bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of the Hippo pathway in the pathogenesis of inflammatory bowel disease
Authors: Xie Zhuo , Wang Ying , Yang Guang , Han Jing , Zhu Liguo , Li Li , Zhang Shenghong
Published: January 2021

Inflammatory bowel disease (IBD) is a chronic and recurrent inflammatory disorder that primarily comprises Crohn’s disease (CD) and ulcerative colitis (UC). Owing to its increasing prevalence in Eastern countries and the intractable challenges faced during IBD treatment, extensive research on IBD has been carried out over the last few years. Although the precise aetiology of IBD is undefined, the currently accepted hypothesis for IBD pathogenesis considers it to be a combination of environment, genetic predisposition, gut microbiota, and abnormal immunity. A recently emerged signalling pathway, the Hippo pathway, acts as a key regulator of cell growth, tissue homoeostasis, organ size, and has been implicated in several human cancers. In the past few years, studies have revealed the importance of the Hippo pathway in gastrointestinal tract physiology and gastrointestinal diseases, such as colorectal cancer and IBD. However, the role of the Hippo pathway and its exact impact in IBD remains to be elucidated. This review summarises the latest scientific literature on the involvement of this pathway in IBD from the following perspectives that account for the IBD pathogenesis: intestinal epithelial cell regeneration, immune regulation, gut microbiota, and angiogenesis. A comprehensive understanding of the specific role of the Hippo pathway in IBD will provide novel insights into future research directions and clinical implications of the Hippo pathway.
CCAAT/Enhancer-binding protein delta mediates glioma stem-like cell enrichment and ATP-binding cassette transporter ABCA1 activation for temozolomide resistance in glioblastoma
Authors: Wang Shao-Ming , Lin Wen-Chi , Lin Hong-Yi , Chen Yen-Lin , Ko Chiung-Yuan , Wang Ju-Ming
Published: January 2021

Glioblastoma (GBM) is the most aggressive brain tumor and relapses after chemo- or radiotherapy in a short time. The anticancer drug temozolamide (TMZ) is commonly used for GBM treatment, but glioma stem-like cells (GSCs) often lead to drug resistance and therapeutic failure. To date, the mechanism of GSC formation in TMZ-treated GBM remains largely unknown. CCAAT/Enhancer-binding protein delta (CEBPD) is an inflammation-responsive transcription factor and is proposed to be oncogenic in the context of drug resistance, prompting us to clarify its role in TMZ-resistant GBM. In this study, we first found that the CEBPD protein levels in GBM patients were significantly increased and further contributed to TMZ resistance by promoting GSC formation. Accordingly, the protein levels of stemness transcription factors, namely, SRY-box transcription factor 2 (SOX2), octamer-binding transcription factor 4 (OCT4), NANOG, and ATP-binding cassette subfamily A member 1 (ABCA1), were increased in GSCs and TMZ-treated GBM cells. Increased binding of CEBPD to promoter regions was observed in GSCs, indicating the direct regulation of these GSC-related genes by CEBPD. In addition, an ABCA1 inhibitor increased the caspase 3/7 activity of TMZ-treated GSCs, suggesting that TMZ efflux is controlled by ABCA1 activity and that the expression levels of the ABCA1 gene are an indicator of the efficiency of TMZ treatment. Together, we revealed the mechanism of CEBPD-mediated GSC drug resistance and proposed ABCA1 inhibition as a potential strategy for the treatment of TMZ-resistant GBM.
Dual EZH2 and G9a inhibition suppresses multiple myeloma cell proliferation by regulating the interferon signal and IRF4-MYC axis
Authors: Ishiguro Kazuya , Kitajima Hiroshi , Niinuma Takeshi , Maruyama Reo , Nishiyama Naotaka , Ohtani Hitoshi , Sudo Gota , Toyota Mutsumi , Sasaki Hajime , Yamamoto Eiichiro , Kai Masahiro , Nakase Hiroshi , Suzuki Hiromu
Published: January 2021

Epigenetic mechanisms such as histone modification play key roles in the pathogenesis of multiple myeloma (MM). We previously showed that EZH2, a histone H3 lysine 27 (H3K27) methyltransferase, and G9, a H3K9 methyltransferase, are potential therapeutic targets in MM. Moreover, recent studies suggest EZH2 and G9a cooperate to regulate gene expression. We therefore evaluated the antitumor effect of dual EZH2 and G9a inhibition in MM. A combination of an EZH2 inhibitor and a G9a inhibitor strongly suppressed MM cell proliferation in vitro by inducing cell cycle arrest and apoptosis. Dual EZH2/G9a inhibition also suppressed xenograft formation by MM cells in vivo. In datasets from the Gene Expression Omnibus, higher EZH2 and EHMT2 (encoding G9a) expression was significantly associated with poorer prognoses in MM patients. Microarray analysis revealed that EZH2/G9a inhibition significantly upregulated interferon (IFN)-stimulated genes and suppressed IRF4-MYC axis genes in MM cells. Notably, dual EZH2/G9a inhibition reduced H3K27/H3K9 methylation levels in MM cells and increased expression of endogenous retrovirus (ERV) genes, which suggests that activation of ERV genes may induce the IFN response. These results suggest that dual targeting of EZH2 and G9a may be an effective therapeutic strategy for MM.
Structure, substrate specificity, and catalytic mechanism of human D-2-HGDH and insights into pathogenicity of disease-associated mutations
Authors: Yang Jun , Zhu Hanwen , Zhang Tianlong , Ding Jianping
Published: January 2021

