bluuebunny/crossref_metadata_2025 huggingface dataset:
The Chimei Submarine Canyon and Fan: A Record of Taiwan Arc‐Continent Collision on the Rapidly Deforming Overriding Plate
Authors: Hsieh Yu‐Huan , Liu Char‐Shine , Suppe John , Byrne Timothy B. , Lallemand Serge
Published: October 2020

The Chimei Canyon is a large, uplifting wedge‐top submarine canyon offshore eastern Taiwan that has delivered sediment since ~1–2 Ma from the rapidly eroding Taiwan orogen to the Chimei Fan in the Huatung Basin, east of the colliding Luzon Arc. In this study, we document the depositional record of the Taiwan arc‐continent collision on the adjacent oceanic Philippine Sea Plate using multichannel seismic reflection data together with high‐resolution bathymetry data to study the morphology, seismic sequences, and structures of the Chimei Canyon‐Fan system. The sedimentary strata are separated into three seismic sequences. The lowest sequence overlies oceanic crust, showing Cenozoic‐Cretaceous pelagic seismic facies that we interpret as pre‐collisional, whereas the middle and upper sequences are syn‐collisional. We propose a model for the development of the Chimei Canyon‐Fan in which the middle sequence first developed ~1–2 Ma, while the main depocenter was to the west in the forearc basin, west of the Luzon Arc. The upper sequence records a shift of depocenter after ~1 Ma from the forearc basin to the Chimei Fan east of the Luzon Arc. At the same time, this antecedent paleochannel‐fan system was deformed rapidly (~60 mm/yr; 62 km minimum shortening) by a complex imbricate thrust belt with the emergence of the arc and forearc basin as the west‐vergent Coastal Range thrust belt and the Chimei Canyon incising the active east‐vergent Offshore East Taiwan thrust belt. The thrust belt underlying the wedge‐top Chimei Canyon‐Fan has undergone >19‐km shortening and ~2.6‐km structure uplift.
Growth factors-based beneficial effects of platelet lysate on umbilical cord-derived stem cells and their synergistic use in osteoarthritis treatment
Authors: Yan Li , Zhou Li , Yan Bo , Zhang Lei , Du Wenxi , Liu Fucun , Yuan Qiang , Tong Peijian , Shan Letian , Efferth Thomas
Published: October 2020

Poor viability of mesenchymal stem cells (MSCs) at the transplanted site often hinders the efficacy of MSCs-based therapy. Platelet lysate (PL) contains rich amounts of growth factors, which benefits cell growth. This study aimed to explore how human PL benefits umbilical cord-derived MSCs (huc-MSCs), and whether they have synergistic potential in osteoarthritis (OA) treatment. As quality control, flow cytometry and specific staining were performed to identify huc-MSCs, and ELISA was used to quantify growth factors in PL. CCK-8 and flow cytometry assays were performed to evaluate the effects of PL on the cell viability and cell cycle progression of huc-MSCs. Wound healing and transwell assays were conducted to assess the migration of huc-MSCs. RNA sequencing, real time PCR, and Western blot assays were conducted to explore the growth factors-based mechanism of PL. The in vitro results showed that PL significantly promoted the proliferation, cell cycle, and migration of huc-MSCs by upregulating relevant genes/proteins and activating beclin1-dependent autophagy via the AMPK/mTOR signaling pathway. The main growth factors (PDGF-AA, IGF-1, TGF-β, EGF, and FGF) contributed to the effects of PL in varying degrees. The in vivo data showed that combined PL and huc-MSCs exerted significant synergistic effect against OA. The overall study determined the beneficial effects and mechanism of PL on huc-MSCs and indicated PL as an adjuvant for huc-MSCs in treating OA. This is the first report on the growth factors-based mechanism of PL on huc-MSCs and their synergistic application. It provides novel knowledge of PLʹs roles and offers a promising strategy for stem cell-based OA therapy by combining PL and huc-MSCs.
RASSF1A inhibits PDGFB-driven malignant phenotypes of nasopharyngeal carcinoma cells in a YAP1-dependent manner
Authors: Liang Ying-Ying , Deng Xu-Bin , Lin Xian-Tao , Jiang Li-Li , Huang Xiao-Ting , Mo Zhi-Wen , Yuan Ya-Wei , Teh Muy-Teck
Published: October 2020

Nasopharyngeal carcinoma (NPC) is a highly aggressive tumor characterized by distant metastasis. Deletion or down-regulation of the tumor suppressor protein ras-association domain family protein1 isoform A (RASSF1A) has been confirmed to be a key event in NPC progression; however, little is known about the effects or underlying mechanism of RASSF1A on the malignant phenotype. In the present study, we observed that RASSF1A expression inhibited the malignant phenotypes of NPC cells. Stable silencing of RASSF1A in NPC cell lines induced self-renewal properties and tumorigenicity in vivo/in vitro and the acquisition of an invasive phenotype in vitro. Mechanistically, RASSF1A inactivated Yes-associated Protein 1 (YAP1), a transcriptional coactivator, through actin remodeling, which further contributed to Platelet Derived Growth Factor Subunit B (PDGFB) transcription inhibition. Treatment with ectopic PDGFB partially increased the malignancy of NPC cells with transient knockdown of YAP1. Collectively, these findings suggest that RASSF1A inhibits malignant phenotypes by repressing PDGFB expression in a YAP1-dependent manner. PDGFB may serve as a potential interest of therapeutic regulators in patients with metastatic NPC.
ERO1L promotes IL6/sIL6R signaling and regulates MUC16 expression to promote CA125 secretion and the metastasis of lung cancer cells
Authors: lei Yuanyuan , Zang Ruochuan , Lu Zhiliang , Zhang Guochao , Huang Jianbing , Liu Chengming , Wang Zhanyu , Mao Shuangshuang , Che Yun , Wang Xinfeng , Zheng Sufei , Fang Lingling , Sun Nan , He Jie
Published: October 2020

