bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kinetic principles underlying pioneer function of GAGA transcription factor in live cells
Authors: Tang Xiaona , Li Taibo , Liu Sheng , Wisniewski Jan , Zheng Qinsi , Rong Yikang , Lavis Luke D. , Wu Carl 
Published: October 2021

AbstractHow pioneer factors interface with chromatin to promote accessibility for transcription control is poorly understood in vivo. Here, we directly visualize chromatin association by the prototypical GAGA pioneer factor (GAF) in live Drosophila hemocytes. Single-particle tracking reveals that the majority of GAF is chromatin-bound, with a stable-binding fraction showing nucleosome-like confinement residing on chromatin for over 2 minutes, far longer than the dynamic range of most transcription factors. These kinetic properties require the full complement of GAF’s DNA-binding, multimerization and intrinsically disordered domains, and are autonomous from recruited chromatin remodelers NURF and PBAP, whose activities primarily benefit GAF’s neighbors such as HSF. Evaluation of GAF kinetics together with its endogenous abundance indicates that despite on-off dynamics, GAF constitutively and fully occupies chromatin targets, thereby providing a temporal mechanism that sustains open chromatin for transcriptional responses to homeostatic, environmental, and developmental signals.
The many layers of BOLD. On the contribution of different vascular compartments to laminar fMRI
Authors: Schellekens Wouter , Bhogal Alex A. , Roefs Emiel C.A. , Báez-Yáñez Mario G. , Siero Jeroen C.W. , Petridou Natalia 
Published: October 2021

ABSTRACTUltra-high field functional Magnetic Resonance Imaging (fMRI) offers the spatial resolution to measure neural activity at the scale of cortical layers. Most fMRI studies make use of the Blood-Oxygen-Level Dependent (BOLD) signal, arising from a complex interaction of changes in cerebral blood flow (CBF) and volume (CBV), and venous oxygenation. However, along with cyto- and myeloarchitectural changes across cortical depth, laminar fMRI is confronted with additional confounds related to vascularization differences that exist across cortical depth. In the current study, we quantify how the non-uniform distribution of macro- and micro-vascular compartments, as measured with Gradient-Echo (GE) and Spin-Echo (SE) scan sequences, respectively, affect laminar BOLD fMRI responses following evoked hypercapnic and hyperoxic breathing conditions. We find that both macro- and micro-vascular compartments are capable of comparable theoretical maximum signal intensities, as represented by the M-scaling parameter. However, the capacity for vessel dilation, as reflected by the cerebrovascular reactivity (CVR), is approximately three times larger for the macro-compared to the micro-vasculature at superficial layers. Finally, there is roughly a 35% difference in CBV estimates between the macro- and micro-vascular compartments, although this relative difference is approximately uniform across cortical depth.
A multiscale model of the cardiovascular system that regulates arterial pressure via closed loop baroreflex control of chronotropism, cell-level contractility, and vascular tone
Authors: Sharifi Hossein , Mann Charles K. , Wenk Jonathan F. , Campbell Kenneth S. 
Published: October 2021

AbstractMultiscale models of the cardiovascular system can provide new insights into physiological and pathological processes. PyMyoVent is a computer model that bridges from molecular to organ-level function and which simulates a left ventricle pumping blood through the systemic circulation. Initial work with PyMyoVent focused on the End Systolic Pressure Volume Relationship and ranked potential therapeutic strategies by their impact on contractility. This manuscript extends the PyMyoVent framework by adding closed loop feedback control of arterial pressure. The control algorithm mimics important features of the physiological baroreflex and was developed as part of a long-term program that focuses on growth and biological remodeling. Inspired by the underlying biology, the reflex algorithm uses an afferent signal derived from arterial pressure to drive a kinetic model that mimics the net result of neural processing in the medulla and cell-level responses to autonomic drive. The kinetic model outputs control signals that are constrained between limits that represent maximum parasympathetic and maximum sympathetic drive and which modulate heart rate, intracellular Ca2+ dynamics, the molecular-level function of both the thick and the thin myofilaments, and vascular tone. Simulations show that the algorithm can regulate mean arterial pressure at user-defined set-points as well as maintaining arterial pressure when challenged by changes in blood volume and/or valve resistance. The reflex also regulates arterial pressure when cell-level contractility is modulated to mimic the idealized impact of myotropes. These capabilities will be important for future work that uses computer modeling to investigate clinical conditions and treatments.
Resistance to chemical carcinogenesis induction via a dampened inflammatory response in naked mole-rats
Authors: Oka Kaori , Fujioka Shusuke , Kawamura Yoshimi , Komohara Yoshihiro , Chujo Takeshi , Sekiguchi Koki , Yamamura Yuki , Oiwa Yuki , Omamiuda-Ishikawa Natsuko , Komaki Shohei , Sutoh Yoichi , Sakurai Satoko , Tomizawa Kazuhito , Bono Hidemasa , Shimizu Atsushi , Araki Kimi , Yamamoto Takuya , Yamada Yasuhiro , Oshiumi Hiroyuki , Miura Kyoko 
Published: October 2021

