bluuebunny/crossref_metadata_2025 huggingface dataset:
Three-dimensional in vitro modeling of malignant bone disease recapitulates experimentally accessible mechanisms of osteoinhibition
Authors: McNeill Eoin P. , Reese Robert W. , Tondon Abishek , Clough Bret H. , Pan Simin , Froese Jeremiah , Palmer Daniel , Krause Ulf , Loeb David M. , Kaunas Roland , Gregory Carl A.
Published: November 2018

Malignant bone disease (MBD) occurs when tumors establish in bone, causing catastrophic tissue damage as a result of accelerated bone destruction and inhibition of repair. The resultant so-called osteolytic lesions (OL) take the form of tumor-filled cavities in bone that cause pain, fractures, and associated morbidity. Furthermore, the OL microenvironment can support survival of tumor cells and resistance to chemotherapy. Therefore, a deeper understanding of OL formation and MBD progression is imperative for the development of future therapeutic strategies. Herein, we describe a novel in vitro platform to study bone–tumor interactions based on three-dimensional co-culture of osteogenically enhanced human mesenchymal stem cells (OEhMSCs) in a rotating wall vessel bioreactor (RWV) while attached to micro-carrier beads coated with extracellular matrix (ECM) composed of factors found in anabolic bone tissue. Osteoinhibition was recapitulated in this model by co-culturing the OEhMSCs with a bone–tumor cell line (MOSJ-Dkk1) that secretes the canonical Wnt (cWnt) inhibitor Dkk-1, a tumor-borne osteoinhibitory factor widely associated with several forms of MBD, or intact tumor fragments from Dkk-1 positive patient-derived xenografts (PDX). Using the model, we observed that depending on the conditions of growth, tumor cells can biochemically inhibit osteogenesis by disrupting cWnt activity in OEhMSCs, while simultaneously co-engrafting with OEhMSCs, displacing them from the niche, perturbing their activity, and promoting cell death. In the absence of detectable co-engraftment with OEhMSCs, Dkk-1 positive PDX fragments had the capacity to enhance OEhMSC proliferation while inhibiting their osteogenic differentiation. The model described has the capacity to provide new and quantifiable insights into the multiple pathological mechanisms of MBD that are not readily measured using monolayer culture or animal models.
Sex separation induces differences in the olfactory sensory receptor repertoires of male and female mice
Authors: van der Linden Carl , Jakob Susanne , Gupta Pooja , Dulac Catherine , Santoro Stephen W.
Published: November 2018

Within the mammalian olfactory sensory epithelium, experience-dependent changes in the rate of neuronal turnover can alter the relative abundance of neurons expressing specific chemoreceptors. Here we investigate how the mouse olfactory sensory receptor repertoire changes as a function of exposure to odors emitted from members of the opposite sex, which are highly complex and sexually dimorphic. Upon housing mice either sex-separated or sex-combined until six months of age, we find that sex-separated mice exhibit significantly more numerous differentially expressed genes within their olfactory epithelia. A subset of these chemoreceptors exhibit altered expression frequencies following both sex-separation and olfactory deprivation. We show that several of these receptors detect either male- or female-specific odors. We conclude that the distinct odor experiences of sex-separated male and female mice induce sex-specific differences in the abundance of neurons that detect sexually dimorphic odors.
Immediate neurophysiological effects of transcranial electrical stimulation
Authors: Liu Anli , Vöröslakos Mihály , Kronberg Greg , Henin Simon , Krause Matthew R. , Huang Yu , Opitz Alexander , Mehta Ashesh , Pack Christopher C. , Krekelberg Bart , Berényi Antal , Parra Lucas C. , Melloni Lucia , Devinsky Orrin , Buzsáki György
Published: November 2018

Noninvasive brain stimulation techniques are used in experimental and clinical fields for their potential effects on brain network dynamics and behavior. Transcranial electrical stimulation (TES), including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), has gained popularity because of its convenience and potential as a chronic therapy. However, a mechanistic understanding of TES has lagged behind its widespread adoption. Here, we review data and modelling on the immediate neurophysiological effects of TES in vitro as well as in vivo in both humans and other animals. While it remains unclear how typical TES protocols affect neural activity, we propose that validated models of current flow should inform study design and artifacts should be carefully excluded during signal recording and analysis. Potential indirect effects of TES (e.g., peripheral stimulation) should be investigated in more detail and further explored in experimental designs. We also consider how novel technologies may stimulate the next generation of TES experiments and devices, thus enhancing validity, specificity, and reproducibility.
Magnetic reconnection driven by electron dynamics
Authors: Kuramitsu Y. , Moritaka T. , Sakawa Y. , Morita T. , Sano T. , Koenig M. , Gregory C. D. , Woolsey N. , Tomita K. , Takabe H. , Liu Y. L. , Chen S. H. , Matsukiyo S. , Hoshino M.
Published: November 2018