The abnormal secretion of CA125, a classic tumor marker, is usually related to a poor prognosis in various tumors. Thus, this study aimed to explore the potential mechanisms that promote CA125 secretion in lung cancer. By querying the database, the gene endoplasmic reticulum oxidoreductase 1L (ERO1L) was identified and chosen as the research subject. The antibody chips were used to screen the lung cancer cell supernatant and found that the most obvious secreted protein was CA125. ERO1L was found to promote the secretion of IL6R by affecting the formation of disulfide bonds. IL6R bound to IL6 and triggered the activation of the NF-κB signaling pathway. Then, NF-κB bound to the promoter of MUC16, resulting in overexpression of MUC16. The extracellular segment of MUC16 was cleaved to form CA125, while the C terminus of MUC16 promoted the EMT phenotype and the release of IL6, forming a positive feedback pathway. In conclusion, ERO1L might affect the secretion of CA125 through the IL6 signaling pathway and form a positive feedback loop to further promote the development of lung cancer. This might expand the application scope of CA125 in lung cancer.
The Janus-like role of proline metabolism in cancer
Authors: Burke Lynsey , Guterman Inna , Palacios Gallego Raquel , Britton Robert G. , Burschowsky Daniel , Tufarelli Cristina , Rufini Alessandro
Published: October 2020

The metabolism of the non-essential amino acid L-proline is emerging as a key pathway in the metabolic rewiring that sustains cancer cells proliferation, survival and metastatic spread. Pyrroline-5-carboxylate reductase (PYCR) and proline dehydrogenase (PRODH) enzymes, which catalyze the last step in proline biosynthesis and the first step of its catabolism, respectively, have been extensively associated with the progression of several malignancies, and have been exposed as potential targets for anticancer drug development. As investigations into the links between proline metabolism and cancer accumulate, the complexity, and sometimes contradictory nature of this interaction emerge. It is clear that the role of proline metabolism enzymes in cancer depends on tumor type, with different cancers and cancer-related phenotypes displaying different dependencies on these enzymes. Unexpectedly, the outcome of rewiring proline metabolism also differs between conditions of nutrient and oxygen limitation. Here, we provide a comprehensive review of proline metabolism in cancer; we collate the experimental evidence that links proline metabolism with the different aspects of cancer progression and critically discuss the potential mechanisms involved.
Interferon-γ signaling synergizes with LRRK2 in neurons and microglia derived from human induced pluripotent stem cells
Authors: Panagiotakopoulou Vasiliki , Ivanyuk Dina , De Cicco Silvia , Haq Wadood , Arsić Aleksandra , Yu Cong , Messelodi Daria , Oldrati Marvin , Schöndorf David C. , Perez Maria-Jose , Cassatella Ruggiero Pio , Jakobi Meike , Schneiderhan-Marra Nicole , Gasser Thomas , Nikić-Spiegel Ivana , Deleidi Michela
Published: October 2020

Parkinson’s disease-associated kinase LRRK2 has been linked to IFN type II (IFN-γ) response in infections and to dopaminergic neuronal loss. However, whether and how LRRK2 synergizes with IFN-γ remains unclear. In this study, we employed dopaminergic neurons and microglia differentiated from patient-derived induced pluripotent stem cells carrying LRRK2 G2019S, the most common Parkinson’s disease-associated mutation. We show that IFN-γ enhances the LRRK2 G2019S-dependent negative regulation of AKT phosphorylation and NFAT activation, thereby increasing neuronal vulnerability to immune challenge. Mechanistically, LRRK2 G2019S suppresses NFAT translocation via calcium signaling and possibly through microtubule reorganization. In microglia, LRRK2 modulates cytokine production and the glycolytic switch in response to IFN-γ in an NFAT-independent manner. Activated LRRK2 G2019S microglia cause neurite shortening, indicating that LRRK2-driven immunological changes can be neurotoxic. We propose that synergistic LRRK2/IFN-γ activation serves as a potential link between inflammation and neurodegeneration in Parkinson’s disease.
Light-steered locomotion of muscle-like hydrogel by self-coordinated shape change and friction modulation
Authors: Zhu Qing Li , Du Cong , Dai Yahao , Daab Matthias , Matejdes Marian , Breu Josef , Hong Wei , Zheng Qiang , Wu Zi Liang
Published: October 2020

Many creatures have the ability to traverse challenging environments by using their active muscles with anisotropic structures as the motors in a highly coordinated fashion. However, most artificial robots require multiple independently activated actuators to achieve similar purposes. Here we report a hydrogel-based, biomimetic soft robot capable of multimodal locomotion fueled and steered by light irradiation. A muscle-like poly(N-isopropylacrylamide) nanocomposite hydrogel is prepared by electrical orientation of nanosheets and subsequent gelation. Patterned anisotropic hydrogels are fabricated by multi-step electrical orientation and photolithographic polymerization, affording programmed deformations. Under light irradiation, the gold-nanoparticle-incorporated hydrogels undergo concurrent fast isochoric deformation and rapid increase in friction against a hydrophobic substrate. Versatile motion gaits including crawling, walking, and turning with controllable directions are realized in the soft robots by dynamic synergy of localized shape-changing and friction manipulation under spatiotemporal light stimuli. The principle and strategy should merit designing of continuum soft robots with biomimetic mechanisms.
Active coacervate droplets as a model for membraneless organelles and protocells
Authors: Donau Carsten , Späth Fabian , Sosson Marilyne , Kriebisch Brigitte A. K. , Schnitter Fabian , Tena-Solsona Marta , Kang Hyun-Seo , Salibi Elia , Sattler Michael , Mutschler Hannes , Boekhoven Job
Published: October 2020

