bluuebunny/crossref_metadata_2025 huggingface dataset:
Temperature Trends in the Northwestern Tibetan Plateau Constrained by Ice Core Water Isotopes Over the Past 7,000 Years
Authors: Pang Hongxi , Hou Shugui , Zhang Wangbin , Wu Shuangye , Jenk Theo M. , Schwikowski Margit , Jouzel Jean
Published: October 2020

The reasons for the Holocene temperature conundrum, known as the inconsistency between the reconstructed cooling and the inferred warming simulations during the Holocene, remain unclear. Temperature reconstructions from the Tibetan Plateau (TP) provide important insights for understanding the Holocene temperature conundrum due to enhanced sensitivity to climate at high altitudes. Given the significant positive correlation between air temperature and δ18O in precipitation over the northern TP, the stable isotopic records of ice cores recovered from this area are widely used for paleotemperature reconstruction. Here we present a new high‐resolution δ18O record from the Chongce ice cores to bedrock, dated back to 7 ka BP by the accelerator mass spectrometry (AMS) 14C dating technique. Our reconstructed temperature record shows a long‐term warming trend until ~2 ka BP, followed by an abrupt change to a relatively cool period until the start of the industrial‐era warming. This record challenges the widely recognized Holocene reconstruction from the neighboring Guliya ice core. It is also different from many previous temperature reconstructions, most of which have summer biases and show a long‐term cooling trend over the past two millennia. In addition, our record shows that temperatures during the recent decades are almost the highest during the past 7 ka BP, highlighting the unusual warming forced by anthropogenic greenhouse gases.
SUV39H1 regulates the progression of MLL-AF9-induced acute myeloid leukemia
Authors: Chu Yajing , Chen Yangpeng , Guo Huidong , Li Mengke , Wang Bichen , Shi Deyang , Cheng Xuelian , Guan Jinxia , Wang Xiaomin , Xue Chenghai , Cheng Tao , Shi Jun , Yuan Weiping
Published: October 2020

Epigenetic regulations play crucial roles in leukemogenesis and leukemia progression. SUV39H1 is the dominant H3K9 methyltransferase in the hematopoietic system, and its expression declines with aging. However, the role of SUV39H1 via its-mediated repressive modification H3K9me3 in leukemogenesis/leukemia progression remains to be explored. We found that SUV39H1 was down-regulated in a variety of leukemias, including MLL-r AML, as compared with normal individuals. Decreased levels of Suv39h1 expression and genomic H3K9me3 occupancy were observed in LSCs from MLL-r-induced AML mouse models in comparison with that of hematopoietic stem/progenitor cells. Suv39h1 overexpression increased leukemia latency and decreased the frequency of LSCs in MLL-r AML mouse models, while Suv39h1 knockdown accelerated disease progression with increased number of LSCs. Increased Suv39h1 expression led to the inactivation of Hoxb13 and Six1, as well as reversion of Hoxa9/Meis1 downstream target genes, which in turn decelerated leukemia progression. Interestingly, Hoxb13 expression is up-regulated in MLL-AF9-induced AML cells, while knockdown of Hoxb13 in MLL-AF9 leukemic cells significantly prolonged the survival of leukemic mice with reduced LSC frequencies. Our data revealed that SUV39H1 functions as a tumor suppressor in MLL-AF9-induced AML progression. These findings provide the direct link of SUV39H1 to AML development and progression.
SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation
Authors: Li Shufen , Zhang Yulan , Guan Zhenqiong , Li Huiling , Ye Meidi , Chen Xi , Shen Jun , Zhou Yiwu , Shi Zheng-Li , Zhou Peng , Peng Ke
Published: October 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to respiratory illness and multi-organ failure in critically ill patients. Although the virus-induced lung damage and inflammatory cytokine storm are believed to be directly associated with coronavirus disease 2019 (COVID-19) clinical manifestations, the underlying mechanisms of virus-triggered inflammatory responses are currently unknown. Here we report that SARS-CoV-2 infection activates caspase-8 to trigger cell apoptosis and inflammatory cytokine processing in the lung epithelial cells. The processed inflammatory cytokines are released through the virus-induced necroptosis pathway. Virus-induced apoptosis, necroptosis, and inflammation activation were also observed in the lung sections of SARS-CoV-2-infected HFH4-hACE2 transgenic mouse model, a valid model for studying SARS-CoV-2 pathogenesis. Furthermore, analysis of the postmortem lung sections of fatal COVID-19 patients revealed not only apoptosis and necroptosis but also massive inflammatory cell infiltration, necrotic cell debris, and pulmonary interstitial fibrosis, typical of immune pathogenesis in the lung. The SARS-CoV-2 infection triggered a dual mode of cell death pathways and caspase-8-dependent inflammatory responses may lead to the lung damage in the COVID-19 patients. These discoveries might assist the development of therapeutic strategies to treat COVID-19.
Modulation of cognition and neuronal plasticity in gain- and loss-of-function mouse models of the schizophrenia risk gene Tcf4
Authors: Badowska D. M. , Brzózka M. M. , Kannaiyan N. , Thomas C. , Dibaj P. , Chowdhury A. , Steffens H. , Turck C. W. , Falkai P. , Schmitt A. , Papiol S. , Scheuss V. , Willig K. I. , Martins-de-Souza D. , Rhee J. S. , Malzahn D. , Rossner M. J.
Published: October 2020