Magnetic reconnections play essential roles in space, astrophysical, and laboratory plasmas, where the anti-parallel magnetic field components re-connect and the magnetic energy is converted to the plasma energy as Alfvénic out flows. Although the electron dynamics is considered to be essential, it is highly challenging to observe electron scale reconnections. Here we show the experimental results on an electron scale reconnection driven by the electron dynamics in laser-produced plasmas. We apply a weak-external magnetic field in the direction perpendicular to the plasma propagation, where the magnetic field is directly coupled with only the electrons but not for the ions. Since the kinetic pressure of plasma is much larger than the magnetic pressure, the magnetic field is distorted and locally anti-parallel. We observe plasma collimations, cusp and plasmoid like features with optical diagnostics. The plasmoid propagates at the electron Alfvén velocity, indicating a reconnection driven by the electron dynamics.
Tumour-vasculature development via endothelial-to-mesenchymal transition after radiotherapy controls CD44v6+ cancer cell and macrophage polarization
Authors: Choi Seo-Hyun , Kim A-Ram , Nam Jae-Kyung , Kim Jin-Mo , Kim Jee-Youn , Seo Haeng Ran , Lee Hae-June , Cho Jaeho , Lee Yoon-Jin
Published: November 2018

It remains controversial whether targeting tumour vasculature can improve radiotherapeutic efficacy. We report that radiation-induced endothelial-to-mesenchymal transition (EndMT) leads to tumour vasculature with abnormal SMA+NG2+ pericyte recruitment during tumour regrowth after radiotherapy. Trp53 (but not Tgfbr2) deletion in endothelial cells (ECs) inhibited radiation-induced EndMT, reducing tumour regrowth and metastases with a high CD44v6+ cancer-stem-cell (CSC) content after radiotherapy. Osteopontin, an EndMT-related angiocrine factor suppressed by EC-Trp53 deletion, stimulated proliferation in dormant CD44v6+ cells in severely hypoxic regions after radiation. Radiation-induced EndMT significantly regulated tumour-associated macrophage (TAM) polarization. CXCR4 upregulation in radioresistant tumour ECs was highly associated with SDF-1+ TAM recruitment and M2 polarization of TAMs, which was suppressed by Trp53 deletion. These EndMT-related phenomena were also observed in irradiated human lung cancer tissues. Our findings suggest that targeting tumour EndMT might enhance radiotherapy efficacy by inhibiting the re-activation of dormant hypoxic CSCs and promoting anti-tumour immune responses.
Robo signalling controls pancreatic progenitor identity by regulating Tead transcription factors
Authors: Escot Sophie , Willnow David , Naumann Heike , Di Francescantonio Silvia , Spagnoli Francesca M.
Published: November 2018

A complex interplay of intrinsic factors and extrinsic signalling pathways controls both cell lineage commitment and maintenance of cell identity. Loss of defined cellular states is the cause of many different cancers, including pancreatic cancer. Recent findings suggest a clinical role for the conserved SLIT/ROBO signalling pathway in pancreatic cancer. However, whilst this pathway has been extensively studied in many processes, a role for Slit and Robo genes in pancreas cell identity and plasticity has not been established yet. Here, we identify Slit/Robo signalling as a key regulator of pancreatic progenitor identity. We find that Robo1 and Robo2 are required for preserving pancreatic cell identity shortly after fate induction and, subsequently, for expansion of the pancreatic progenitor pool in the mouse. Furthermore, we show that Robo receptors control the expression of Tead transcription factors as well as its downstream transcriptional activity. Our work identifies an interplay between Slit/Robo pathway and Tead intrinsic regulators, functioning as gatekeeper of pancreatic cell identity.
Fast kinetics of multivalent intercalation chemistry enabled by solvated magnesium-ions into self-established metallic layered materials
Authors: Li Zhenyou , Mu Xiaoke , Zhao-Karger Zhirong , Diemant Thomas , Behm R. Jürgen , Kübel Christian , Fichtner Maximilian
Published: November 2018