Membraneless organelles like stress granules are active liquid-liquid phase-separated droplets that are involved in many intracellular processes. Their active and dynamic behavior is often regulated by ATP-dependent reactions. However, how exactly membraneless organelles control their dynamic composition remains poorly understood. Herein, we present a model for membraneless organelles based on RNA-containing active coacervate droplets regulated by a fuel-driven reaction cycle. These droplets emerge when fuel is present, but decay without. Moreover, we find these droplets can transiently up-concentrate functional RNA which remains in its active folded state inside the droplets. Finally, we show that in their pathway towards decay, these droplets break apart in multiple droplet fragments. Emergence, decay, rapid exchange of building blocks, and functionality are all hallmarks of membrane-less organelles, and we believe that our work could be powerful as a model to study such organelles.
Controlling the symmetry of inorganic ionic nanofilms with optical chirality
Authors: Kelly Christopher , MacLaren Donald A. , McKay Katie , McFarlane Anthony , Karimullah Affar S. , Gadegaard Nikolaj , Barron Laurence D. , Franke-Arnold Sonja , Crimin Frances , Götte Jörg B. , Barnett Stephen M. , Kadodwala Malcolm
Published: October 2020

Manipulating symmetry environments of metal ions to control functional properties is a fundamental concept of chemistry. For example, lattice strain enables control of symmetry in solids through a change in the nuclear positions surrounding a metal centre. Light–matter interactions can also induce strain but providing dynamic symmetry control is restricted to specific materials under intense laser illumination. Here, we show how effective chemical symmetry can be tuned by creating a symmetry-breaking rotational bulk polarisation in the electronic charge distribution surrounding a metal centre, which we term a meta-crystal field. The effect arises from an interface-mediated transfer of optical spin from a chiral light beam to produce an electronic torque that replicates the effect of strain created by high pressures. Since the phenomenon does not rely on a physical rearrangement of nuclear positions, material constraints are lifted, thus providing a generic and fully reversible method of manipulating effective symmetry in solids.
Near-real-time monitoring of global CO2 emissions reveals the effects of the COVID-19 pandemic
Authors: Liu Zhu , Ciais Philippe , Deng Zhu , Lei Ruixue , Davis Steven J. , Feng Sha , Zheng Bo , Cui Duo , Dou Xinyu , Zhu Biqing , Guo Rui , Ke Piyu , Sun Taochun , Lu Chenxi , He Pan , Wang Yuan , Yue Xu , Wang Yilong , Lei Yadong , Zhou Hao , Cai Zhaonan , Wu Yuhui , Guo Runtao , Han Tingxuan , Xue Jinjun , Boucher Olivier , Boucher Eulalie , Chevallier Frédéric , Tanaka Katsumasa , Wei Yiming , Zhong Haiwang , Kang Chongqing , Zhang Ning , Chen Bin , Xi Fengming , Liu Miaomiao , Bréon François-Marie , Lu Yonglong , Zhang Qiang , Guan Dabo , Gong Peng , Kammen Daniel M. , He Kebin , Schellnhuber Hans Joachim
Published: October 2020

The COVID-19 pandemic is impacting human activities, and in turn energy use and carbon dioxide (CO2) emissions. Here we present daily estimates of country-level CO2 emissions for different sectors based on near-real-time activity data. The key result is an abrupt 8.8% decrease in global CO2 emissions (−1551 Mt CO2) in the first half of 2020 compared to the same period in 2019. The magnitude of this decrease is larger than during previous economic downturns or World War II. The timing of emissions decreases corresponds to lockdown measures in each country. By July 1st, the pandemic’s effects on global emissions diminished as lockdown restrictions relaxed and some economic activities restarted, especially in China and several European countries, but substantial differences persist between countries, with continuing emission declines in the U.S. where coronavirus cases are still increasing substantially.
CRISPR screening of porcine sgRNA library identifies host factors associated with Japanese encephalitis virus replication
Authors: Zhao Changzhi , Liu Hailong , Xiao Tianhe , Wang Zichang , Nie Xiongwei , Li Xinyun , Qian Ping , Qin Liuxing , Han Xiaosong , Zhang Jinfu , Ruan Jinxue , Zhu Mengjin , Miao Yi-Liang , Zuo Bo , Yang Kui , Xie Shengsong , Zhao Shuhong
Published: October 2020

Japanese encephalitis virus (JEV) is a mosquito-borne zoonotic flavivirus that causes encephalitis and reproductive disorders in mammalian species. However, the host factors critical for its entry, replication, and assembly are poorly understood. Here, we design a porcine genome-scale CRISPR/Cas9 knockout (PigGeCKO) library containing 85,674 single guide RNAs targeting 17,743 protein-coding genes, 11,053 long ncRNAs, and 551 microRNAs. Subsequently, we use the PigGeCKO library to identify key host factors facilitating JEV infection in porcine cells. Several previously unreported genes required for JEV infection are highly enriched post-JEV selection. We conduct follow-up studies to verify the dependency of JEV on these genes, and identify functional contributions for six of the many candidate JEV-related host genes, includingEMC3andCALR. Additionally, we identify that four genes associated with heparan sulfate proteoglycans (HSPGs) metabolism, specifically those responsible for HSPGs sulfurylation, facilitate JEV entry into porcine cells. Thus, beyond our development of the largest CRISPR-based functional genomic screening platform for pig research to date, this study identifies multiple potentially vulnerable targets for the development of medical and breeding technologies to treat and prevent diseases caused by JEV.
Th17-inducing autologous dendritic cell vaccination promotes antigen-specific cellular and humoral immunity in ovarian cancer patients
Authors: Block Matthew S. , Dietz Allan B. , Gustafson Michael P. , Kalli Kimberly R. , Erskine Courtney L. , Youssef Bahaaeldin , Vijay Geraldine V. , Allred Jacob B. , Pavelko Kevin D. , Strausbauch Michael A. , Lin Yi , Grudem Megan E. , Jatoi Aminah , Klampe Carolyn M. , Wahner-Hendrickson Andrea E. , Weroha S. John , Glaser Gretchen E. , Kumar Amanika , Langstraat Carrie L. , Solseth Mary L. , Deeds Michael C. , Knutson Keith L. , Cannon Martin J.
Published: October 2020