The transcription factor TCF4 was confirmed in several large genome-wide association studies as one of the most significant schizophrenia (SZ) susceptibility genes. Transgenic mice moderately overexpressing Tcf4 in forebrain (Tcf4tg) display deficits in fear memory and sensorimotor gating. As second hit, we exposed Tcf4tg animals to isolation rearing (IR), chronic social defeat (SD), enriched environment (EE), or handling control (HC) conditions and examined mice with heterozygous deletion of the exon 4 (Tcf4Ex4δ+/−) to unravel gene-dosage effects. We applied multivariate statistics for behavioral profiling and demonstrate that IR and SD cause strong cognitive deficits of Tcf4tg mice, whereas EE masked the genetic vulnerability. We observed enhanced long-term depression in Tcf4tg mice and enhanced long-term potentiation in Tcf4Ex4δ+/− mice indicating specific gene-dosage effects. Tcf4tg mice showed higher density of immature spines during development as assessed by STED nanoscopy and proteomic analyses of synaptosomes revealed concurrently increased levels of proteins involved in synaptic function and metabolic pathways. We conclude that environmental stress and Tcf4 misexpression precipitate cognitive deficits in 2-hit mouse models of relevance for schizophrenia.
N6-methyladenosine-dependent pri-miR-17-92 maturation suppresses PTEN/TMEM127 and promotes sensitivity to everolimus in gastric cancer
Authors: Sun Yiting , Li Song , Yu Wenbin , Zhao Zeyi , Gao Jing , Chen Cheng , Wei Meng , Liu Teng , Li Lanbo , Liu Lian
Published: October 2020

N6-methyladenosine (m6A) is the most common epigenetic RNA modification with essential roles in cancer progression. However, roles of m6A and its regulator METTL3 on non-coding RNA in gastric cancer are unknown. In this study, we found elevated levels of m6A and METTL3 in gastric cancer. Increased METTL3 expression indicated poor outcomes of patients and high malignancy in vitro and in vivo. Mechanically, m6A facilitated processing of pri-miR-17-92 into the miR-17-92 cluster through an m6A/DGCR8-dependent mechanism. The m6A modification that mediated this process occurred on the A879 locus of pri-miR-17-92. The miR-17-92 cluster activated the AKT/mTOR pathway by targeting PTEN or TMEM127. Compared with those with low levels of METTL3, METTL3-high tumors showed preferred sensitivity to an mTOR inhibitor, everolimus. These results reveal a perspective on epigenetic regulations of non-coding RNA in gastric cancer progression and provide a theoretical rationale for use of everolimus in the treatment of m6A/METTL3-high gastric cancer.
Reconstructing the maize leaf regulatory network using ChIP-seq data of 104 transcription factors
Authors: Tu Xiaoyu , Mejía-Guerra María Katherine , Valdes Franco Jose A. , Tzeng David , Chu Po-Yu , Shen Wei , Wei Yingying , Dai Xiuru , Li Pinghua , Buckler Edward S. , Zhong Silin
Published: October 2020

The transcription regulatory network inside a eukaryotic cell is defined by the combinatorial actions of transcription factors (TFs). However, TF binding studies in plants are too few in number to produce a general picture of this complex network. In this study, we use large-scale ChIP-seq to reconstruct it in the maize leaf, and train machine-learning models to predict TF binding and co-localization. The resulting network covers 77% of the expressed genes, and shows a scale-free topology and functional modularity like a real-world network. TF binding sequence preferences are conserved within family, while co-binding could be key for their binding specificity. Cross-species comparison shows that core network nodes at the top of the transmission of information being more conserved than those at the bottom. This study reveals the complex and redundant nature of the plant transcription regulatory network, and sheds light on its architecture, organizing principle and evolutionary trajectory.
Ethnic and biological differences in the association between physical activity and survival after breast cancer
Authors: Cao Yunfeng , Baumgartner Kathy B. , Visvanathan Kala , Boone Stephanie D. , Baumgartner Richard N. , Connor Avonne E.
Published: October 2020

Physical activity is recommended for most cancer patients as a nonpharmacological therapy to improve prognosis. Few studies have investigated the association between physical activity and breast cancer prognosis by ethnicity, biological, and modifiable risk factors for mortality. We investigated the association between physical activity and long-term survival among breast cancer survivors. A total of 397 survivors (96 Hispanic and 301 non-Hispanic White (NHW)) from the New Mexico HEAL study contributed baseline and biological data approximately 6 months after diagnosis. Study outcomes included all-cause, breast cancer-specific, and non-breast cancer mortality. The exposure was self-reported physical activity within the past month. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox Proportional Hazards regression. A total of 133 deaths (53 breast cancer-specific deaths) were observed after a median follow-up time of 13 years. Engaging in >6.9 metabolic equivalent hours/week (MET-h/week) of moderate to vigorous physical activity (active) was inversely associated with all-cause mortality among all women (HR 0.66, 95% CI 0.43–0.99) and NHWs (HR 0.58, 95% CI 0.36–0.94). Active NHW women also had a reduced risk of non-breast cancer mortality (HR 0.56, 95% CI 0.31–0.99), compared to inactive women (0 MET-h/week). In subgroups, we observed the inverse associations with all-cause mortality among women >58 years old (p-interaction= 0.03) and with localized stage (p-interaction = 0.046). Our results confirm the protective association between physical activity and mortality after breast cancer diagnosis, and demonstrate that this association significantly differs by age and cancer stage. Larger studies are warranted to substantiate our findings.
Pragmatic trial on inhaled corticosteroid withdrawal in patients with COPD in general practice
Authors: van den Bemt Lisette , van den Nieuwenhof Lotte , Rutjes Anne , van der Meer Victor , Stege Gerben , Wensing Michel , Teichert Martina , Schermer Tjard
Published: October 2020

