helen F. , Abzhanov Arhat , Mahadevan L. 
Published: February 2023

AbstractAdaptive avian radiations associated with the diversification of bird beaks into a multitude of forms enabling different functions are exemplified by Darwin’s finches and Hawaiian honeycreepers. To elucidate the nature of these radiations, we quantified beak shape and skull shape using a variety of geometric measures that allowed us to collapse the variability of beak shape into a minimal set of geometric parameters. Furthermore, we find that just two measures of beak shape, the ratio of the width to length and the normalized sharpening rate (increase in the transverse beak curvature near the tip relative to that at the base of the beak), are both strongly correlated with diet, and thus indicative of how bite forces are correlated with beak shape. Finally, by considering how transverse sections to the beak centerline evolve with distance from the tip, we show that a simple geometry-driven growth law termed “modified mean curvature flow” captures the beak shapes of Darwin’s finches and Hawaiian honeycreepers. A surprising consequence of the simple growth law is that beak shapes that are not allowed based on the developmental program of the beak are also not observed in nature, suggesting a link between evolutionary morphology and development in terms of growth-driven developmental constraints.
Elevational Range Sizes of Woody plants Increase with Climate Variability in the Tropical Andes
Authors: Montaño-Centellas Flavia , Fuentes Alfredo F. , Cayola Leslie , Macía Manuel J. , Arellano Gabriel , Loza M. Isabel , Nieto-Ariza Beatriz , Tello J. Sebastián 
Published: February 2023

AbstractAimThe climate variability hypothesis proposes that species subjected to wide variation in climatic conditions will evolve wider niches, resulting in larger distributions. We test this hypothesis in tropical plants across a broad elevational gradient; specifically, we use a species-level approach to evaluate whether elevational range sizes are explained by the levels of thermal variability experienced by species.LocationCentral AndesTime periodPresent dayMajor taxa studiedWoody plantsMethodsCombining data from 479 forest plots, we determined the elevational distributions of nearly 2300 species along an elevational gradient (∼209 – 3800 m). For each species, we calculated the maximum annual variation in temperature experienced across its elevational distribution. We used phylogenetic generalized least square models to evaluate the effect of thermal variability on range size. Our models included additional covariates that might affect range size: body size, local abundance, mean temperature and total precipitation. We also considered interactions between thermal variability and mean temperature or precipitation. To account for geometric constraints, we repeated our analyses with a standardized measure of range size, calculated by comparing observed range sizes with values obtained from a null model.ResultsOur results supported the main prediction of the climate variability hypothesis. Thermal variability had a strong positive effect on the range size, with species exposed to higher thermal variability having broader elevational distributions. Body size and local abundance also had positive, yet weak effects, on elevational range size. Furthermore, there was a strong positive interaction between thermal variability and mean annual temperature.Main conclusionsThermal variability had an overriding importance in driving elevational range sizes of woody plants in the Central Andes. Moreover, the relationship between thermal variability and range size might be even stronger in warmer regions, underlining the potential vulnerability of tropical montane floras to the effects of global warming.
Hypoxia dampens innate immune signalling at early time points and increases Zika virus replication in iPSC-derived macrophages
Authors: Schilling Mirjam , Vaughan-Jackson Alun , James William , McKeating Jane A 
Published: February 2023

AbstractType I interferons (IFNs) are the major host defence against viral infection and are induced following activation of cell surface or intracellular pattern recognition receptors, including retinoic-acid-inducible gene I (RIGI)-like receptors (RLRs). All cellular processes are shaped by the microenvironment and one important factor is the local oxygen tension. The majority of published studies on IFN signalling are conducted under atmospheric (18%) oxygen conditions, that do not reflect the physiological oxygen levels in most organs (1-5% O2). We studied the effect of low oxygen on IFN induction and signalling in induced Pluripotent Stem Cell (iPSC)-derived macrophages as a model for tissue-resident macrophages and assessed the consequence for Zika virus (ZIKV) replication. Hypoxic conditions dampened the expression of interferon-stimulated genes (ISGs) following RLR stimulation or IFN treatment at early time points. RNA-sequencing and bio-informatic analysis uncovered several pathways including changes in transcription factor availability, the presence of HIF binding sites in promoter regions, and CpG content that may contribute to the reduced ISG expression. Importantly, hypoxic conditions increased ZIKV replication at early time points, emphasizing the importance of understanding how low oxygen conditions in the local microenvironment affect pathogen sensing and host defence.
Shear-induced phenotypic transformation of microgliain vitro
Authors: Park Eunyoung , Ahn Song Ih , Park Jin-Sung , Shin Jennifer H. 
Published: February 2023

AbstractBrain cells are influenced by continuous fluid shear stress driven by varying hydrostatic and osmotic pressure conditions, depending on the brain’s pathophysiological conditions. While all brain cells are sensitive to the subtle changes in various physicochemical factors in the microenvironment, microglia, the resident brain immune cells, exhibit the most dramatic morphodynamic transformation. However, little is known about the phenotypic alterations in microglia in response to the changes in fluid shear stress. In this study, we first established a flow-controlled microenvironment to investigate the effects of shear flow on microglial phenotypes, including morphology, motility, and activation states. Microglia exhibited two distinct morphologies with different migratory phenotypes in a static condition: bipolar cells that oscillate along their long axis and unipolar cells that migrate persistently. When exposed to flow, a significant fraction of bipolar cells showed unstable oscillation with an increased amplitude of oscillation and a decreased frequency, which consequently led to the phenotypic transformation of oscillating cells into migrating cells. Interestingly, the level of pro-inflammatory genes increased in response to shear stress, while there were no significant changes in the level of anti-inflammatory genes. Our findings suggest that an interstitial fluid-level stimulus can cause a dramatic phenotypic shift in microglia toward pro-inflammatory states, shedding light on pathological outbreaks of severe brain diseases. Given that the fluidic environment in the brain can be locally disrupted in pathological circumstances, the mechanical stimulus by a fluid flow should also be considered a crucial element in regulating the immune activities of the microglia in brain diseases.Statement of SignificanceCellular morphology and motility are important factors that encompass the alterations in protein and gene-level expressions within cells. In pathological conditions, microglia, the resident brain immune cells, are known to undergo morphodynamic transformations in response to various physicochemical stimuli. Besides the commonly known soluble biochemical factors in the microenvironment, the differential flow characteristics of ISF have been linked to several neurological diseases, such as Alzheimer’s, Parkinson’s, and brain tumors. Microglial cells, which are extremely sensitive to subtle changes in extracellular stimuli, have been identified as key players in these pathological conditions. Despite its importance, however, it has been challenging to study the sole effect of a shear flow on microglia. We investigated the morphodynamic features of microglia in response to precisely controlled interstitial-level fluid flow conditions using a microfluidic system in which isolated microglia are monitored in real-time while the undesirable effects from other extracellular factors are minimized.