In ovarian cancer (OC), IL-17-producing T cells (Th17s) predict improved survival, whereas regulatory T cells predict poorer survival. We previously developed a vaccine whereby patient-derived dendritic cells (DCs) are programmed to induce Th17 responses to the OC antigen folate receptor alpha (FRα). Here we report the results of a single-arm open-label phase I clinical trial designed to determine vaccine safety and tolerability (primary outcomes) and recurrence-free survival (secondary outcome). Immunogenicity is also evaluated. Recruitment is complete with a total of 19 Stage IIIC-IV OC patients in first remission after conventional therapy. DCs are generated using our Th17-inducing protocol and are pulsed with HLA class II epitopes from FRα. Mature antigen-loaded DCs are injected intradermally. All patients have completed study-related interventions. No grade 3 or higher adverse events are seen. Vaccination results in the development of Th1, Th17, and antibody responses to FRα in the majority of patients. Th1 and antibody responses are associated with prolonged recurrence-free survival. Antibody-dependent cell-mediated cytotoxic activity against FRα is also associated with prolonged RFS. Of 18 patients evaluable for efficacy, 39% (7/18) remain recurrence-free at the time of data censoring, with a median follow-up of 49.2 months. Thus, vaccination with Th17-inducing FRα-loaded DCs is safe, induces antigen-specific immunity, and is associated with prolonged remission.
Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation
Authors: Napoli Marco , Li Xiaobo , Ackerman Hayley D. , Deshpande Avani A. , Barannikov Ivan , Pisegna Marlese A. , Bedrosian Isabelle , Mitsch Jürgen , Quinlan Philip , Thompson Alastair , Rajapakshe Kimal , Coarfa Cristian , Gunaratne Preethi H. , Marchion Douglas C. , Magliocco Anthony M. , Tsai Kenneth Y. , Flores Elsa R.
Published: October 2020

The most frequent genetic alterations across multiple human cancers are mutations in TP53 and the activation of the PI3K/AKT pathway, two events crucial for cancer progression. Mutations in TP53 lead to the inhibition of the tumour and metastasis suppressor TAp63, a p53 family member. By performing a mouse-human cross species analysis between the TAp63 metastatic mammary adenocarcinoma mouse model and models of human breast cancer progression, we identified two TAp63-regulated oncogenic lncRNAs, TROLL-2 and TROLL-3. Further, using a pan-cancer analysis of human cancers and multiple mouse models of tumour progression, we revealed that these two lncRNAs induce the activation of AKT to promote cancer progression by regulating the nuclear to cytoplasmic translocation of their effector, WDR26, via the shuttling protein NOLC1. Our data provide preclinical rationale for the implementation of these lncRNAs and WDR26 as therapeutic targets for the treatment of human tumours dependent upon mutant TP53 and/or the PI3K/AKT pathway.
Genome-wide translational profiling of amygdala Crh-expressing neurons reveals role for CREB in fear extinction learning
Authors: McCullough Kenneth M. , Chatzinakos Chris , Hartmann Jakob , Missig Galen , Neve Rachael L. , Fenster Robert J. , Carlezon William A. , Daskalakis Nikolaos P. , Ressler Kerry J.
Published: October 2020

Fear and extinction learning are adaptive processes caused by molecular changes in specific neural circuits. Neurons expressing the corticotropin-releasing hormone gene (Crh) in central amygdala (CeA) are implicated in threat regulation, yet little is known of cell type-specific gene pathways mediating adaptive learning. We translationally profiled the transcriptome of CeA Crh-expressing cells (Crh neurons) after fear conditioning or extinction in mice using translating ribosome affinity purification (TRAP) and RNAseq. Differential gene expression and co-expression network analyses identified diverse networks activated or inhibited by fear vs extinction. Upstream regulator analysis demonstrated that extinction associates with reduced CREB expression, and viral vector-induced increased CREB expression in Crh neurons increased fear expression and inhibited extinction. These findings suggest that CREB, within CeA Crh neurons, may function as a molecular switch that regulates expression of fear and its extinction. Cell-type specific translational analyses may suggest targets useful for understanding and treating stress-related psychiatric illness.
Observation of a high degree of stopping for laser-accelerated intense proton beams in dense ionized matter
Authors: Ren Jieru , Deng Zhigang , Qi Wei , Chen Benzheng , Ma Bubo , Wang Xing , Yin Shuai , Feng Jianhua , Liu Wei , Xu Zhongfeng , Hoffmann Dieter H. H. , Wang Shaoyi , Fan Quanping , Cui Bo , He Shukai , Cao Zhurong , Zhao Zongqing , Cao Leifeng , Gu Yuqiu , Zhu Shaoping , Cheng Rui , Zhou Xianming , Xiao Guoqing , Zhao Hongwei , Zhang Yihang , Zhang Zhe , Li Yutong , Wu Dong , Zhou Weimin , Zhao Yongtao
Published: October 2020