Rechargeable magnesium batteries are one of the most promising candidates for next-generation battery technologies. Despite recent significant progress in the development of efficient electrolytes, an on-going challenge for realization of rechargeable magnesium batteries remains to overcome the sluggish kinetics caused by the strong interaction between double charged magnesium-ions and the intercalation host. Herein, we report that a magnesium battery chemistry with fast intercalation kinetics in the layered molybdenum disulfide structures can be enabled by using solvated magnesium-ions ([Mg(DME)x]2+). Our study demonstrates that the high charge density of magnesium-ion may be mitigated through dimethoxyethane solvation, which avoids the sluggish desolvation process at the cathode-electrolyte interfaces and reduces the trapping force of the cathode lattice to the cations, facilitating magnesium-ion diffusion. The concept of using solvation effect could be a general and effective route to tackle the sluggish intercalation kinetics of magnesium-ions, which can potentially be extended to other host structures.
Contactless steam generation and superheating under one sun illumination
Authors: Cooper Thomas A. , Zandavi Seyed H. , Ni George W. , Tsurimaki Yoichiro , Huang Yi , Boriskina Svetlana V. , Chen Gang
Published: November 2018

Steam generation using solar energy provides the basis for many sustainable desalination, sanitization, and process heating technologies. Recently, interest has arisen for low-cost floating structures that absorb solar radiation and transfer energy to water via thermal conduction, driving evaporation. However, contact between water and the structure leads to fouling and pins the vapour temperature near the boiling point. Here we demonstrate solar-driven evaporation using a structure not in contact with water. The structure absorbs solar radiation and re-radiates infrared photons, which are directly absorbed by the water within a sub-100 μm penetration depth. Due to the physical separation from the water, fouling is entirely avoided. Due to the thermal separation, the structure is no longer pinned at the boiling point, and is used to superheat the generated steam. We generate steam with temperatures up to 133 °C, demonstrating superheated steam in a non-pressurized system under one sun illumination.
ROBO2 is a stroma suppressor gene in the pancreas and acts via TGF-β signalling
Authors: Pinho Andreia V. , Van Bulck Mathias , Chantrill Lorraine , Arshi Mehreen , Sklyarova Tatyana , Herrmann David , Vennin Claire , Gallego-Ortega David , Mawson Amanda , Giry-Laterriere Marc , Magenau Astrid , Leuckx Gunther , Baeyens Luc , Gill Anthony J. , Phillips Phoebe , Timpson Paul , Biankin Andrew V. , Wu Jianmin , Rooman Ilse
Published: November 2018

Whereas genomic aberrations in the SLIT-ROBO pathway are frequent in pancreatic ductal adenocarcinoma (PDAC), their function in the pancreas is unclear. Here we report that in pancreatitis and PDAC mouse models, epithelial Robo2 expression is lost while Robo1 expression becomes most prominent in the stroma. Cell cultures of mice with loss of epithelial Robo2 (Pdx1Cre;Robo2F/F) show increased activation of Robo1+ myofibroblasts and induction of TGF-β and Wnt pathways. During pancreatitis, Pdx1Cre;Robo2F/F mice present enhanced myofibroblast activation, collagen crosslinking, T-cell infiltration and tumorigenic immune markers. The TGF-β inhibitor galunisertib suppresses these effects. In PDAC patients, ROBO2 expression is overall low while ROBO1 is variably expressed in epithelium and high in stroma. ROBO2low;ROBO1high patients present the poorest survival. In conclusion, Robo2 acts non-autonomously as a stroma suppressor gene by restraining myofibroblast activation and T-cell infiltration. ROBO1/2 expression in PDAC patients may guide therapy with TGF-β inhibitors or other stroma /immune modulating agents.
Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression
Authors: Rice Christopher M. , Davies Luke C. , Subleski Jeff J. , Maio Nunziata , Gonzalez-Cotto Marieli , Andrews Caroline , Patel Nimit L. , Palmieri Erika M. , Weiss Jonathan M. , Lee Jung-Min , Annunziata Christina M. , Rouault Tracey A. , Durum Scott K. , McVicar Daniel W.
Published: November 2018