The therapeutic value of inhaled corticosteroids (ICSs) for COPD is limited. In published RCTs, ICS could be withdrawn in COPD patients without increasing exacerbation risk when bronchodilator treatment is optimized. Here we report on the feasibility and risks of ICS withdrawal in Dutch general practice for COPD patients without an indication for ICSs. In our pragmatic trial, general practitioners decided autonomously which of their COPD patients on ICS treatment could stop this, how this was done, and whether additional bronchodilator therapy was needed. We recruited 62 COPD patients (58 analysed) who were eligible for ICS withdrawal in 79 practices. In 32 patients (55.2%, 95% CI: 42.5–67.3%) ICS was withdrawn successfully, 19 (32.8%, 95% CI: 22.1–45.6%) restarted ICS treatment within six months, 12 patients (20.7%, 95% CI: 12.3–32.8%) had a moderate exacerbation, and one patient had a severe exacerbation. ICS withdrawal was successful in just over half of the patients with COPD without an indication for ICS.
Myoelectric digit action decoding with multi-output, multi-class classification: an offline analysis
Authors: Krasoulis Agamemnon , Nazarpour Kianoush
Published: October 2020

The ultimate goal of machine learning-based myoelectric control is simultaneous and independent control of multiple degrees of freedom (DOFs), including wrist and digit artificial joints. For prosthetic finger control, regression-based methods are typically used to reconstruct position/velocity trajectories from surface electromyogram (EMG) signals. Unfortunately, such methods have thus far met with limited success. In this work, we propose action decoding, a paradigm-shifting approach for independent, multi-digit movement intent prediction based on multi-output, multi-class classification. At each moment in time, our algorithm decodes movement intent for each available DOF into one of three classes: open, close, or stall (i.e., no movement). Despite using a classifier as the decoder, arbitrary hand postures are possible with our approach. We analyse a public dataset previously recorded and published by us, comprising measurements from 10 able-bodied and two transradial amputee participants. We demonstrate the feasibility of using our proposed action decoding paradigm to predict movement action for all five digits as well as rotation of the thumb. We perform a systematic offline analysis by investigating the effect of various algorithmic parameters on decoding performance, such as feature selection and choice of classification algorithm and multi-output strategy. The outcomes of the offline analysis presented in this study will be used to inform the real-time implementation of our algorithm. In the future, we will further evaluate its efficacy with real-time control experiments involving upper-limb amputees.
Habitat segregation and migration in tropical anguillid eels, Anguilla bengalensis bengalensis and A. bicolor bicolor
Authors: Arai Takaomi , Chai Inn-Ju , Iizuka Yoshiyuki , Chang Chih-Wei
Published: October 2020

Anguillid eels of the genus Anguilla, which have a unique catadromous life history, are widely distributed across many parts of the world. However, little research has been conducted on the behavioural mechanisms of habitat segregation between sympatric species in tropical anguillid eels. To understand the ecological and behavioural mechanisms involved in the life history and migration of tropical anguillid eels, strontium (Sr):calcium (Ca) ratios were examined in otoliths of A. bengalensis bengalensis (41 specimens) and A. bicolor bicolor (130 specimens) collected from ten rivers in northwestern Peninsular Malaysia. The otolith Sr:Ca ratios revealed different habitat use between the two species. The broad range of otolith Sr:Ca ratios and habitat shift found in A. bicolor bicolor suggested that its habitat utilization was opportunistic in environments of varying salinity. A. bicolor bicolor prefers to live in the midstream to downstream areas with tidal influences. A. bengalensis bengalensis, however, was found to only reside in freshwater environments throughout their continental growth. A. bengalensis bengalensis tends to live in upstream area with no tidal influence. Their habitat use, migratory history, and habitat distribution indicate that habitat segregation occurs between the two species, leading to the different habitat preferences in tropical river systems.
Long-term potentiation of glycinergic synapses by semi-natural stimulation patterns during tonotopic map refinement
Authors: Bach Eva C. , Kandler Karl
Published: October 2020

Before the onset of hearing, cochlea-generated patterns of spontaneous spike activity drive the maturation of central auditory circuits. In the glycinergic sound localization pathway from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO) this spontaneous activity guides the strengthening and silencing of synapses which underlies tonotopic map refinement. However, the mechanisms by which patterned activity regulates synaptic refinement in the MNTB-LSO pathway are still poorly understood. To address this question, we recorded from LSO neurons in slices from prehearing mice while stimulating MNTB afferents with stimulation patterns that mimicked those present in vivo. We found that these semi-natural stimulation patterns reliably elicited a novel form of long-term potentiation (LTP) of MNTB-LSO synapses. Stimulation patterns that lacked the characteristic high-frequency (200 Hz) component of prehearing spike activity failed to elicit potentiation. LTP was calcium dependent, required the activation of both g-protein coupled GABABand metabotropic glutamate receptors and involved an increase in postsynaptic glycine receptor-mediated currents. Our results provide a possible mechanism linking spontaneous spike bursts to tonotopic map refinement and further highlight the importance of the co-release of GABA and glutamate from immature glycinergic MNTB terminals.
Robust deep learning classification of adamantinomatous craniopharyngioma from limited preoperative radiographic images
Authors: Prince Eric W. , Whelan Ros , Mirsky David M. , Stence Nicholas , Staulcup Susan , Klimo Paul , Anderson Richard C. E. , Niazi Toba N. , Grant Gerald , Souweidane Mark , Johnston James M. , Jackson Eric M. , Limbrick David D. , Smith Amy , Drapeau Annie , Chern Joshua J. , Kilburn Lindsay , Ginn Kevin , Naftel Robert , Dudley Roy , Tyler-Kabara Elizabeth , Jallo George , Handler Michael H. , Jones Kenneth , Donson Andrew M. , Foreman Nicholas K. , Hankinson Todd C.
Published: October 2020