D-2-hydroxyglutarate dehydrogenase (D-2-HGDH) catalyzes the oxidation of D-2-hydroxyglutarate (D-2-HG) into 2-oxoglutarate, and genetic D-2-HGDH deficiency leads to abnormal accumulation of D-2-HG which causes type I D-2-hydroxyglutaric aciduria and is associated with diffuse large B-cell lymphoma. This work reports the crystal structures of human D-2-HGDH in apo form and in complexes with D-2-HG, D-malate, D-lactate, L-2-HG, and 2-oxoglutarate, respectively. D-2-HGDH comprises a FAD-binding domain, a substrate-binding domain, and a small C-terminal domain. The active site is located at the interface of the FAD-binding domain and the substrate-binding domain. The functional roles of the key residues involved in the substrate binding and catalytic reaction and the mutations identified in D-2-HGDH-deficient diseases are analyzed by biochemical studies. The structural and biochemical data together reveal the molecular mechanism of the substrate specificity and catalytic reaction of D-2-HGDH and provide insights into the pathogenicity of the disease-associated mutations.
The roles of microglia in viral encephalitis: from sensome to therapeutic targeting
Authors: Chhatbar Chintan , Prinz Marco
Published: January 2021

Viral encephalitis is a devastating disease with high mortality, and survivors often suffer from severe neurological complications. Microglia are innate immune cells of the central nervous system (CNS) parenchyma whose turnover is reliant on local proliferation. Microglia express a diverse range of proteins, which allows them to continuously sense the environment and quickly react to changes. Under inflammatory conditions such as CNS viral infection, microglia promote innate and adaptive immune responses to protect the host. However, during viral infection, a dysregulated microglia-T-cell interplay may result in altered phagocytosis of neuronal synapses by microglia that causes neurocognitive impairment. In this review, we summarize the current knowledge on the role of microglia in viral encephalitis, propose questions to be answered in the future and suggest possible therapeutic targets.
Diverse pathological lesions of primary aldosteronism and their clinical significance
Authors:   JRAS Study Group, Nishimoto Koshiro , Umakoshi Hironobu , Seki Tsugio , Yasuda Masanori , Araki Ryuichiro , Otsuki Michio , Katabami Takuyuki , Shibata Hirotaka , Ogawa Yoshihiro , Wada Norio , Sone Masakatsu , Okamura Shintaro , Izawa Shoichiro , Miyauchi Shozo , Yoshimoto Takanobu , Tsuiki Mika , Naruse Mitsuhide
Published: January 2021

Primary aldosteronism (PA) is mainly clinically classified as unilateral aldosterone-producing adenoma (APA) or bilateral idiopathic hyperaldosteronism. Immunohistochemistry for aldosterone synthase reveals a diverse PA pathology, including pathological APA and aldosterone-producing cell clusters. The relationship between PA pathology and adrenalectomy outcomes was examined herein. Data from 219 unilaterally adrenalectomized PA cases were analyzed. Pathological analyses revealed diverse putative aldosterone-producing lesions. Postoperative biochemical outcomes in 114 cases (test cohort) were classified as complete success (n = 85), partial success (n = 19), and absent success (n = 10). Outcomes in the large and small PA lesion groups, rather than between PA lesion types, were compared at five threshold values for PA lesion sizes (2–6 mm with 1-mm increments) to streamline the results. The proportion of complete success was significantly higher in the large PA lesion group than in the small PA lesion group at the 5-mm threshold only. The proportion of absent success was significantly higher in the small PA lesion group than in the large PA lesion group at all thresholds. Univariate and multivariate analyses of the test cohort identified serum K as an independent predictive factor for the small PA lesion group, which was confirmed in the 105-case validation cohort. Chi-squared automatic interaction detector analysis revealed that the best threshold of serum K for predicting large PA lesions was 2.82 mEq/L. These results will be beneficial for treating PA in clinical settings because patients with low serum K levels and apparent adrenal masses on CT may be subjected to adrenalectomy even if the adrenal venous sampling test is unavailable.
Strong optomechanical coupling at room temperature by coherent scattering
Authors: de los Ríos Sommer Andrés , Meyer Nadine , Quidant Romain
Published: January 2021

Quantum control of a system requires the manipulation of quantum states faster than any decoherence rate. For mesoscopic systems, this has so far only been reached by few cryogenic systems. An important milestone towards quantum control is the so-called strong coupling regime, which in cavity optomechanics corresponds to an optomechanical coupling strength larger than cavity decay rate and mechanical damping. Here, we demonstrate the strong coupling regime at room temperature between a levitated silica particle and a high finesse optical cavity. Normal mode splitting is achieved by employing coherent scattering, instead of directly driving the cavity. The coupling strength achieved here approaches three times the cavity linewidth, crossing deep into the strong coupling regime. Entering the strong coupling regime is an essential step towards quantum control with mesoscopic objects at room temperature.
Anomalous circular bulk photovoltaic effect in BiFeO3 thin films with stripe-domain pattern
Authors: Knoche David S. , Steimecke Matthias , Yun Yeseul , Mühlenbein Lutz , Bhatnagar Akash
Published: January 2021

Multiferroic bismuth ferrite, BiFeO3, offers a vast landscape to study the interplay between different ferrroic orders. Another aspect which is equally exciting, and yet underutilized, is the possibility of large-scale ordering of domains. Along with symmetry-driven bulk photovoltaic effect, BiFeO3 presents opportunities to conceptualize novel light-based devices. In this work, we investigate the evolution of the bulk photovoltaic effect in BiFeO3 thin films with stripe-domain pattern as the polarization of light is modulated from linear to elliptical to circular. The open-circuit voltages under circularly polarized light exceed ± 25 V. The anomalous character of the effect arises from the contradiction with the analytical assessment involving tensorial analysis. The assessment highlights the need for a domain-specific interaction of light which is further analyzed with spatially-resolved Raman measurements. Appropriate positioning of electrodes allows observation of a switch-like photovoltaic effect, i.e., ON and OFF state, by changing the helicity of circularly polarized light.
Avalanche criticality during ferroelectric/ferroelastic switching
Authors: Casals Blai , Nataf Guillaume F. , Salje Ekhard K. H.
Published: January 2021