AbstractNaked mole-rats (NMRs) have a very low spontaneous carcinogenesis rate, which has prompted scientists to study their cancer resistance mechanisms in order to provide clues for human cancer prevention. Although cancer resistance in NMRs has been intensively investigated at the cellular level, it is still unknown how strongly resistant NMR individuals are to carcinogenesis and how NMR tissues respond to experimental carcinogenesis induction. Here, we show that NMRs exhibit extraordinary resistance against potent chemical carcinogenesis induction through a dampened inflammatory response. Although carcinogenic insults damaged skin cells of both NMRs and mice, NMR skin showed markedly lower immune cell infiltration and reduced induction of inflammatory genes. NMRs harbor loss-of-function mutations in receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) genes, which are essential for necroptosis, a type of necrotic cell death that activates strong inflammation. A necroptosis-inducing stimulus did not increase death of NMR cells. After carcinogenic insults, leakage of the HMGB1, a marker of necrotic cell death, was not increased in NMR skin. In mice, inhibition or knockout of RIPK3 reduced immune cell infiltration and delayed the onset of chemical carcinogenesis. Therefore, necroptosis deficiency may serve as a cancer resistance mechanism via attenuating the inflammatory response in NMRs. Our study sheds light on the importance of a dampened inflammatory response as a non-cell-autonomous cancer resistance mechanism in NMRs. Further in vivo study of the unusual tissue immune system and carcinogenesis resistance of NMRs may lead to the development of new strategies to prevent carcinogenesis in humans.Significance StatementIn contrast with intensive studies of cancer resistance mechanisms in naked mole-rats (NMRs) at the cellular level, little is known about how NMR individuals respond to carcinogenesis induction, despite the fact that cell-to-cell interactions in tissues regulate carcinogenesis in vivo. Here, we demonstrate that NMRs are remarkably resistant to chemical carcinogenesis induction and characteristically have attenuated tissue inflammatory responses to carcinogenic insults. NMRs have loss-of-function mutations inRIPK3andMLKLgenes and thus cannot activate necroptosis, a type of inflammation-inducing cell death. RIPK3 inhibition in mice reduced immune cell infiltration in response to carcinogenic insults and delayed the onset of chemical-induced carcinogenesis. Our results highlight the importance of studies on dampened tissue inflammatory responses to understand cancer resistance of NMRs.
The epidemiology and genomics of a virulent emerging fungal pathogen in an Australian reptile
Authors: Class B. , Powell D. , Terraube J. , Albery G. , Delmé C. , Bansal S. , Frère C.H. 
Published: October 2021