Neutrophils are a vital component of immune protection, yet in cancer they may promote tumour progression, partly by generating reactive oxygen species (ROS) that disrupts lymphocyte functions. Metabolically, neutrophils are often discounted as purely glycolytic. Here we show that immature, c-Kit+ neutrophils subsets can engage in oxidative mitochondrial metabolism. With limited glucose supply, oxidative neutrophils use mitochondrial fatty acid oxidation to support NADPH oxidase-dependent ROS production. In 4T1 tumour-bearing mice, mitochondrial fitness is enhanced in splenic neutrophils and is driven by c-Kit signalling. Concordantly, tumour-elicited oxidative neutrophils are able to maintain ROS production and T cell suppression when glucose utilisation is restricted. Consistent with these findings, peripheral blood neutrophils from patients with cancer also display increased immaturity, mitochondrial content and oxidative phosphorylation. Together, our data suggest that the glucose-restricted tumour microenvironment induces metabolically adapted, oxidative neutrophils to maintain local immune suppression.
Opposite macroevolutionary responses to environmental changes in grasses and insects during the Neogene grassland expansion
Authors: Kergoat Gael J. , Condamine Fabien L. , Toussaint Emmanuel F. A. , Capdevielle-Dulac Claire , Clamens Anne-Laure , Barbut Jérôme , Goldstein Paul Z. , Le Ru Bruno
Published: November 2018

The rise of Neogene C4 grasslands is one of the most drastic changes recently experienced by the biosphere. A central - and widely debated - hypothesis posits that Neogene grasslands acted as a major adaptive zone for herbivore lineages. We test this hypothesis with a novel model system, the Sesamiina stemborer moths and their associated host-grasses. Using a comparative phylogenetic framework integrating paleoenvironmental proxies we recover a negative correlation between the evolutionary trajectories of insects and plants. Our results show that paleoenvironmental changes generated opposing macroevolutionary dynamics in this insect-plant system and call into question the role of grasslands as a universal adaptive cradle. This study illustrates the importance of implementing environmental proxies in diversification analyses to disentangle the relative impacts of biotic and abiotic drivers of macroevolutionary dynamics.
Raman fingerprint of two terahertz spin wave branches in a two-dimensional honeycomb Ising ferromagnet
Authors: Jin Wencan , Kim Hyun Ho , Ye Zhipeng , Li Siwen , Rezaie Pouyan , Diaz Fabian , Siddiq Saad , Wauer Eric , Yang Bowen , Li Chenghe , Tian Shangjie , Sun Kai , Lei Hechang , Tsen Adam W. , Zhao Liuyan , He Rui
Published: November 2018

Two-dimensional (2D) magnetism has been long sought-after and only very recently realized in atomic crystals of magnetic van der Waals materials. So far, a comprehensive understanding of the magnetic excitations in such 2D magnets remains missing. Here we report polarized micro-Raman spectroscopy studies on a 2D honeycomb ferromagnet CrI3. We show the definitive evidence of two sets of zero-momentum spin waves at frequencies of 2.28 terahertz (THz) and 3.75 THz, respectively, that are three orders of magnitude higher than those of conventional ferromagnets. By tracking the thickness dependence of both spin waves, we reveal that both are surface spin waves with lifetimes an order of magnitude longer than their temporal periods. Our results of two branches of high-frequency, long-lived surface spin waves in 2D CrI3 demonstrate intriguing spin dynamics and intricate interplay with fluctuations in the 2D limit, thus opening up opportunities for ultrafast spintronics incorporating 2D magnets.
Plasma redox imbalance caused by albumin oxidation promotes lung-predominant NETosis and pulmonary cancer metastasis
Authors: Inoue Minoru , Nakashima Ryota , Enomoto Masahiro , Koike Yuhki , Zhao Xiao , Yip Kenneth , Huang Shao Hui , Waldron John N. , Ikura Mitsuhiko , Liu Fei-Fei , Bratman Scott V.
Published: November 2018

Neutrophil extracellular traps (NETs) promote cancer metastasis in preclinical models following massive exogenous inflammatory stimuli. It remains unknown whether cancer hosts under physiologic conditions experience NETosis and consequent metastasis. Here we show that plasma redox imbalance caused by albumin oxidation promotes inflammation-independent NETosis. Albumin is the major source of free thiol that maintains redox balance. Oxidation of albumin-derived free thiol is sufficient to trigger NETosis via accumulation of reactive oxygen species within neutrophils. The resultant NETs are found predominantly within lungs where they contribute to the colonization of circulating tumor cells leading to pulmonary metastases. These effects are abrogated by pharmacologic inhibition of NET formation. Moreover, albumin oxidation is associated with pulmonary metastasis in a cohort of head and neck cancer patients. These results implicate plasma redox balance as an endogenous and physiologic regulator of NETosis and pulmonary cancer metastasis, providing new therapeutic and diagnostic opportunities for combatting cancer progression.
Z-ring membrane anchors associate with cell wall synthases to initiate bacterial cell division
Authors: Pazos Manuel , Peters Katharina , Casanova Mercedes , Palacios Pilar , VanNieuwenhze Michael , Breukink Eefjan , Vicente Miguel , Vollmer Waldemar
Published: November 2018