Field induced domain wall displacements define ferroelectric/ferroelastic hysteresis loops, which are at the core of piezoelectric, magnetoelectric and memristive devices. These collective displacements are scale invariant jumps with avalanche characteristics. Here, we analyse the spatial distribution of avalanches in ferroelectrics with different domain and transformation patterns: Pb(Mg1/3Nb2/3)O3–PbTiO3 contains complex domains with needles and junction patterns, while BaTiO3 has parallel straight domains. Nevertheless, their avalanche characteristics are indistinguishable. The energies, areas and perimeters of the switched regions are power law distributed with exponents close to predicted mean field values. At the coercive field, the area exponent decreases, while the fractal dimension increases. This fine structure of the switching process has not been detected before and suggests that switching occurs via criticality at the coercive field with fundamentally different switching geometries at and near this critical point. We conjecture that the domain switching process in ferroelectrics is universal at the coercive field.
Dwarf planet (1) Ceres surface bluing due to high porosity resulting from sublimation
Authors: Schröder Stefan E. , Poch Olivier , Ferrari Marco , Angelis Simone De , Sultana Robin , Potin Sandra M. , Beck Pierre , De Sanctis Maria Cristina , Schmitt Bernard
Published: January 2021

The Dawn mission found that the dominant colour variation on the surface of dwarf planet Ceres is a change of the visible spectral slope, where fresh impact craters are surrounded by blue (negative spectral-sloped) ejecta. The origin of this colour variation is still a mystery. Here we investigate a scenario in which an impact mixes the phyllosilicates present on the surface of Ceres with the water ice just below. In our experiment, Ceres analogue material is suspended in liquid water to create intimately mixed ice particles, which are sublimated under conditions approximating those on Ceres. The sublimation residue has a highly porous, foam-like structure made of phyllosilicates that scattered light in similar blue fashion as the Ceres surface. Our experiment provides a mechanism for the blue colour of fresh craters that can naturally emerge from the Ceres environment.
Pyroelectric nanoplates for reduction of CO2 to methanol driven by temperature-variation
Authors: Xiao Lingbo , Xu Xiaoli , Jia Yanmin , Hu Ge , Hu Jun , Yuan Biao , Yu Yi , Zou Guifu
Published: January 2021

Carbon dioxide (CO2) is a problematic greenhouse gas, although its conversion to alternative fuels represents a promising approach to limit its long-term effects. Here, pyroelectric nanostructured materials are shown to utilize temperature-variations and to reduce CO2 for methanol. Layered perovskite bismuth tungstate nanoplates harvest heat energy from temperature-variation, driving pyroelectric catalytic CO2 reduction for methanol at temperatures between 15 °C and 70 °C. The methanol yield can be as high as 55.0 μmol⋅g−1 after experiencing 20 cycles of temperature-variation. This efficient, cost-effective, and environmental-friendly pyroelectric catalytic CO2 reduction route provides an avenue towards utilizing natural diurnal temperature-variation for future methanol economy.
Structural insights into TSC complex assembly and GAP activity on Rheb
Authors: Yang Huirong , Yu Zishuo , Chen Xizi , Li Jiabei , Li Ningning , Cheng Jiaxuan , Gao Ning , Yuan Hai-Xin , Ye Dan , Guan Kun-Liang , Xu Yanhui
Published: January 2021

Tuberous sclerosis complex (TSC) integrates upstream stimuli and regulates cell growth by controlling the activity of mTORC1. TSC complex functions as a GTPase-activating protein (GAP) towards small GTPase Rheb and inhibits Rheb-mediated activation of mTORC1. Mutations in TSC genes cause tuberous sclerosis. In this study, the near-atomic resolution structure of human TSC complex reveals an arch-shaped architecture, with a 2:2:1 stoichiometry of TSC1, TSC2, and TBC1D7. This asymmetric complex consists of two interweaved TSC1 coiled-coil and one TBC1D7 that spans over the tail-to-tail TSC2 dimer. The two TSC2 GAP domains are symmetrically cradled within the core module formed by TSC2 dimerization domain and central coiled-coil of TSC1. Structural and biochemical analyses reveal TSC2 GAP-Rheb complimentary interactions and suggest a catalytic mechanism, by which an asparagine thumb (N1643) stabilizes γ-phosphate of GTP and accelerate GTP hydrolysis of Rheb. Our study reveals mechanisms of TSC complex assembly and GAP activity.
circNDUFB2 inhibits non-small cell lung cancer progression via destabilizing IGF2BPs and activating anti-tumor immunity
Authors: Li Botai , Zhu Lili , Lu Chunlai , Wang Cun , Wang Hui , Jin Haojie , Ma Xuhui , Cheng Zhuoan , Yu Chengtao , Wang Siying , Zuo Qiaozhu , Zhou Yangyang , Wang Jun , Yang Chen , Lv Yuanyuan , Jiang Liyan , Qin Wenxin
Published: January 2021