Intense particle beams generated from the interaction of ultrahigh intensity lasers with sample foils provide options in radiography, high-yield neutron sources, high-energy-density-matter generation, and ion fast ignition. An accurate understanding of beam transportation behavior in dense matter is crucial for all these applications. Here we report the experimental evidence on one order of magnitude enhancement of intense laser-accelerated proton beam stopping in dense ionized matter, in comparison with the current-widely used models describing individual ion stopping in matter. Supported by particle-in-cell (PIC) simulations, we attribute the enhancement to the strong decelerating electric field approaching 1 GV/m that can be created by the beam-driven return current. This collective effect plays the dominant role in the stopping of laser-accelerated intense proton beams in dense ionized matter. This finding is essential for the optimum design of ion driven fast ignition and inertial confinement fusion.
Vegetation forcing modulates global land monsoon and water resources in a CO2-enriched climate
Authors: Cui Jiangpeng , Piao Shilong , Huntingford Chris , Wang Xuhui , Lian Xu , Chevuturi Amulya , Turner Andrew G. , Kooperman Gabriel J.
Published: October 2020

The global monsoon is characterised by transitions between pronounced dry and wet seasons, affecting food security for two-thirds of the world’s population. Rising atmospheric CO2 influences the terrestrial hydrological cycle through climate-radiative and vegetation-physiological forcings. How these two forcings affect the seasonal intensity and characteristics of monsoonal precipitation and runoff is poorly understood. Here we use four Earth System Models to show that in a CO2-enriched climate, radiative forcing changes drive annual precipitation increases for most monsoon regions. Further, vegetation feedbacks substantially affect annual precipitation in North and South America and Australia monsoon regions. In the dry season, runoff increases over most monsoon regions, due to stomatal closure-driven evapotranspiration reductions and associated atmospheric circulation change. Our results imply that flood risks may amplify in the wet season. However, the lengthening of the monsoon rainfall season and reduced evapotranspiration will shorten the water resources scarcity period for most monsoon regions.
Physical limits to sensing material properties
Authors: Beroz Farzan , Zhou Di , Mao Xiaoming , Lubensky David K.
Published: October 2020

All materials respond heterogeneously at small scales, which limits what a sensor can learn. Although previous studies have characterized measurement noise arising from thermal fluctuations, the limits imposed by structural heterogeneity have remained unclear. In this paper, we find that the least fractional uncertainty with which a sensor can determine a material constant λ0 of an elastic medium is approximately $$\delta {\lambda }_{0}/{\lambda }_{0} \sim ({\Delta }_{\lambda }^{1/2}/{\lambda }_{0}){(d/a)}^{D/2}{(\xi /a)}^{D/2}$$
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, and D > 1, where a is the size of the sensor, d is its spatial resolution, ξ is the correlation length of fluctuations in λ0, Δλ is the local variability of λ0, and D is the dimension of the medium. Our results reveal how one can construct devices capable of sensing near these limits, e.g. for medical diagnostics. We use our theoretical framework to estimate the limits of mechanosensing in a biopolymer network, a sensory process involved in cellular behavior, medical diagnostics, and material fabrication.
Conformational equilibrium shift underlies altered K+ channel gating as revealed by NMR
Authors: Iwahashi Yuta , Toyama Yuki , Imai Shunsuke , Itoh Hiroaki , Osawa Masanori , Inoue Masayuki , Shimada Ichio
Published: October 2020

The potassium ion (K+) channel plays a fundamental role in controlling K+ permeation across the cell membrane and regulating cellular excitabilities. Mutations in the transmembrane pore reportedly affect the gating transitions of K+ channels, and are associated with the onset of neural disorders. However, due to the lack of structural and dynamic insights into the functions of K+ channels, the structural mechanism by which these mutations cause K+ channel dysfunctions remains elusive. Here, we used nuclear magnetic resonance spectroscopy to investigate the structural mechanism underlying the decreased K+-permeation caused by disease-related mutations, using the prokaryotic K+ channel KcsA. We demonstrated that the conformational equilibrium in the transmembrane region is shifted toward the non-conductive state with the closed intracellular K+-gate in the disease-related mutant. We also demonstrated that this equilibrium shift is attributable to the additional steric contacts in the open-conductive structure, which are evoked by the increased side-chain bulkiness of the residues lining the transmembrane helix. Our results suggest that the alteration in the conformational equilibrium of the intracellular K+-gate is one of the fundamental mechanisms underlying the dysfunctions of K+ channels caused by disease-related mutations.
Author Correction: Synergy between the anthocyanin and RDR6/SGS3/DCL4 siRNA pathways expose hidden features of Arabidopsis carbon metabolism
Authors: Jiang Nan , Gutierrez-Diaz Aimer , Mukundi Eric , Lee Yun Sun , Meyers Blake C. , Otegui Marisa S. , Grotewold Erich
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Author Correction: Plasma activity of Thioredoxin Reductase as a Novel Biomarker in Gastric Cancer
Authors: Peng Wei , Zhou Zhaofei , Zhong Yuejiao , Sun Yan , Wang Yajing , Zhu Zili , Jiao Wenxuan , Bai Man , Sun Jing , Lu Jianwei , Yin Hanwei
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Biomarkers for the toxicity of sublethal concentrations of triclosan to the early life stages of carps
Authors: Dar Owias Iqbal , Sharma Sunil , Singh Kirpal , Sharma Anket , Bhardwaj Renu , Kaur Arvinder
Published: October 2020