During the transition from elongation to septation, Escherichia coli establishes a ring-like peptidoglycan growth zone at the future division site. This preseptal peptidoglycan synthesis does not require the cell division-specific peptidoglycan transpeptidase PBP3 or most of the other cell division proteins, but it does require FtsZ, its membrane-anchor ZipA and at least one of the bi-functional transglycosylase-transpeptidases, PBP1A or PBP1B. Here we show that PBP1A and PBP1B interact with ZipA and localise to preseptal sites in cells with inhibited PBP3. ZipA stimulates the glycosyltransferase activity of PBP1A. The membrane-anchored cell division protein FtsN localises at preseptal sites and stimulates both activities of PBP1B. Genes zipA and ftsN can be individually deleted in ftsA* mutant cells, but the simultaneous depletion of both proteins is lethal and cells do not establish preseptal sites. Our data support a model according to which ZipA and FtsN-FtsA have semi-redundant roles in connecting the cytosolic FtsZ ring with the membrane-anchored peptidoglycan synthases during the preseptal phase of envelope growth.
miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC
Authors: Jeon Young-Jun , Kim Taewan , Park Dongju , Nuovo Gerard J. , Rhee Siyeon , Joshi Pooja , Lee Bum-Kyu , Jeong Johan , Suh Sung-suk , Grotzke Jeff E. , Kim Sung-Hak , Song Jieun , Sim Hosung , Kim Yonghwan , Peng Yong , Jeong Youngtae , Garofalo Michela , Zanesi Nicola , Kim Jonghwan , Liang Guang , Nakano Ichiro , Cresswell Peter , Nana-Sinkam Patrick , Cui Ri , Croce Carlo M.
Published: November 2018

Non-small cell lung carcinoma (NSCLC) is leading cause of cancer-related deaths in the world. The Tumor Suppressor Candidate 3 (TUSC3) at chromosome 8p22 known to be frequently deleted in cancer is often found to be deleted in advanced stage of solid tumors. However, the role of TUSC3 still remains controversial in lung cancer and context-dependent in several cancers. Here we propose that miR-224/-520c-dependent TUSC3 deficiency enhances the metastatic potential of NSCLC through the alteration of three unfolded protein response pathways and HRD1-dependent ERAD. ATF6α-dependent UPR is enhanced whereas the affinity of HRD1 to its substrates, PERK, IRE1α and p53 is weakened. Consequently, the alteration of UPRs and the suppressed p53-NM23H1/2 pathway by TUSC3 deficiency is ultimately responsible for enhancing metastatic potential of lung cancer. These findings provide mechanistic insight of unrecognized roles of TUSC3 in cancer progression and the oncogenic role of HRD1-dependent ERAD in cancer metastasis.
Nanoribbons self-assembled from short peptides demonstrate the formation of polar zippers between β-sheets
Authors: Wang Meng , Wang Jiqian , Zhou Peng , Deng Jing , Zhao Yurong , Sun Yawei , Yang Wei , Wang Dong , Li Zongyi , Hu Xuzhi , King Stephen M. , Rogers Sarah E. , Cox Henry , Waigh Thomas A. , Yang Jun , Lu Jian Ren , Xu Hai
Published: November 2018

Peptide self-assembly is a hierarchical process, often starting with the formation of α-helices, β-sheets or β-hairpins. However, how the secondary structures undergo further assembly to form higher-order architectures remains largely unexplored. The polar zipper originally proposed by Perutz is formed between neighboring β-strands of poly-glutamine via their side-chain hydrogen bonding and helps to stabilize the sheet. By rational design of short amphiphilic peptides and their self-assembly, here we demonstrate the formation of polar zippers between neighboring β-sheets rather than between β-strands within a sheet, which in turn intermesh the β-sheets into wide and flat ribbons. Such a super-secondary structural template based on well-defined hydrogen bonds could offer an agile route for the construction of distinctive nanostructures and nanomaterials beyond β-sheets.
A monoclinic polymorph of sodium birnessite for ultrafast and ultrastable sodium ion storage
Authors: Xia Hui , Zhu Xiaohui , Liu Jizi , Liu Qi , Lan Si , Zhang Qinghua , Liu Xinyu , Seo Joon Kyo , Chen Tingting , Gu Lin , Meng Ying Shirley
Published: November 2018