Circular RNAs (circRNA) are a class of covalently closed single-stranded RNAs that have been implicated in cancer progression. Here we identify circNDUFB2 to be downregulated in non-small cell lung cancer (NSCLC) tissues, and to negatively correlate with NSCLC malignant features. Elevated circNDUFB2 inhibits growth and metastasis of NSCLC cells. Mechanistically, circNDUFB2 functions as a scaffold to enhance the interaction between TRIM25 and IGF2BPs, a positive regulator of tumor progression and metastasis. This TRIM25/circNDUFB2/IGF2BPs ternary complex facilitates ubiquitination and degradation of IGF2BPs, with this effect enhanced by N6-methyladenosine (m6A) modification of circNDUFB2. Moreover, circNDUFB2 is also recognized by RIG-I to activate RIG-I-MAVS signaling cascades and recruit immune cells into the tumor microenvironment (TME). Our data thus provide evidences that circNDUFB2 participates in the degradation of IGF2BPs and activation of anti-tumor immunity during NSCLC progression via the modulation of both protein ubiquitination and degradation, as well as cellular immune responses.
Reconciling bubble nucleation in explosive eruptions with geospeedometers
Authors: Hajimirza Sahand , Gonnermann Helge M. , Gardner James E.
Published: January 2021

Magma from Plinian volcanic eruptions contains an extraordinarily large numbers of bubbles. Nucleation of those bubbles occurs because pressure decreases as magma rises to the surface. As a consequence, dissolved magmatic volatiles, such as water, become supersaturated and cause bubbles to nucleate. At the same time, diffusion of volatiles into existing bubbles reduces supersaturation, resulting in a dynamical feedback between rates of nucleation due to magma decompression and volatile diffusion. Because nucleation rate increases with supersaturation, bubble number density (BND) provides a proxy record of decompression rate, and hence the intensity of eruption dynamics. Using numerical modeling of bubble nucleation, we reconcile a long-standing discrepancy in decompression rate estimated from BND and independent geospeedometers. We demonstrate that BND provides a record of the time-averaged decompression rate that is consistent with independent geospeedometers, if bubble nucleation is heterogeneous and facilitated by magnetite crystals.
Inferring high-resolution human mixing patterns for disease modeling
Authors: Mistry Dina , Litvinova Maria , Pastore y Piontti Ana , Chinazzi Matteo , Fumanelli Laura , Gomes Marcelo F. C. , Haque Syed A. , Liu Quan-Hui , Mu Kunpeng , Xiong Xinyue , Halloran M. Elizabeth , Longini Ira M. , Merler Stefano , Ajelli Marco , Vespignani Alessandro
Published: January 2021

Mathematical and computational modeling approaches are increasingly used as quantitative tools in the analysis and forecasting of infectious disease epidemics. The growing need for realism in addressing complex public health questions is, however, calling for accurate models of the human contact patterns that govern the disease transmission processes. Here we present a data-driven approach to generate effective population-level contact matrices by using highly detailed macro (census) and micro (survey) data on key socio-demographic features. We produce age-stratified contact matrices for 35 countries, including 277 sub-national administratvie regions of 8 of those countries, covering approximately 3.5 billion people and reflecting the high degree of cultural and societal diversity of the focus countries. We use the derived contact matrices to model the spread of airborne infectious diseases and show that sub-national heterogeneities in human mixing patterns have a marked impact on epidemic indicators such as the reproduction number and overall attack rate of epidemics of the same etiology. The contact patterns derived here are made publicly available as a modeling tool to study the impact of socio-economic differences and demographic heterogeneities across populations on the epidemiology of infectious diseases.
Deep subwavelength control of valley polarized cathodoluminescence in h-BN/WSe2/h-BN heterostructure
Authors: Zheng Liheng , Liu Zhixin , Liu Donglin , Wang Xingguo , Li Yu , Jiang Meiling , Lin Feng , Zhang Han , Shen Bo , Zhu Xing , Gong Yongji , Fang Zheyu
Published: January 2021

Valley pseudospin in transition metal dichalcogenides monolayers intrinsically provides additional possibility to control valley carriers, raising a great impact on valleytronics in following years. The spin-valley locking directly contributes to optical selection rules which allow for valley-dependent addressability of excitons by helical optical pumping. As a binary photonic addressable route, manipulation of valley polarization states is indispensable while effective control methods at deep-subwavelength scale are still limited. Here, we report the excitation and control of valley polarization in h-BN/WSe2/h-BN and Au nanoantenna hybrid structure by electron beam. Near-field circularly polarized dipole modes can be excited via precise stimulation and generate the valley polarized cathodoluminescence via near-field interaction. Effective manipulation of valley polarization degree can be realized by variation of excitation position. This report provides a near-field excitation methodology of valley polarization, which offers exciting opportunities for deep-subwavelength valleytronics investigation, optoelectronic circuits integration and future quantum information technologies.
Accurate protein structure prediction with hydroxyl radical protein footprinting data
Authors: Biehn Sarah E. , Lindert Steffen
Published: January 2021

Hydroxyl radical protein footprinting (HRPF) in combination with mass spectrometry reveals the relative solvent exposure of labeled residues within a protein, thereby providing insight into protein tertiary structure. HRPF labels nineteen residues with varying degrees of reliability and reactivity. Here, we are presenting a dynamics-driven HRPF-guided algorithm for protein structure prediction. In a benchmark test of our algorithm, usage of the dynamics data in a score term resulted in notable improvement of the root-mean-square deviations of the lowest-scoring ab initio models and improved the funnel-like metric Pnear for all benchmark proteins. We identified models with accurate atomic detail for three of the four benchmark proteins. This work suggests that HRPF data along with side chain dynamics sampled by a Rosetta mover ensemble can be used to accurately predict protein structure.
Overexpression of neuregulin 1 in GABAergic interneurons results in reversible cortical disinhibition
Authors: Wang Yao-Yi , Zhao Bing , Wu Meng-Meng , Zheng Xiao-Li , Lin Longnian , Yin Dong-Min
Published: January 2021