AbstractEmerging infectious fungal diseases (EIFDs) represent a major conservation concern worldwide. Here, we provide early insights into the potential threat thatNannizziopsis barbatae(Nb), a novel EIFD, poses to Australian herpetological biodiversity. First known to the reptile pet trade as a primary pathogen causing untreatable severe dermatomycosis, since 2013,Nbhas emerged in a growing number of phylogenetically and ecologically distant free-living reptiles across Australia. Observing its emergence in a long-term study population of wild eastern water dragons (Intellagama lesueurii), we demonstrate the pathogen’s virulence-related genomic features, within-population spatiotemporal spread, and survival costs, all of which imply thatNbcould pose a threat to Australian reptiles in the future. Our findings highlight the need to closely monitor this pathogen in Australian ecosystems.
Disentangling the role of poultry farms and wild birds in the spread of highly pathogenic avian influenza virus H5N8 in Europe
Authors: Guinat Claire , Agui Cecilia Valenzuela , Vaughan Timothy G. , Scire Jérémie , Pohlmann Anne , Staubach Christoph , King Jacqueline , Swieton Edyta , Dan Adam , Cernikova Lenka , Ducatez Mariette F. , Stadler Tanja 
Published: October 2021

AbstractRecent outbreaks of highly pathogenic avian influenza H5N8 virus in Europe have caused severe damage to animal health, wildlife conservation and livestock economic sustainability. While epidemiological and phylogenetic studies have generated important clues about the virus spread in Europe, they remained opaque to the specific role of poultry farms and wild birds. Using a phylodynamic framework, we inferred the H5N8 virus transmission dynamics among poultry farms and wild birds in four severely affected countries and investigated drivers of spread between farms across borders during the 2016-17 epidemic. Based on existing genetic data, we showed that the virus was likely introduced into poultry farms during the autumn, in line with the timing of arrival of migratory wild birds. Then, transmission was mainly driven by farm-to-farm transmission in Germany, Hungary and Poland, suggesting that better understanding of how infected farms are connected in those countries would greatly help control efforts. In contrast, the epidemic was dominated by wild bird-to-farm transmission in Czech Republic, meaning that more sustainable prevention strategies should be developed to reduce virus exposure from wild birds. We inferred effective reproduction number Re estimates among poultry farms and wild birds. We expect those estimates being useful to parameterize predictive models of virus spread aiming at optimising control strategies. None of the investigated predictors related to live poultry trade, poultry census and geographic proximity were identified as supportive predictors of the viral spread between farms across borders, suggesting that other drivers should be considered in future studies.Significance statementIn winter 2016-17, Europe was severely hit by an unprecedented epidemic of highly pathogenic avian influenza (HPAI) H5N8 virus, causing significant impact on animal health, wildlife conservation and livestock economic sustainability. By applying phylodynamic tools to H5N8 sequence data collected from poultry farms and wild birds during the epidemic, we quantified how effectively the first infections were detected, how fast the virus spread, how many infections were missed and how many transmission events occurred at the wildlife-domestic interface. Also, we investigated predictors of the virus spread between farms across borders. These results are crucial to better understand the virus transmission dynamics, with the view to inform policy decision-making and reduce the impact of future epidemics of HPAI viruses.
Wiring multiple microenvironment proteomes uncovers the biology in head and neck cancer
Authors: Busso-Lopes Ariane Fidelis , Rivera César , Neves Leandro Xavier , Granato Daniela Campos , Patroni Fábio Malta de Sá , Mazo Tatiane de Rossi , Normando Ana Gabriela Costa , Domingues Romênia Ramos , Heberle Henry , Pretti Marco Antônio , de Mello Barbara Pereira , Rodrigues Andre Nimtz , Lacerda Pammela Araujo , Galdino Nayane Alves de Lima , Gollob Kenneth John , Medina Tiago da Silva , Cervigne Nilva de Karla , Prado-Ribeiro Ana Carolina , Brandão Thaís Bianca , Villa Luisa Lina , Uno Miyuki , Boroni Mariana , Kowalski Luiz Paulo , González-Arriagada Wilfredo , Paes Leme Adriana Franco 
Published: October 2021