Deep learning (DL) is a widely applied mathematical modeling technique. Classically, DL models utilize large volumes of training data, which are not available in many healthcare contexts. For patients with brain tumors, non-invasive diagnosis would represent a substantial clinical advance, potentially sparing patients from the risks associated with surgical intervention on the brain. Such an approach will depend upon highly accurate models built using the limited datasets that are available. Herein, we present a novel genetic algorithm (GA) that identifies optimal architecture parameters using feature embeddings from state-of-the-art image classification networks to identify the pediatric brain tumor, adamantinomatous craniopharyngioma (ACP). We optimized classification models for preoperative Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and combined CT and MRI datasets with demonstrated test accuracies of 85.3%, 83.3%, and 87.8%, respectively. Notably, our GA improved baseline model performance by up to 38%. This work advances DL and its applications within healthcare by identifying optimized networks in small-scale data contexts. The proposed system is easily implementable and scalable for non-invasive computer-aided diagnosis, even for uncommon diseases.
Thermodynamic insight into the growth of nanoscale inclusion of Al-deoxidation in Fe–O–Al melt
Authors: Lei Hong , Xiao Yuanyou , Wang Guocheng , Zhang Hongwei , Jin Wei , Zhang Lifeng
Published: October 2020

Products of Al-deoxidation reaction in iron melt are the most common inclusions and play an important effect on steel performance. Understanding the thermodynamics on nano-alumina (or nano-hercynite) is very critical to explore the relationship between Al-deoxidation reaction and products growth in iron melt. In present study, a thermodynamic modeling of nano-alumina inclusions in Fe–O–Al melt has been developed. The thermodynamic results show that the Gibbs free energy changes for the formation of nano-Al2O3 and nano-FeAl2O4 decrease with the increasing size and increase with the increasing temperature. The Gibbs free energy changes for transformation of nano-Al2O3 into bulk-Al2O3 increase with the increasing size and temperature. The thermodynamic curve of nano-alumina (or nano-hercynite) and the equilibrium curve of bulk-alumina (or bulk-hercynite) obtained in this work are agree with the published experimental data of Al-deoxidation equilibria in liquid iron. In addition, the thermodynamic coexisting points about Al2O3 and FeAl2O4 in liquid iron are in a straight line and coincide with the various previous data. It suggested that these scattered experimental data maybe in the different thermodynamic state of Al-deoxidized liquid iron and the reaction products for most of the previous Al-deoxidation experiments are nano-alumina (or nano-hercynite).
Sources of predictive information in dynamical neural networks
Authors: Candadai Madhavun , Izquierdo Eduardo J.
Published: October 2020

Behavior involves the ongoing interaction between an organism and its environment. One of the prevailing theories of adaptive behavior is that organisms are constantly making predictions about their future environmental stimuli. However, how they acquire that predictive information is still poorly understood. Two complementary mechanisms have been proposed: predictions are generated from an agent’s internal model of the world or predictions are extracted directly from the environmental stimulus. In this work, we demonstrate that predictive information, measured using bivariate mutual information, cannot distinguish between these two kinds of systems. Furthermore, we show that predictive information cannot distinguish between organisms that are adapted to their environments and random dynamical systems exposed to the same environment. To understand the role of predictive information in adaptive behavior, we need to be able to identify where it is generated. To do this, we decompose information transfer across the different components of the organism-environment system and track the flow of information in the system over time. To validate the proposed framework, we examined it on a set of computational models of idealized agent-environment systems. Analysis of the systems revealed three key insights. First, predictive information, when sourced from the environment, can be reflected in any agent irrespective of its ability to perform a task. Second, predictive information, when sourced from the nervous system, requires special dynamics acquired during the process of adapting to the environment. Third, the magnitude of predictive information in a system can be different for the same task if the environmental structure changes.
Comparison of wavelength selection methods for in-vitro estimation of lactate: a new unconstrained, genetic algorithm-based wavelength selection
Authors: Mamouei Mohammad , Budidha Karthik , Baishya Nystha , Qassem Meha , Kyriacou Panayiotis
Published: October 2020