Cortical disinhibition is a common feature of several neuropsychiatric diseases such as schizophrenia, autism and intellectual disabilities. However, the underlying mechanisms are not fully understood. To mimic increased expression of Nrg1, a schizophrenia susceptibility gene in GABAergic interneurons from patients with schizophrenia, we generated gtoNrg1 mice with overexpression of Nrg1 in GABAergic interneurons. gtoNrg1 mice showed cortical disinhibition at the cellular, synaptic, neural network and behavioral levels. We revealed that the intracellular domain of NRG1 interacts with the cytoplasmic loop 1 of Nav1.1, a sodium channel critical for the excitability of GABAergic interneurons, and inhibits Nav currents. Intriguingly, activation of GABAergic interneurons or restoring NRG1 expression in adulthood could rescue the hyperactivity and impaired social novelty in gtoNrg1 mice. These results identify mechanisms underlying cortical disinhibition related to schizophrenia and raise the possibility that restoration of NRG1 signaling and GABAergic function is beneficial in certain neuropsychiatric disorders.
Ultra-high dynamic range quantum measurement retaining its sensitivity
Authors: Herbschleb E. D. , Kato H. , Makino T. , Yamasaki S. , Mizuochi N.
Published: January 2021

Quantum sensors are highly sensitive since they capitalise on fragile quantum properties such as coherence, while enabling ultra-high spatial resolution. For sensing, the crux is to minimise the measurement uncertainty in a chosen range within a given time. However, basic quantum sensing protocols cannot simultaneously achieve both a high sensitivity and a large range. Here, we demonstrate a non-adaptive algorithm for increasing this range, in principle without limit, for alternating-current field sensing, while being able to get arbitrarily close to the best possible sensitivity. Therefore, it outperforms the standard measurement concept in both sensitivity and range. Also, we explore this algorithm thoroughly by simulation, and discuss the T−2 scaling that this algorithm approaches in the coherent regime, as opposed to the T−1/2 of the standard measurement. The same algorithm can be applied to any modulo-limited sensor.
Viral speciation through subcellular genetic isolation and virogenesis incompatibility
Authors: Chaikeeratisak Vorrapon , Birkholz Erica A. , Prichard Amy M. , Egan MacKennon E. , Mylvara Avani , Nonejuie Poochit , Nguyen Katrina T. , Sugie Joseph , Meyer Justin R. , Pogliano Joe
Published: January 2021

Understanding how biological species arise is critical for understanding the evolution of life on Earth. Bioinformatic analyses have recently revealed that viruses, like multicellular life, form reproductively isolated biological species. Viruses are known to share high rates of genetic exchange, so how do they evolve genetic isolation? Here, we evaluate two related bacteriophages and describe three factors that limit genetic exchange between them: 1) A nucleus-like compartment that physically separates replicating phage genomes, thereby limiting inter-phage recombination during co-infection; 2) A tubulin-based spindle that orchestrates phage replication and forms nonfunctional hybrid polymers; and 3) A nuclear incompatibility factor that reduces phage fitness. Together, these traits maintain species differences through Subcellular Genetic Isolation where viral genomes are physically separated during co-infection, and Virogenesis Incompatibility in which the interaction of cross-species components interferes with viral production.
Selective filling of n-hexane in a tight nanopore
Authors: Qu Haoran , Rayabharam Archith , Wu Xiaojian , Wang Peng , Li Yunfeng , Fagan Jeffrey , Aluru Narayana R. , Wang YuHuang
Published: January 2021

Molecular sieving may occur when two molecules compete for a nanopore. In nearly all known examples, the nanopore is larger than the molecule that selectively enters the pore. Here, we experimentally demonstrate the ability of single-wall carbon nanotubes with a van der Waals pore size of 0.42 nm to separate n-hexane from cyclohexane—despite the fact that both molecules have kinetic diameters larger than the rigid nanopore. This unexpected finding challenges our current understanding of nanopore selectivity and how molecules may enter a tight channel. Ab initio molecular dynamics simulations reveal that n-hexane molecules stretch by nearly 11.2% inside the nanotube pore. Although at a relatively low probability (28.5% overall), the stretched state of n-hexane does exist in the bulk solution, allowing the molecule to enter the tight pore even at room temperature. These insights open up opportunities to engineer nanopore selectivity based on the molecular degrees of freedom.
Carbon nano-onion-mediated dual targeting of P-selectin and P-glycoprotein to overcome cancer drug resistance
Authors: Wang Hai , Liang Yutong , Yin Yue , Zhang Jie , Su Wen , White Alisa M. , Bin Jiang  , Xu Jiangsheng , Zhang Yuntian , Stewart Samantha , Lu Xiongbin , He Xiaoming
Published: January 2021

The transmembrane P-glycoprotein (P-gp) pumps that efflux drugs are a major mechanism of cancer drug resistance. They are also important in protecting normal tissue cells from poisonous xenobiotics and endogenous metabolites. Here, we report a fucoidan-decorated silica-carbon nano-onion (FSCNO) hybrid nanoparticle that targets tumor vasculature to specifically release P-gp inhibitor and anticancer drug into tumor cells. The tumor vasculature targeting capability of the nanoparticle is demonstrated using multiple models. Moreover, we reveal the superior light absorption property of nano-onion in the near infrared region (NIR), which enables triggered drug release from the nanoparticle at a low NIR power. The released inhibitor selectively binds to P-gp pumps and disables their function, which improves the bioavailability of anticancer drug inside the cells. Furthermore, free P-gp inhibitor significantly increases the systemic toxicity of a chemotherapy drug, which can be resolved by delivering them with FSCNO nanoparticles in combination with a short low-power NIR laser irradiation.
Recurrent network dynamics shape direction selectivity in primary auditory cortex
Authors: Aponte Destinee A. , Handy Gregory , Kline Amber M. , Tsukano Hiroaki , Doiron Brent , Kato Hiroyuki K.
Published: January 2021