Accumulation, contents of protein, non-enzymatic antioxidant glutathione (GSH and GSSG), lipid peroxidation product (melondialdehyde-MDA) and organic acids (fumarate, succinate, malate and citrate), and activities of neurological (acetylcholinesterase-AChE), detoxification (glutathione S-transferase-GST) and metabolic (lactate dehydrogenase-LDH, aspartate transaminase-AST and alanine transaminase-ALT) enzymes were recorded in the hatchlings of Cyprinus carpio, Ctenopharyngodon idella, Labeo rohita and Cirrhinus mrigala after 7 and 14 days exposure and 10 days post exposure (recovery period) to sublethal concentrations (0.005, 0.01, 0.02 and 0.05 mg/L) of triclosan, a highly toxic and persistent biocide used in personal care products. Accumulation was maximum between 7–14 days at 0.01 mg/L for C. carpio and L. rohita but at 0.005 mg/L for C. idella and C. mrigala. No triclosan was observed at 0.005 mg/L in C. carpio and C. mrigala after recovery. Significant decline in protein, glutathione and acetylcholinesterase but increase in glutathione S-transferase, lactate dehydrogenase, aspartate transaminase, alanine transaminase, melondialdehyde and organic acids over control during exposure continued till the end of recovery period. Integrated biomarker response (IBR) analysis depicted higher star plot area for glutathione and glutathione S-transferase during initial 7 days of exposure, thereafter, during 7–14 days of exposure and the recovery period, higher star plot area was observed for acetylcholinesterase, aspartate transaminase, alanine transaminase and organic acids. Higher star plot area was observed for protein in all the species throughout the study. The study shows that L. rohita is most sensitive and glutathione, acetylcholinesterase, aspartate transaminase and alanine transaminase are the biomarkers for the toxicity of sublethal concentrations of TCS.
Transforming self-reported outcomes from a stroke register to the modified Rankin Scale: a cross-sectional, explorative study
Authors: Abzhandadze Tamar , Reinholdsson Malin , Palstam Annie , Eriksson Marie , Sunnerhagen Katharina S.
Published: October 2020

The aim was to create an algorithm to transform self-reported outcomes from a stroke register to the modified Rankin Scale (mRS). Two stroke registers were used: the Väststroke, a local register in Gothenburg, Sweden, and the Riksstroke, a Swedish national register. The reference variable, mRS (from Väststroke), was mapped with seven self-reported questions from Riksstroke. The transformation algorithm was created as a result of manual mapping performed by healthcare professionals. A supervised machine learning method—decision tree—was used to further evaluate the transformation algorithm. Of 1145 patients, 54% were male, the mean age was 71 y. The mRS grades 0, 1 and 2 could not be distinguished as a result of manual mapping or by using the decision tree analysis. Thus, these grades were merged. With manual mapping, 78% of the patients were correctly classified, and the level of agreement was almost perfect, weighted Kappa (Kw) was 0.81. With the decision tree, 80% of the patients were correctly classified, and substantial agreement was achieved, Kw = 0.67. The self-reported outcomes from a stroke register can be transformed to the mRS. A mRS algorithm based on manual mapping might be useful for researchers using self-reported questionnaire data.
Unravelling the health status of brachycephalic dogs in the UK using multivariable analysis
Authors: O’Neill D. G. , Pegram C. , Crocker P. , Brodbelt D. C. , Church D. B. , Packer R. M. A.
Published: October 2020

Brachycephalic dog breeds are regularly asserted as being less healthy than non-brachycephalic breeds. Using primary-care veterinary clinical data, this study aimed to identify predispositions and protections in brachycephalic dogs and explore differing inferences between univariable and multivariable results. All disorders during 2016 were extracted from a random sample of 22,333 dogs within the VetCompass Programme from a sampling frame of 955,554 dogs under UK veterinary care in 2016. Univariable and multivariable binary logistic regression modelling explored brachycephaly as a risk factor for each of a series of common disorders. Brachycephalic dogs were younger, lighter and less likely to be neutered than mesocephalic, dolichocephalic and crossbred dogs. Brachycephalic differed to non-brachycephalic types in their odds for 10/30 (33.33%) common disorders. Of these, brachycephalic types were predisposed for eight disorders and were protected for two disorders. Univariable and multivariable analyses generated differing inference for 11/30 (30.67%) disorders. This study provides strong evidence that brachycephalic breeds are generally less healthy than their non-brachycephalic counterparts. Results from studies that report only univariable methods should be treated with extreme caution due to potential confounding effects that have not been accounted for during univariable study design or analysis.
Genome wide in-silico miRNA and target network prediction from stress responsive Horsegram (Macrotyloma uniflorum) accessions
Authors: Yasin Jeshima Khan , Mishra Bharat Kumar , Pillai M. Arumugam , Verma Nidhi , Wani Shabir H. , Elansary Hosam O. , El-Ansary Diaa O. , Pandey P. S. , Chinnusamy Viswanathan
Published: October 2020