Biochemical and medical literature establish lactate as a fundamental biomarker that can shed light on the energy consumption dynamics of the body at cellular and physiological levels. It is therefore, not surprising that it has been linked to many critical conditions ranging from the morbidity and mortality of critically ill patients to the diagnosis and prognosis of acute ischemic stroke, septic shock, lung injuries, insulin resistance in diabetic patients, and cancer. Currently, the gold standard for the measurement of lactate requires blood sampling. The invasive and costly nature of this procedure severely limits its application outside intensive care units. Optical sensors can provide a non-invasive, inexpensive, easy-to-use, continuous alternative to blood sampling. Previous efforts to achieve this have shown significant potential, but have been inconclusive. A measure that has been previously overlooked in this context, is the use of variable selection methods to identify regions of the optical spectrum that are most sensitive to and representative of the concentration of lactate. In this study, several wavelength selection methods are investigated and a new genetic algorithm-based wavelength selection method is proposed. This study shows that the development of more accurate and parsimonious models for optical estimation of lactate is possible. Unlike many existing methods, the proposed method does not impose additional locality constraints on the spectral features and therefore helps provide a much more granular interpretation of wavelength importance.
Highly efficient photon detection systems for noble liquid detectors based on perovskite quantum dots
Authors: Datta Amlan , Barman Biplob , Magill Stephen , Motakef Shariar
Published: October 2020

Wavelength shifting photon detection systems (PDS) are the critical functioning components in noble liquid detectors used for high energy physics (HEP) experiments and dark matter search. The vacuum ultraviolet (VUV) scintillation light emitted by these Liquid argon (LAr) and liquid Xenon (LXe) detectors are shifted to higher wavelengths resulting in its efficient detection using the state-of-the-art photodetectors such as silicon photomultipliers (SiPM). The currently used organic wavelength shifting materials [such as 1,1,4,4 Tetraphenyl Butadiene (TPB)] have several disadvantages and are unreliable for longterm use. In this study, we demonstrate the application of the inorganic perovskite cesium lead bromide (CsPbBr3) quantum dots (QDs) as highly efficient wavelength shifters. The absolute photoluminescence quantum yield of the PDS fabricated using these QDs exceeds 70%. CsPbBr3-based PDS demonstrated an enhancement in the SiPM signal enhancement by up to 3 times when compared to a 3 µm-thick TPB-based PDS. The emission spectrum from the QDs was optimized to match the highest quantum efficiency region of the SiPMs. In addition, we have demonstrated the deposition of the QD-based wavelength shifting material on a large area PDS substrate using low capital cost and widely scalable solution-based techniques providing a pathway appropriate for meter-scale PDS fabrication and widespread use for other wavelength shifting applications.
Molecular dynamics of the histamine H3 membrane receptor reveals different mechanisms of GPCR signal transduction
Authors: Herrera-Zúñiga Leonardo David , Moreno-Vargas Liliana Marisol , Ballaud Luck , Correa-Basurto José , Prada-Gracia Diego , Pastré David , Curmi Patrick A. , Arrang Jean Michel , Maroun Rachid C.
Published: October 2020

In this work, we studied the mechanisms of classical activation and inactivation of signal transduction by the histamine H3 receptor, a 7-helix transmembrane bundle G-Protein Coupled Receptor through long-time-scale atomistic molecular dynamics simulations of the receptor embedded in a hydrated double layer of dipalmitoyl phosphatidyl choline, a zwitterionic polysaturated ordered lipid. Three systems were prepared: the apo receptor, representing the constitutively active receptor; and two holo-receptors—the receptor coupled to the antagonist/inverse agonist ciproxifan, representing the inactive state of the receptor, and the receptor coupled to the endogenous agonist histamine and representing the active state of the receptor. An extensive analysis of the simulation showed that the three states of H3R present significant structural and dynamical differences as well as a complex behavior given that the measured properties interact in multiple and interdependent ways. In addition, the simulations described an unexpected escape of histamine from the orthosteric binding site, in agreement with the experimental modest affinities and rapid off-rates of agonists.
Three-dimensional data capture and analysis of intact eye lenses evidences emmetropia-associated changes in epithelial cell organization
Authors: Kalligeraki Alexia A. , Isted Archie , Jarrin Miguel , Uwineza Alice , Pal Robert , Saunter Christopher D. , Girkin John M. , Obara Boguslaw , Quinlan Roy A.
Published: October 2020

Organ and tissue development are highly coordinated processes; lens growth and functional integration into the eye (emmetropia) is a robust example. An epithelial monolayer covers the anterior hemisphere of the lens, and its organization is the key to lens formation and its optical properties throughout all life stages. To better understand how the epithelium supports lens function, we have developed a novel whole tissue imaging system using conventional confocal light microscopy and a specialized analysis software to produce three-dimensional maps for the epithelium of intact mouse lenses. The open source software package geometrically determines the anterior pole position, the equatorial diameter, and three-dimensional coordinates for each detected cell in the epithelium. The user-friendly cell maps, which retain global lens geometry, allow us to document age-dependent changes in the C57/BL6J mouse lens cell distribution characteristics. We evidence changes in epithelial cell density and distribution in C57/BL6J mice during the establishment of emmetropia between postnatal weeks 4–6. These epithelial changes accompany a previously unknown spheroid to lentoid shape transition of the lens as detected by our analyses. When combined with key findings from previous mouse genetic and cell biological studies, we suggest a cytoskeleton-based mechanism likely underpins these observations.
Exploitation of the chick embryo chorioallantoic membrane (CAM) as a platform for anti-metastatic drug testing
Authors: Pawlikowska P. , Tayoun T. , Oulhen M. , Faugeroux V. , Rouffiac V. , Aberlenc A. , Pommier A. L. , Honore A. , Marty V. , Bawa O. , Lacroix L. , Scoazec J. Y. , Chauchereau A. , Laplace-Builhe C. , Farace F.
Published: October 2020