Detecting the direction of frequency modulation (FM) is essential for vocal communication in both animals and humans. Direction-selective firing of neurons in the primary auditory cortex (A1) has been classically attributed to temporal offsets between feedforward excitatory and inhibitory inputs. However, it remains unclear how cortical recurrent circuitry contributes to this computation. Here, we used two-photon calcium imaging and whole-cell recordings in awake mice to demonstrate that direction selectivity is not caused by temporal offsets between synaptic currents, but by an asymmetry in total synaptic charge between preferred and non-preferred directions. Inactivation of cortical somatostatin-expressing interneurons (SOM cells) reduced direction selectivity, revealing its cortical contribution. Our theoretical models showed that charge asymmetry arises due to broad spatial topography of SOM cell-mediated inhibition which regulates signal amplification in strongly recurrent circuitry. Together, our findings reveal a major contribution of recurrent network dynamics in shaping cortical tuning to behaviorally relevant complex sounds.
Structural basis of GABARAP-mediated GABAA receptor trafficking and functions on GABAergic synaptic transmission
Authors: Ye Jin , Zou Guichang , Zhu Ruichi , Kong Chao , Miao Chenjian , Zhang Mingjie , Li Jianchao , Xiong Wei , Wang Chao
Published: January 2021

GABAA receptors (GABAARs) are the primary fast inhibitory ion channels in the central nervous system. Dysfunction of trafficking and localization of GABAARs to cell membranes is clinically associated with severe psychiatric disorders in humans. The GABARAP protein is known to support the stability of GABAARs in synapses, but the underlying molecular mechanisms remain to be elucidated. Here, we show that GABARAP/GABARAPL1 directly binds to a previously unappreciated region in the γ2 subunit of GABAAR. We demonstrate that GABARAP functions to stabilize GABAARs via promoting its trafficking pathway instead of blocking receptor endocytosis. The GABARAPL1–γ2-GABAAR crystal structure reveals the mechanisms underlying the complex formation. We provide evidence showing that phosphorylation of γ2-GABAAR differentially modulate the receptor’s binding to GABARAP and the clathrin adaptor protein AP2. Finally, we demonstrate that GABAergic synaptic currents are reduced upon specific blockage of the GABARAP–GABAAR complex formation. Collectively, our results reveal that GABARAP/GABARAPL1, but not other members of the Atg8 family proteins, specifically regulates synaptic localization of GABAARs via modulating the trafficking of the receptor.
Author Correction: Stretchable, dynamic covalent polymers for soft, long-lived bioresorbable electronic stimulators designed to facilitate neuromuscular regeneration
Authors: Choi Yeon Sik , Hsueh Yuan-Yu , Koo Jahyun , Yang Quansan , Avila Raudel , Hu Buwei , Xie Zhaoqian , Lee Geumbee , Ning Zheng , Liu Claire , Xu Yameng , Lee Young Joong , Zhao Weikang , Fang Jun , Deng Yujun , Lee Seung Min , Vázquez-Guardado Abraham , Stepien Iwona , Yan Ying , Song Joseph W. , Haney Chad , Oh Yong Suk , Liu Wentai , Yoon Hong-Joon , Banks Anthony , MacEwan Matthew R. , Ameer Guillermo A. , Ray Wilson Z. , Huang Yonggang , Xie Tao , Franz Colin K. , Li Song , Rogers John A.
Published: January 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20857-y
Assembling mitogenome of Himalayan Black Bear (U. t. laniger) from low depth reads and its application in drawing phylogenetic inferences
Authors: Bit Amrita , Thakur Mukesh , Singh Sujeet Kumar , Joshi Bheem Dutt , Singh Vinay Kumar , Sharma Lalit Kumar , Tripathy Basudev , Chandra Kailash
Published: January 2021

The complete mitogenome of Himalayan black bear (Ursus thibetanus laniger) from Indian Himalayan region was assembled following the modified approach of mitochondrial baiting and mapping using the next-generation sequencing reads. The complete mitogenome was of 16,556 bp long, consisted of 37 genes that contained 13 protein-coding genes, 22 tRNAs, 2 rRNAs and 1 control region. The complete base composition was 31.33% A, 15.24% G, 25.45%C, and 27.98%T and gene arrangement was similar to the other sub-species of Asiatic black bear. The relative synonymous codon usage analysis revealed the maximum abundance of Isoleucine, Tyrosine, Leucine and Threonine. The assembled mitogenome of U. t. laniger exhibited 99% similarity with the mitogenomes of Himalayan black bear available from Nepal and Tibetan Plateau-Himalaya region. The findings of the present study has proven low depth sequencing data, adequate and highly efficient in rapid recovering the mitochondrial genome by overcoming the conventional strategies of obtaining long-range PCR and subsequently drawing phylogenetic inferences.
Assumptions about fence permeability influence density estimates for brown hyaenas across South Africa
Authors: Williams Kathryn S. , Williams Samual T. , Welch Rebecca J. , Marneweck Courtney J. , Mann Gareth K. H. , Pitman Ross T. , Whittington-Jones Gareth , Balme Guy A. , Parker Daniel M. , Hill Russell A.
Published: January 2021