SUMMARYThe poor prognosis of head and neck cancer (HNC) is associated with the presence of metastasis within the lymph nodes (LNs). Herein, the proteome of 140 multisite samples from a 59-HNC patient cohort, including primary and matched LN-negative or -positive tissues, saliva, and blood cells, reveals insights into the biology and potential metastasis biomarkers that may assist in clinical decision making. Protein profiles are strictly associated with immune modulation across datasets, and this provides the basis for investigating immune markers associated with metastasis. The proteome of LN metastatic cells recapitulates the proteome of the primary tumor sites. Conversely, the LN microenvironment proteome highlights the candidate prognostic markers. By integrating prioritized peptide, protein, and transcript levels with machine learning models, we identified a nodal metastasis signature in the blood and saliva. In summary, we present the deepest proteome characterization wiring multiple sampling sites in HNC, thus providing a promising basis for understanding tumoral biology and identifying metastasis-associated signatures.
Loss of epigenetic regulation disrupts lineage integrity, reactivates multipotency and promotes breast cancer
Authors: Langille Ellen R. , Al-Zahrani Khalid N. , Ma Zhibo , Malik Ahmad , Loganathan Sampath K. , Trcka Dan , Liu Jeff , Kozma Katelyn , Tsai Ricky , Teng Katie , Espin Roderic , Barutcu Seda , Nguyen Thomas , Bremner Rod , Jackson Hartland W. , Knudsen Erik S. , Bader Gary , Egan Sean E. , Pujana Miquel Angel , Wrana Jeff , Wahl Geoffrey M. , Schramek Daniel 
Published: October 2021

AbstractSystematically investigating the scores of genes mutated in cancer and discerning real drivers from inconsequential bystanders is a prerequisite for Precision Medicine, but remains challenging. Here, we developed a somatic CRISPR/Cas9 mutagenesis screen to study 215 recurrent ‘long-tail’ breast cancer genes, which revealed epigenetic regulation as major tumor suppressive mechanism. We report that core or accessory components of the COMPASS histone methylase complex including KMT2C, KDM6A, BAP1 and ASXL2 (“EpiDrivers”) cooperate with PIK3CAH1047R to transform mouse and human breast epithelial cells. Mechanistically, we find that Cre-mediated activation of PIK3CAH1047R elicited an aberrant alveolar lactation program in luminal cells, which was exacerbated upon loss of EpiDrivers. Remarkably, EpiDriver loss in basal cells also triggered an alveolar-like lineage conversion and accelerated formation of luminal-like tumors, suggesting a basal origin for luminal tumors. As EpiDrivers are mutated in 39% of human breast cancers, lineage infidelity and lactation mimicry may significantly contribute to early steps of breast cancer progression.Statement of significanceInfrequently mutated genes comprise most of the mutational burden in breast tumors but are poorly understood. In-vivo CRISPR screening identified functional tumor suppressors that converged on epigenetic regulation. Loss of epigenetic regulators accelerated tumorigenesis and revealed lineage infidelity and aberrant expression of lactation genes as potential early events in tumorigenesis.
Oxytocin reduces interoceptive influences on empathy-for-pain in the anterior insula
Authors: Betka Sophie , Van Praag Cassandra Gould , Rae Charlotte L , Pfeifer Gaby , Sequeira Henrique , Duka Theodora , Critchley Hugo 
Published: October 2021

AbstractEmpathy-for-pain states are underpinned byinteroception, i.e the central representation of internal states. Cardiac signals occur in a phasic manner; baroreceptor discharges at systole communicate the heartbeats’ strength. These signals modulate pain and emotion processing. We tested whether these phasic interoceptive signals modulate empathy-for-pain. As oxytocin (OT) enhances empathy and modulates interoceptive signals’ precision, we also tested if OT administration impacts empathy-for-pain via interoceptive mechanisms.Male subjects (N=32) attended three sessions to perform psychometric tests and an fMRI empathy-for-pain task, after intranasal administration of OT or placebo (40IU). Pictures of hands in painful or non-painful context were presented at systole or diastole. Effects of drug, emotion and cardiac timing on behaviour and brain activity was tested using general and mixed-effects linear models.Across conditions, activation was observed within regions implicated in pain and empathy-for-pain, with insula activation greater in the right than left hemisphere. OT administration, compared to placebo, attenuated the reactivity of some regions, including anterior cingulate cortex, but presentation of stimuli at systole blocked the OT attenuating effect.Our data suggest that OT alters the processing of motivationally-salient social cues, interacting with interoceptive signals. Our findings may inform targeted use of OT in psychiatric conditions linked to aberrant interoceptive processing.
Safb1 regulates cell fate determination in adult neural stem cells by enhancing Drosha cleavage of NFIB mRNA
Authors: Iffländer Niklas , Rolando Chiara , Balta Elli-Anna , Forcella Pascal , Mukhtar Tanzila , Bock Thomas , Taylor Verdon 
Published: October 2021