The establishment of clinically relevant models for tumor metastasis and drug testing is a major challenge in cancer research. Here we report a physiologically relevant assay enabling quantitative analysis of metastatic capacity of tumor cells following implantation into the chorioallantoic membrane (CAM). Engraftment of as few as 103 non-small cell lung cancer (NSCLC) and prostate cancer (PCa) cell lines was sufficient for both primary tumor and metastasis formation. Standard 2D-imaging as well as 3D optical tomography imaging were used for the detection of fluorescent metastatic foci in the chick embryo. H2228- and H1975-initiated metastases were confirmed by genomic analysis. We quantified the inhibitory effect of docetaxel on LNCaP, and that of cisplatin on A549- and H1299-initiated metastatic growths.
The CAM assay also mimicked the sensitivity of ALK-rearranged H2228 and EGFR-mutated H1975 NSCLC cells to tyrosine kinase inhibitors crizotinib and gefitinib respectively, as well as sensitivity of LNCaP cells to androgen-dependent enzalutamide therapy. The assay was suggested to reconstitute the bone metastatic tropism of PCa cells. We show that the CAM chick embryo model may be a powerful preclinical platform for testing and targeting of the metastatic capacity of cancer cells.
Monolithic focus-tunable lens technology enabled by disk-type dielectric-elastomer actuators
Authors: Park Bong Je , Park Suntak , Choi Meejeong , Park Seung Koo , Yun Sungryul , Shin Eunjin , Yoon Jae Woong
Published: October 2020

We propose a monolithic focus-tunable lens structure based on the dielectric-elastomer actuator (DEA) technology. In our focus-tunable lens, a soft lens and radial in-plane actuator mimicking the ocular focal-tuning mechanism are constructed in a single body of an optimized dielectric-elastomer film. We provide device fabrication methods including elastomer synthesis, structure formation, and packaging process steps. Performance test measurements show 93% focal tunability and 7 ms response time under static and dynamic electrical driving conditions, respectively. These performance characteristics are substantially enhanced from the previous polylithic DEA tunable lens by a factor 1.4 for the focal tunability and a factor 9.4 for the dynamic tuning-speed limit. Therefore, we obtain greatly enhanced focal tuning control in a remarkably simple and compact device structure.
The C. elegans miR-235 regulates the toxicity of graphene oxide via targeting the nuclear hormone receptor DAF-12 in the intestine
Authors: Guo Tiantian , Cheng Lu , Zhao Huimin , Liu Yingying , Yang Yunhan , Liu Jie , Wu Qiuli
Published: October 2020

The increased application of graphene oxide (GO), a new carbon-based engineered nanomaterial, has generated a potential toxicity in humans and the environment. Previous studies have identified some dysregulated microRNAs (miRNAs), such as up-regulated mir-235, in organisms exposed to GO. However, the detailed mechanisms of the dysregulation of miRNA underlying GO toxicity are still largely elusive. In this study, we employed Caenorhabditis elegans as an in vivo model to investigate the biological function and molecular basis of mir-235 in the regulation of GO toxicity. After low concentration GO exposure, mir-235 (n4504) mutant nematodes were sensitive to GO toxicity, implying that mir-235 mediates a protection mechanism against GO toxicity. Tissue-specific assays suggested that mir-235 expressed in intestine is required for suppressing the GO toxicity in C. elegans. daf-12, a gene encoding a member of the steroid hormone receptor superfamily, acts as a target gene of mir-235 in the nematode intestine in response to GO treatment, and RNAi knockdown of daf-12 suppressed the sensitivity of mir-235(n4503) to GO toxicity. Further genetic analysis showed that DAF-12 acted in the upstream of DAF-16 in insulin/IGF-1 signaling pathway and PMK-1 in p38 MAPK signaling pathway in parallel to regulate GO toxicity. Altogether, our results revealed that mir-235 may activate a protective mechanism against GO toxicity by suppressing the DAF-12-DAF-16 and DAF-12-PMK-1 signaling cascade in nematodes, which provides an important molecular basis for the in vivo toxicity of GO at the miRNA level.
Author Correction: Metabolism of the predominant human milk oligosaccharide fucosyllactose by an infant gut commensal
Authors: James Kieran , Bottacini Francesca , Contreras Jose Ivan Serrano , Vigoureux Mariane , Egan Muireann , Motherway Mary O’connell , Holmes Elaine , van Sinderen Douwe
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher Correction: Relevance of Titin Missense and Non-Frameshifting Insertions/Deletions Variants in Dilated Cardiomyopathy
Authors: Akinrinade Oyediran , Heliö Tiina , Lekanne Deprez Ronald H. , Jongbloed Jan D. H. , Boven Ludolf G. , van den Berg Maarten P. , Pinto Yigal M. , Alastalo Tero-Pekka , Myllykangas Samuel , van Spaendonck-Zwarts Karin , van Tintelen J. Peter , van der Zwaag Paul A. , Koskenvuo Juha
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Identification and characterization of mutations responsible for the β-lactam resistance in oxacillin-susceptible mecA-positive Staphylococcus aureus
Authors: Boonsiri Tanit , Watanabe Shinya , Tan Xin-Ee , Thitiananpakorn Kanate , Narimatsu Ryu , Sasaki Kosuke , Takenouchi Remi , Sato’o Yusuke , Aiba Yoshifumi , Kiga Kotaro , Sasahara Teppei , Taki Yusuke , Li Feng-Yu , Zhang Yuancheng , Azam Aa Haeruman , Kawaguchi Tomofumi , Cui Longzhu
Published: October 2020