Wildlife population density estimates provide information on the number of individuals in an area and influence conservation management decisions. Thus, accuracy is vital. A dominant feature in many landscapes globally is fencing, yet the implications of fence permeability on density estimation using spatial capture-recapture modelling are seldom considered. We used camera trap data from 15 fenced reserves across South Africa to examine the density of brown hyaenas (Parahyaena brunnea). We estimated density and modelled its relationship with a suite of covariates when fenced reserve boundaries were assumed to be permeable or impermeable to hyaena movements. The best performing models were those that included only the influence of study site on both hyaena density and detection probability, regardless of assumptions of fence permeability. When fences were considered impermeable, densities ranged from 2.55 to 15.06 animals per 100 km2, but when fences were considered permeable, density estimates were on average 9.52 times lower (from 0.17 to 1.59 animals per 100 km2). Fence permeability should therefore be an essential consideration when estimating density, especially since density results can considerably influence wildlife management decisions. In the absence of strong evidence to the contrary, future studies in fenced areas should assume some degree of permeability in order to avoid overestimating population density.
Repeated electromagnetic field stimulation lowers amyloid-β peptide levels in primary human mixed brain tissue cultures
Authors: Perez Felipe P. , Maloney Bryan , Chopra Nipun , Morisaki Jorge J. , Lahiri Debomoy K.
Published: January 2021

Late Onset Alzheimer’s Disease is the most common cause of dementia, characterized by extracellular deposition of plaques primarily of amyloid-β (Aβ) peptide and tangles primarily of hyperphosphorylated tau protein. We present data to suggest a noninvasive strategy to decrease potentially toxic Aβ levels, using repeated electromagnetic field stimulation (REMFS) in primary human brain (PHB) cultures. We examined effects of REMFS on Aβ levels (Aβ40 and Aβ42, that are 40 or 42 amino acid residues in length, respectively) in PHB cultures at different frequencies, powers, and specific absorption rates (SAR). PHB cultures at day in vitro 7 (DIV7) treated with 64 MHz, and 1 hour daily for 14 days (DIV 21) had significantly reduced levels of secreted Aβ40 (p = 001) and Aβ42 (p = 0.029) peptides, compared to untreated cultures. PHB cultures (DIV7) treated at 64 MHz, for 1 or 2 hour during 14 days also produced significantly lower Aβ levels. PHB cultures (DIV28) treated with 64 MHz 1 hour/day during 4 or 8 days produced a similar significant reduction in Aβ40 levels. 0.4 W/kg was the minimum SAR required to produce a biological effect. Exposure did not result in cellular toxicity nor significant changes in secreted Aβ precursor protein-α (sAPPα) levels, suggesting the decrease in Aβ did not likely result from redirection toward the α-secretase pathway. EMF frequency and power used in our work is utilized in human magnetic resonance imaging (MRI, thus suggesting REMFS can be further developed in clinical settings to modulate Aβ deposition.
The randomized ZIPANGU trial of ranibizumab and adjunct laser for macular edema following branch retinal vein occlusion in treatment-naïve patients
Authors: Murata Toshinori , Kondo Mineo , Inoue Makoto , Nakao Shintaro , Osaka Rie , Shiragami Chieko , Sogawa Kenji , Mochizuki Akikazu , Shiraga Rumiko , Ohashi Yohei , Kaneko Takeumi , Chandrasekhar Chikatapu , Tsujikawa Akitaka , Kamei Motohiro
Published: January 2021

The ZIPANGU study assessed the efficacy and safety of ranibizumab as a one loading dose + pro re nata (one + PRN) regimen with/without focal/grid laser among treatment-naïve patients suffering from macular edema (ME) following branch retinal vein occlusion (BRVO). ZIPANGU was a phase IV, prospective, randomized, open-label, active-controlled, 12-month, two-arm, multicenter study. Treatment-naïve patients with visual impairment (19–73 letters) caused by ME, defined as central subfield thickness (CSFT) > 300 µm, due to BRVO were randomly assigned to ranibizumab monotherapy (n = 29) or combination therapy (ranibizumab + focal/grid short-pulse laser, n = 30). The primary endpoint was the number of ranibizumab injections. Secondary endpoints were mean changes in best-corrected visual acuity (BCVA) and CSFT, and safety. There were no statistically significant differences in the mean number of ranibizumab injections between monotherapy (4.3 injections) vs. combination (4.1 injections) therapy, or in CSFT. BCVA improvement in the monotherapy arm (22.0 letters) was better than the combination therapy arm (15.0 letters) (p = 0.035). Overall, both regimens appeared to be safe and well tolerated. One + PRN ranibizumab is safe and efficacious in treatment-naïve patients with ME secondary to BRVO. A conjunctive laser treatment did not lead to better functional outcomes or fewer ranibizumab injections.
Population exposure across central India to PM2.5 derived using remotely sensed products in a three-stage statistical model
Authors: Maheshwarkar Prem , Sunder Raman Ramya
Published: January 2021