Horsegram (Macrotyloma uniflorum (Lam.) Verdc.) is a drought hardy food and fodder legume of Indo-African continents with diverse germplasm sources demonstrating alternating mechanisms depicting contrasting adaptations to different climatic zones. Tissue specific expression of genes contributes substantially to location specific adaptations. Regulatory networks of such adaptive genes are elucidated for downstream translational research. MicroRNAs are small endogenous regulatory RNAs which alters the gene expression profiles at a particular time and type of tissue. Identification of such small regulatory RNAs in low moisture stress hardy crops can help in cross species transfer and validation confirming stress tolerance ability. This study outlined prediction of conserved miRNAs from transcriptome shotgun assembled sequences and EST sequences of horsegram. We could validate eight out of 15 of the identified miRNAs to demonstrate their role in deficit moisture stress tolerance mechanism of horsegram variety Paiyur1 with their target networks. The putative mumiRs were related to other food legumes indicating the presence of gene regulatory networks. Differential miRNA expression among drought specific tissues indicted the probable energy conservation mechanism. Targets were identified for functional characterization and regulatory network was constructed to find out the probable pathways of post-transcriptional regulation. The functional network revealed mechanism of biotic and abiotic stress tolerance, energy conservation and photoperiod responsiveness.
From stress to depression: development of extracellular matrix-dependent cognitive impairment following social stress
Authors: Koskinen Maija-Kreetta , van Mourik Yvar , Smit August Benjamin , Riga Danai , Spijker Sabine
Published: October 2020

Stress can predispose to depressive episodes, yet the molecular mechanisms regulating the transition from the initial stress response to a persistent pathological depressive state remain poorly understood. We profiled the development of an enduring depressive-like state by assessing affective behavior and hippocampal function during the 2 months following social-defeat stress. We measured remodeling of hippocampal extracellular matrix (ECM) during this period, as we recently identified ECM changes to mediate cognitive impairment during the sustained depressive-like state. Affective disturbance and cognitive impairments develop disparately after social stress, with gradual appearance of affective deficits. In contrast, spatial memory was impaired both early after stress and during the late-emerging chronic depressive-like state, while intact in-between. Similarly, we observed a biphasic regulation of the hippocampal ECM coinciding with hippocampus-dependent memory deficits. Together our data (1) reveal a dichotomy between affective and cognitive impairments similar to that observed in patients, (2) indicate different molecular processes taking place during early stress and the chronic depressive-like state, and (3) support a role of the ECM in mediating long-lasting effects on memory. From a translational point of view, it is important to prioritize on temporal phenotypic aspects in animal models to elucidate the underlying mechanisms of depression.
Hyperactive sensorimotor cortex during voice perception in spasmodic dysphonia
Authors: Kanazawa Yuji , Kishimoto Yo , Tateya Ichiro , Ishii Toru , Sanuki Tetsuji , Hiroshiba Shinya , Aso Toshihiko , Omori Koichi , Nakamura Kimihiro
Published: October 2020

Spasmodic dysphonia (SD) is characterized by an involuntary laryngeal muscle spasm during vocalization. Previous studies measured brain activation during voice production and suggested that SD arises from abnormal sensorimotor integration involving the sensorimotor cortex. However, it remains unclear whether this abnormal sensorimotor activation merely reflects neural activation produced by abnormal vocalization. To identify the specific neural correlates of SD, we used a sound discrimination task without overt vocalization to compare neural activation between 11 patients with SD and healthy participants. Participants underwent functional MRI during a two-alternative judgment task for auditory stimuli, which could be modal or falsetto voice. Since vocalization in falsetto is intact in SD, we predicted that neural activation during speech perception would differ between the two groups only for modal voice and not for falsetto voice. Group-by-stimulus interaction was observed in the left sensorimotor cortex and thalamus, suggesting that voice perception activates different neural systems between the two groups. Moreover, the sensorimotor signals positively correlated with disease severity of SD, and classified the two groups with 73% accuracy in linear discriminant analysis. Thus, the sensorimotor cortex and thalamus play a central role in SD pathophysiology and sensorimotor signals can be a new biomarker for SD diagnosis.
Seven novel genetic variants in a North Indian cohort with classical homocystinuria
Authors: Kaur Rajdeep , Attri Savita V. , Saini Arushi G. , Sankhyan Naveen , Singh Satwinder , Faruq Mohammed , Ramprasad V. L. , Sharda Sheetal , Murugan Sakthivel
Published: October 2020

Classical homocystinuria is the most common cause of isolated homocystinuria. The variants of the CBS gene remain unidentified in Indian children with this disorder. Based on the hallmark clinical features, family history, and/or biochemical clues for classical homocystinuria, 16 children below the age of 18 years were evaluated by Sanger sequencing of the coding exons of CBS gene with flanking intronic regions. The common C677T variant of the MTHFR gene was also screened by restriction fragment length polymorphism. Fifteen children were clinically suspected of having classical homocystinuria and one asymptomatic child with positive family history. Only seven children had biochemical features of classical homocystinuria. Sanger sequencing of the CBS gene confirmed 15 different pathogenic or likely pathogenic variants in 14 cases. Of these, seven variants were novel (three frameshift deletions, two nonsense, one missense, one splice site variant) and were predicted to be deleterious by Mutation Taster software. Seven cases were homozygous, another six were compound heterozygous, and one case was single heterozygous in the study. None of the three most frequent mutations reported worldwide viz., I278T, G307S, and IVS 11-2A>C were found in our cohort. No variants were detected in the exons 2, 8, 12, and 14 as compared to reported literature. Eleven out of 15 variants were associated with the conserved catalytic domain of the CBS polypeptide. The MTHFR polymorphism C677T was observed in heterozygous state in six cases. Our study reports the detailed genotype and seven novel variants in the CBS gene, causing classical homocystinuria in Indian children. The genetic analysis will help to offer accurate genetic counseling, prenatal diagnosis, and development of mutation-based novel therapeutic strategies.
A critical evaluation of visual proportion of Gleason 4 and maximum cancer core length quantified by histopathologists
Authors: Carmona Echeverria Lina Maria , Haider Aiman , Freeman Alex , Stopka-Farooqui Urszula , Rosenfeld Avi , Simpson Benjamin S. , Hu Yipeng , Hawkes David , Pye Hayley , Heavey Susan , Stavrinides Vasilis , Norris Joseph M. , Bosaily Ahmed El-Shater , Cardona Barrena Cristina , Bott Simon , Brown Louise , Burns-Cox Nick , Dudderidge Tim , Henderson Alastair , Hindley Richard , Kaplan Richard , Kirkham Alex , Oldroyd Robert , Ghei Maneesh , Persad Raj , Punwani Shonit , Rosario Derek , Shergill Iqbal , Winkler Mathias , Ahmed Hashim U. , Emberton Mark , Whitaker Hayley C.
Published: October 2020