Staphylococcus aureus strains that are susceptible to the β-lactam antibiotic oxacillin despite carrying mecA (OS-MRSA) cause serious clinical problems globally because of their ability to easily acquire β-lactam resistance. Understanding the genetic mechanism(s) of acquisition of the resistance is therefore crucial for infection control management. For this purpose, a whole-genome sequencing-based analysis was performed using 43 clinical OS-MRSA strains and 100 mutants with reduced susceptibility to oxacillin (MICs 1.0–256 µg/mL) generated from 26 representative OS-MRSA strains. Genome comparison between the mutants and their respective parent strains identified a total of 141 mutations in 46 genes and 8 intergenic regions. Among them, the mutations are frequently found in genes related to RNA polymerase (rpoBC), purine biosynthesis (guaA, prs, hprT), (p)ppGpp synthesis (relSau), glycolysis (pykA, fbaA, fruB), protein quality control (clpXP, ftsH), and tRNA synthase (lysS, gltX), whereas no mutations existed in mec and bla operons. Whole-genome transcriptional profile of the resistant mutants demonstrated that expression of genes associated with purine biosynthesis, protein quality control, and tRNA synthesis were significantly inhibited similar to the massive transcription downregulation seen in S. aureus during the stringent response, while the levels of mecA expression and PBP2a production were varied. We conclude that a combination effect of mecA upregulation and stringent-like response may play an important role in acquisition of β-lactam resistance in OS-MRSA.
The role of action intentionality and effector in the subjective expansion of temporal duration after saccadic eye movements
Authors: Melcher David , Kumar Devpriya , Srinivasan Narayanan
Published: October 2020

Visual perception is based on periods of stable fixation separated by saccadic eye movements. Although naive perception seems stable (in space) and continuous (in time), laboratory studies have demonstrated that events presented around the time of saccades are misperceived spatially and temporally. Saccadic chronostasis, the “stopped clock illusion”, represents one such temporal distortion in which the movement of the clock hand after the saccade is perceived as lasting longer than usual. Multiple explanations for chronostasis have been proposed including action-backdating, temporal binding of the action towards the moment of its effect (“intentional binding”) and post-saccadic temporal dilation. The current study aimed to resolve this debate by using different types of action (keypress vs saccade) and varying the intentionality of the action. We measured both perceived onset of the motor action and perceived onset of an auditory tone presented at different delays after the keypress/saccade. The results showed intentional binding for the keypress action, with perceived motor onset shifted forwards in time and the time of the tone shifted backwards. Saccades resulted in the opposite pattern, showing temporal expansion rather than compression, especially with cued saccades. The temporal illusion was modulated by intentionality of the movement. Our findings suggest that saccadic chronostasis is not solely dependent on a backward shift in perceived saccade onset, but instead reflects a temporal dilation. This percept of an effectively “longer” period at the beginning of a new fixation may reflect the pattern of suppressed, and then enhanced, visual processing around the time of saccades.
Five rules for friendly rivalry in direct reciprocity
Authors: Murase Yohsuke , Baek Seung Ki
Published: October 2020

Direct reciprocity is one of the key mechanisms accounting for cooperation in our social life. According to recent understanding, most of classical strategies for direct reciprocity fall into one of two classes, ‘partners’ or ‘rivals’. A ‘partner’ is a generous strategy achieving mutual cooperation, and a ‘rival’ never lets the co-player become better off. They have different working conditions: For example, partners show good performance in a large population, whereas rivals do in head-to-head matches. By means of exhaustive enumeration, we demonstrate the existence of strategies that act as both partners and rivals. Among them, we focus on a human-interpretable strategy, named ‘CAPRI’ after its five characteristic ingredients, i.e., cooperate, accept, punish, recover, and defect otherwise. Our evolutionary simulation shows excellent performance of CAPRI in a broad range of environmental conditions.
The influence of the rib cage on the static and dynamic stability responses of the scoliotic spine
Authors: Jia Shaowei , Lin Liying , Yang Hufei , Fan Jie , Zhang Shunxin , Han Li
Published: October 2020

The thoracic cage plays an important role in maintaining the stability of the thoracolumbar spine. In this study, the influence of a rib cage on static and dynamic responses in normal and scoliotic spines was investigated. Four spinal finite element (FE) models (T1–S), representing a normal spine with rib cage (N1), normal spine without rib cage (N2), a scoliotic spine with rib cage (S1) and a scoliotic spine without rib cage (S2), were established based on computed tomography (CT) images, and static, modal, and steady-state analyses were conducted. In S2, the Von Mises stress (VMS) was clearly decreased compared to S1 for four bending loadings. N2 and N1 showed a similar VMS to each other, and there was a significant increase in axial compression in N2 and S2 compared to N1 and S1, respectively. The U magnitude values of N2 and S2 were higher than in N1 and S1 for five loadings, respectively. The resonant frequencies of N2 and S2 were lower than those in N1 and S1, respectively. In steady-state analysis, maximum amplitudes of vibration for N2 and S2 were significantly larger than N1 and S1, respectively. This study has revealed that the rib cage improves spinal stability in vibrating environments and contributes to stability in scoliotic spines under static and dynamic loadings.
The KDEL trafficking receptor exploits pH to tune the strength of an unusual short hydrogen bond
Authors: Wu Zhiyi , Newstead Simon , Biggin Philip C.
Published: October 2020