Surface PM2.5 concentrations are required for exposure assessment studies. Remotely sensed Aerosol Optical Depth (AOD) has been used to derive PM2.5 where ground data is unavailable. However, two key challenges in estimating surface PM2.5 from AOD using statistical models are (i) Satellite data gaps, and (ii) spatio-temporal variability in AOD-PM2.5 relationships. In this study, we estimated spatially continuous (0.03° × 0.03°) daily surface PM2.5 concentrations using MAIAC AOD over Madhya Pradesh (MP), central India for 2018 and 2019, and validated our results against surface measurements. Daily MAIAC AOD gaps were filled using MERRA-2 AOD. Imputed AOD together with MERRA-2 meteorology and land use information were then used to develop a linear mixed effect (LME) model. Finally, a geographically weighted regression was developed using the LME output to capture spatial variability in AOD-PM2.5 relationship. Final Cross-Validation (CV) correlation coefficient, r2, between modelled and observed PM2.5 varied from 0.359 to 0.689 while the Root Mean Squared Error (RMSE) varied from 15.83 to 35.85 µg m−3, over the entire study region during the study period. Strong seasonality was observed with winter seasons (2018 and 2019) PM2.5 concentration (mean value 82.54 µg m−3) being the highest and monsoon seasons being the lowest (mean value of 32.10 µg m−3). Our results show that MP had a mean PM2.5 concentration of 58.19 µg m−3 and 56.32 µg m−3 for 2018 and 2019, respectively, which likely caused total premature deaths of 0.106 million (0.086, 0.128) at the 95% confidence interval including 0.056 million (0.045, 0.067) deaths due to Ischemic Heart Disease (IHD), 0.037 million (0.031, 0.045) due to strokes, 0.012 million (0.009, 0.014) due to Chronic Obstructive Pulmonary Disease (COPD), and 1.2 thousand (1.0, 1.5) due to lung cancer (LNC) during this period.
The long developmental trajectory of body representation plasticity following tool use
Authors: Martel Marie , Finos Livio , Koun Eric , Farnè Alessandro , Roy Alice Catherine
Published: January 2021

Humans evolution is distinctly characterized by their exquisite mastery of tools, allowing them to shape their environment in more elaborate ways compared to other species. This ability is present ever since infancy and most theories indicate that children become proficient with tool use very early. In adults, tool use has been shown to plastically modify metric aspects of the arm representation, as indexed by changes in movement kinematics. To date, whether and when the plastic capability of updating the body representation develops during childhood remains unknown. This question is particularly important since body representation plasticity could be impacted by the fact that the human body takes years to achieve a stable metric configuration. Here we assessed the kinematics of 90 young participants (8–21 years old) required to reach for an object before and after tool use, as a function of their pubertal development. Results revealed that tool incorporation, as indexed by the adult typical kinematic pattern, develops very slowly and displays a u-shaped developmental trajectory. From early to mid puberty, the changes in kinematics following tool use seem to reflect a shortened arm representation, opposite to what was previously reported in adults. This pattern starts reversing after mid puberty, which is characterized by the lack of any kinematics change following tool use. The typical adult-like pattern emerges only at late puberty, when body size is stable. These findings reveal the complex dynamics of tool incorporation across development, possibly indexing the transition from a vision-based to a proprioception-based body representation plasticity.
A preliminary study of post-progressive nail-art effects on in vivo nail plate using optical coherence tomography-based intensity profiling assessment
Authors: Saleah Sm Abu , Kim Pilun , Seong Daewoon , Wijesinghe Ruchire Eranga , Jeon Mansik , Kim Jeehyun
Published: January 2021

Nail beautification is a widely applied gender independent practice. Excessive nail beautifications and nail-arts have a direct impact on the nail structure and can cause nail disorders. Therefore, the assessment of post-progressive nail-art effects on the nail is essential to maintain optimal nail health and to avoid any undesirable disorders. In this study, in vivo nails were examined in control stage, with a nail-art stage, and after removing the nail-art stage using a 1310 nm spectral-domain optical coherence tomography (SD-OCT) system. The acquired cross-sectional OCT images were analyzed by a laboratory customized signal processing algorithm to obtain scattered intensity profiling assessments that could reveal the effects of nail beautification on the nail plate. The formation and progression of cracks on the nail plate surface were detected as an effect of nail beautification after 72 h of nail-art removal. Changes in backscattered light intensity and nail plate thickness of control and art-removed nails were quantitatively compared. The results revealed the potential feasibility of the developed OCT-based inspection procedure to diagnose post-progressive nail-art effects on in vivo nail plate, which can be helpful to prevent nail plate damages during art removal through real-time monitoring of the boundary between the nail plate and nail-art. Besides nail-art effects, the developed method can also be used for the investigation of nail plate abnormalities by examining the inconsistency of internal and external nail plate structure, which can be diagnosed with both qualitative and quantitative assessments from a clinical perspective.
MITO-Luc/GFP zebrafish model to assess spatial and temporal evolution of cell proliferation in vivo
Authors: de Latouliere Luisa , Manni Isabella , Ferrari Laura , Pisati Federica , Totaro Maria Grazia , Gurtner Aymone , Marra Emanuele , Pacello Lucrezia , Pozzoli Ombretta , Aurisicchio Luigi , Capogrossi Maurizio C. , Deflorian Gianluca , Piaggio Giulia
Published: January 2021

We developed a novel reporter transgenic zebrafish model called MITO-Luc/GFP zebrafish in which GFP and luciferase expression are under the control of the master regulator of proliferation NF-Y. In MITO-Luc/GFP zebrafish it is possible to visualize cell proliferation in vivo by fluorescence and bioluminescence. In this animal model, GFP and luciferase expression occur in early living embryos, becoming tissue specific in juvenile and adult zebrafish. By in vitro and ex vivo experiments we demonstrate that luciferase activity in adult animals occurs in intestine, kidney and gonads, where detectable proliferating cells are located. Further, by time lapse experiments in live embryos, we observed a wave of GFP positive cells following fin clip. In adult zebrafish, in addition to a bright bioluminescence signal on the regenerating tail, an early unexpected signal coming from the kidney occurs indicating not only a fin cell proliferation, but also a systemic response to tissue damage. Finally, we observed that luciferase activity was inhibited by anti-proliferative interventions, i.e. 5FU, cell cycle inhibitors and X-Rays. In conclusion, MITO-Luc/GFP zebrafish is a novel animal model that may be crucial to assess the spatial and temporal evolution of cell proliferation in vivo.