SummaryDuring brain homeostasis, stem cell fate determination is crucial to guarantee function, adaptation and regeneration while preventing neurodegeneration and cognitive impairment. How neural stem cells (NSCs) are instructed to generate neurons or glia is not well understood. Here we addressed how fate is resolved in multipotent adult hippocampal NSCs, and identify Scaffold Attachment Factor B1 (Safb1) as a determinant of neuron production by blocking glial commitment. Safb1 is sufficient to block oligodendrocytic differentiation of NSCs by preventing expression of the transcription factor NFIB at the post-transcriptional level. Detailed interrogation of the Drosha interactome and functional validation revealed that Safb1 enhances NFIB mRNA cleavage in a Drosha-dependent fashion. Thus, our study provides a cellular mechanism for selective NSC fate regulation by post-transcriptional destabilization of mRNAs. Given the importance of NSC maintenance and fate determination in the adult brain, our findings have major implications for cell-specific gene expression, brain disease and aging.
Visual occipito-temporal sensitivity to digits through elementary school
Authors: Fraga-González Gorka , Di Pietro Sarah V. , Pleisch Georgette , Neuenschwander Jasmin , Walitza Susanne , Brandeis Daniel , Karipidis Iliana I. , Brem Silvia 
Published: October 2021

AbstractNumber processing abilities are important for academic and personal development. The course of initial specialization of ventral occipito-temporal cortex (vOTC) for visual number processing is crucial for the development of numeric and arithmetic skills. We examined the visual N1, the electrophysiological correlate of vOTC activations across five time points in kindergarten (T1), middle and end of first grade (T2, T3), second (T4) and fifth grade (T5). 62 children (35 female) performed a target detection task which included visual presentation of digits, false fonts, and letters. Arithmetic skills were measured at T4 and T5 with standardized math tests. Stronger N1 amplitudes for digits than false fonts were found across all 5 measurements. Arithmetic skills correlated negatively with visual N1 sensitivity to digits at T4 (2nd grade, mean age 8.3 yrs) over the left hemisphere, possibly reflecting allocation of more attentional or cognitive resources with poorer arithmetic skills. Our main result shows persistent visual N1 sensitivity to digits that is already present early on in pre-school and remains stable until fifth grade. This differs from the relatively sharp rise and fall of the visual N1 sensitivity to words or letters between kindergarten and middle of elementary school. The present study thus indicates different trajectories in the development of visual processing for written characters that are relevant to numeracy and literacy.
Decoding personalized motor cortical excitability states from human electroencephalography
Authors: Hussain Sara J , Quentin Romain 
Published: October 2021

AbstractBrain state-dependent transcranial magnetic stimulation (TMS) requires real-time identification of cortical excitability states. Current approaches deliver TMS during brain states that correlate with motor cortex (M1) excitability at the group level. Here, we hypothesized that machine learning classifiers could successfully discriminate between high and low M1 excitability states in individual participants using information obtained from low-density electroencephalography (EEG) signals. To test this, we analyzed a publicly available dataset that delivered 600 single TMS pulses to the right M1 during EEG and electromyography (EMG) recordings in 20 healthy adults. Multivariate pattern classification was used to discriminate between brain states during which TMS evoked small and large motor-evoked potentials (MEPs). Results show that personalized classifiers successfully discriminated between low and high M1 excitability states in 80% of tested participants. MEPs elicited during classifier-predicted high excitability states were significantly larger than those elicited during classifier-predicted low excitability states in 90% of tested participants. Personalized classifiers did not generalize across participants. Overall, results show that individual participants exhibit unique brain activity patterns which predict low and high M1 excitability states and that these patterns can be efficiently captured using low-density EEG signals. Our findings suggest that deploying individualized classifiers during brain state-dependent TMS may enable fully personalized neuromodulation in the future.