The endoplasmic reticulum (ER) is the main site of protein synthesis in eukaryotic cells and requires a high concentration of luminal chaperones to function. During protein synthesis, ER luminal chaperones are swept along the secretory pathway and must be retrieved to maintain cell viability. ER protein retrieval is achieved by the KDEL receptor, which recognises a C-terminal Lys-Asp-Glu-Leu (KDEL) sequence. Recognition of ER proteins by the KDEL receptor is pH dependent, with binding occurring under acidic conditions in the Golgi and release under conditions of higher pH in the ER. Recent crystal structures of the KDEL receptor in the apo and peptide bound state suggested that peptide binding drives the formation of a short-hydrogen bond that locks the KDEL sequence in the receptor and activates the receptor for COPI binding in the cytoplasm. Using quantum mechanical calculations we demonstrate that the strength of this short hydrogen bond is reinforced following protonation of a nearby histidine, providing a conceptual link between receptor protonation and KDEL peptide binding. Protonation also controls the water networks adjacent to the peptide binding site, leading to a conformational change that ultimately allows the receptor-complex to be recognized by the COPI system.
Sustainability of soil organic carbon in consolidated gully land in China’s Loess Plateau
Authors: Yan Qina , Kumar Praveen , Wang Yunqiang , Zhao Yali , Lin Henry , Ran Qihua , An Zhisheng , Zhou Weijian
Published: October 2020

Massive gully land consolidation projects, launched in China’s Loess Plateau, aim to restore 2667 $$\mathrm{km}^2$$

km

2

agricultural lands in total by consolidating 2026 highly eroded gullies. This effort represents a social engineering project where the economic development and livelihood of the farming families are closely tied to the ability of these emergent landscapes to provide agricultural services. Whether these ‘time zero’ landscapes have the resilience to provide a sustainable soil condition such as soil organic carbon (SOC) content remains unknown. By studying two watersheds, one of which is a control site, we show that the consolidated gully serves as an enhanced carbon sink, where the magnitude of SOC increase rate (1.0 $$\mathrm{g\,C}/\mathrm{m}^2/\mathrm{year}$$

g

C

/

m

2

/
year

) is about twice that of the SOC decrease rate (− 0.5 $$\mathrm{g\,C}/\mathrm{m}^2/\mathrm{year}$$

g

C

/

m

2

/
year

) in the surrounding natural watershed. Over a 50-year co-evolution of landscape and SOC turnover, we find that the dominant mechanisms that determine the carbon cycling are different between the consolidated gully and natural watersheds. In natural watersheds, the flux of SOC transformation is mainly driven by the flux of SOC transport; but in the consolidated gully, the transport has little impact on the transformation. Furthermore, we find that extending the surface carbon residence time has the potential to efficiently enhance carbon sequestration from the atmosphere with a rate as high as 8 $$\mathrm{g\,C}/\mathrm{m}^2/\mathrm{year}$$

g

C

/

m

2

/
year

compared to the current 0.4 $$\mathrm{g\,C}/\mathrm{m}^2/\mathrm{year}$$

g

C

/

m

2

/
year

. The success for the completion of all gully consolidation would lead to as high as 26.67 $$\mathrm{Gg\,C}/\mathrm{year}$$

Gg

C

/
year

sequestrated into soils. This work, therefore, not only provides an assessment and guidance of the long-term sustainability of the ‘time zero’ landscapes but also a solution for sequestration $$\hbox {CO}_2$$

CO
2

into soils.
Author Correction: Bone Anabolic Response in the Calvaria Following Mild Traumatic Brain Injury is Mediated by the Cannabinoid-1 Receptor
Authors: Eger Michal , Bader Miaad , Bree Dara , Hadar Rivka , Nemirovski Alina , Tam Joseph , Levy Dan , Pick Chaim G. , Gabet Yankel
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
A universal method for high-quality RNA extraction from plant tissues rich in starch, proteins and fiber
Authors: Vennapusa Amaranatha R. , Somayanda Impa M. , Doherty Colleen J. , Jagadish S. V. Krishna
Published: October 2020

Using existing protocols, RNA extracted from seeds rich in starch often results in poor quality RNA, making it inappropriate for downstream applications. Though some methods are proposed for extracting RNA from plant tissue rich in starch and other polysaccharides, they invariably yield less and poor quality RNA. In order to obtain high yield and quality RNA from seeds and other plant tissues including roots a modified SDS-LiCl method was compared with existing methods, including TRIZOL kit (Invitrogen), Plant RNeasy mini kit (Qiagen), Furtado (2014) method, and CTAB-LiCl method. Modifications in the extraction buffer and solutions used for RNA precipitation resulted in a robust method for extracting RNA in seeds and roots, where extracting quality RNA is challenging. The modified SDS-LiCl method revealed intense RNA bands through gel electrophoresis and a nanodrop spectrophotometer detected ratios of ≥ 2 and 1.8 for A260/A230 and A260/A280, respectively. The absence of starch co-precipitation during RNA extraction resulted in enhanced yield and quality of RNA with RIN values of 7–9, quantified using a bioanalyzer. The high-quality RNA obtained was demonstrated to be suitable for downstream applications, such as cDNA synthesis, gene amplification, and RT-qPCR. The method was also effective in extracting RNA from seeds of other cereals including field-grown sorghum and corn. The modified SDS-LiCl method is a robust and highly reproducible RNA extraction method for plant tissues rich in starch and other secondary metabolites. The modified SDS-LiCl method successfully extracted high yield and quality RNA from mature, developing, and germinated seeds, leaves, and roots exposed to different abiotic stresses.