Gleason score 7 prostate cancer with a higher proportion of pattern 4 (G4) has been linked to genomic heterogeneity and poorer patient outcome. The current assessment of G4 proportion uses estimation by a pathologist, with a higher proportion of G4 more likely to trigger additional imaging and treatment over active surveillance. This estimation method has been shown to have inter-observer variability. Fifteen patients with Prostate Grade Group (GG) 2 (Gleason 3 + 4) and fifteen patients with GG3 (Gleason 4 + 3) disease were selected from the PROMIS study with 192 haematoxylin and eosin-stained slides scanned. Two experienced uropathologists assessed the maximum cancer core length (MCCL) and G4 proportion using the current standard method (visual estimation) followed by detailed digital manual annotation of each G4 area and measurement of MCCL (planimetric estimation) using freely available software by the same two experts. We aimed to compare visual estimation of G4 and MCCL to a pathologist-driven digital measurement. We show that the visual and digital MCCL measurement differs up to 2 mm in 76.6% (23/30) with a high degree of agreement between the two measurements; Visual gave a median MCCL of 10 ± 2.70 mm (IQR 4, range 5–15 mm) compared to digital of 9.88 ± 3.09 mm (IQR 3.82, range 5.01–15.7 mm) (p = 0.64) The visual method for assessing G4 proportion over-estimates in all patients, compared to digital measurements [median 11.2% (IQR 38.75, range 4.7–17.9%) vs 30.4% (IQR 18.37, range 12.9–50.76%)]. The discordance was higher as the amount of G4 increased (Bias 18.71, CI 33.87–48.75, r 0.7, p < 0.0001). Further work on assessing actual G4 burden calibrated to clinical outcomes might lead to the use of differing G4 thresholds of significance if the visual estimation is used or by incorporating semi-automated methods for G4 burden measurement.
Diel vertical migration into anoxic and high-pCO2 waters: acoustic and net-based krill observations in the Humboldt Current
Authors: Riquelme-Bugueño Ramiro , Pérez-Santos Iván , Alegría Nicolás , Vargas Cristian A. , Urbina Mauricio A. , Escribano Rubén
Published: October 2020

A select group of marine organisms can enter the Oxygen Minimum Zones (OMZs) and even anoxic waters, while performing diel vertical migration (DVM). DVM of the euphausiid Euphausia eximia off northern Chile in the spring of 2015 was documented based on acoustic measurements using an echo sounder along with net samplings. Dissolved oxygen (DO) concentrations were obtained using a vertical profiler, and water samples were collected to obtain in situ nitrite (NO2−) concentrations as well as pHT, total alkalinity (AT), and therefore carbon dioxide partial pressure (pCO2) was estimated. Krill were found to migrate up to the surface (0–50 m) during the night and returned to ca. 200–300 m depth during the day, spending between 11 and 14 h at these layers. At the surface, DO and NO2− concentrations were 208 and 0.14 μM respectively, while pHT was 8.04 and 405 μatm pCO2. In contrast, at the deeper layers (200–300 m), DO and NO2− were < 3 and 6.3 μM respectively, with pHT 7.53 and 1490 μatm pCO2. The pHT and high pCO2 values at depths represent the conditions predicted for open ocean waters in a worst-case global warming scenario by 2150. The acoustic scatter suggested that > 60% of the krill swarms enter the OMZ and anoxic waters during the daytime. These frequent migrations suggest that krill can tolerate such extreme conditions associated with anoxic and high-pCO2 waters. The inferences drawn from the observation of these migrations might have strong implications for the current oceanic carbon pump models, highlighting the need for understanding the molecular and physiological adaptations allowing these migrations.
Reduced apparent fiber density in the white matter of premature-born adults
Authors: Menegaux Aurore , Hedderich Dennis M. , Bäuml Josef G. , Manoliu Andrei , Daamen Marcel , Berg Ronja C. , Preibisch Christine , Zimmer Claus , Boecker Henning , Bartmann Peter , Wolke Dieter , Sorg Christian , Stämpfli Philipp
Published: October 2020

Premature-born adults exhibit lasting white matter alterations as demonstrated by widespread reduction in fractional anisotropy (FA) based on diffusion-weighted imaging (DWI). FA reduction, however, is non-specific for microscopic underpinnings such as aberrant myelination or fiber density (FD). Using recent advances in DWI, we tested the hypothesis of reduced FD in premature-born adults and investigated its link with the degree of prematurity and cognition. 73 premature- and 89 mature-born adults aged 25–27 years underwent single-shell DWI, from which a FD measure was derived using convex optimization modeling for microstructure informed tractography (COMMIT). Premature-born adults exhibited lower FD in numerous tracts including the corpus callosum and corona radiata compared to mature-born adults. These FD alterations were associated with both the degree of prematurity, as assessed via gestational age and birth weight, as well as with reduced cognition as measured by full-scale IQ. Finally, lower FD overlapped with lower FA, suggesting lower FD underlie unspecific FA reductions. Results provide evidence that premature birth leads to lower FD in adulthood which links with lower full-scale IQ. Data suggest that lower FD partly underpins FA reductions of premature birth but that other processes such as hypomyelination might also take place.