Sodium transition metal oxides with layered structures are attractive cathode materials for sodium-ion batteries due to their large theoretical specific capacities. However, these layered oxides suffer from poor cyclability and low rate performance because of structural instability and sluggish electrode kinetics. In the present work, we show the sodiation reaction of Mn3O4 to yield crystal water free NaMnO2−y−δ(OH)2y, a monoclinic polymorph of sodium birnessite bearing Na/Mn(OH)8 hexahedra and Na/MnO6 octahedra. With the new polymorph, NaMnO2−y−δ(OH)2y exhibits an enlarged interlayer distance of about 7 Å, which is in favor of fast sodium ion migration and good structural stability. In combination of the favorable nanosheet morphology, NaMn2−y−δ(OH)2y cathode delivers large specific capacity up to 211.9 mAh g–1, excellent cycle performance (94.6% capacity retention after 1000 cycles), and outstanding rate capability (156.0 mAh g–1 at 50 C). This study demonstrates an effective approach in tailoring the structural and electrochemical properties of birnessite towards superior cathode performance in sodium-ion batteries.
Human preprocalcitonin self-antigen generates TAP-dependent and -independent epitopes triggering optimised T-cell responses toward immune-escaped tumours
Authors: Durgeau Aurélie , Virk Yasemin , Gros Gwendoline , Voilin Elodie , Corgnac Stéphanie , Djenidi Fayçal , Salmon Jérôme , Adam Julien , de Montpréville Vincent , Validire Pierre , Ferrone Soldano , Chouaib Salem , Eggermont Alexander , Soria Jean-Charles , Lemonnier François , Tartour Eric , Chaput Nathalie , Besse Benjamin , Mami-Chouaib Fathia
Published: November 2018

Tumours often evade CD8 T-cell immunity by downregulating TAP. T-cell epitopes associated with impaired peptide processing are immunogenic non-mutated neoantigens that emerge during tumour immune evasion. The preprocalcitonin (ppCT)16–25neoepitope belongs to this category of antigens. Here we show that most human lung tumours display altered expression of TAP and frequently express ppCT self-antigen. We also show that ppCT includes HLA-A2-restricted epitopes that are processed by TAP-independent and -dependent pathways. Processing occurs in either the endoplasmic reticulum, by signal peptidase and signal peptide peptidase, or in the cytosol after release of a signal peptide precursor or retrotranslocation of a procalcitonin substrate by endoplasmic-reticulum-associated degradation. Remarkably, ppCT peptide-based immunotherapy induces efficient T-cell responses toward antigen processing and presenting machinery-impaired tumours transplanted into HLA-A*0201-transgenic mice and in NOD-scid-Il2rγnullmice adoptively transferred with human PBMC. Thus, ppCT-specific T lymphocytes are promising effectors for treatment of tumours that have escaped immune recognition.
Birth mode is associated with earliest strain-conferred gut microbiome functions and immunostimulatory potential
Authors: Wampach Linda , Heintz-Buschart Anna , Fritz Joëlle V. , Ramiro-Garcia Javier , Habier Janine , Herold Malte , Narayanasamy Shaman , Kaysen Anne , Hogan Angela H. , Bindl Lutz , Bottu Jean , Halder Rashi , Sjöqvist Conny , May Patrick , Andersson Anders F. , de Beaufort Carine , Wilmes Paul
Published: November 2018

The rate of caesarean section delivery (CSD) is increasing worldwide. It remains unclear whether disruption of mother-to-neonate transmission of microbiota through CSD occurs and whether it affects human physiology. Here we perform metagenomic analysis of earliest gut microbial community structures and functions. We identify differences in encoded functions between microbiomes of vaginally delivered (VD) and CSD neonates. Several functional pathways are over-represented in VD neonates, including lipopolysaccharide (LPS) biosynthesis. We link these enriched functions to individual-specific strains, which are transmitted from mothers to neonates in case of VD. The stimulation of primary human immune cells with LPS isolated from early stool samples of VD neonates results in higher levels of tumour necrosis factor (TNF-α) and interleukin 18 (IL-18). Accordingly, the observed levels of TNF-α and IL-18 in neonatal blood plasma are higher after VD. Taken together, our results support that CSD disrupts mother-to-neonate transmission of specific microbial strains, linked functional repertoires and immune-stimulatory potential during a critical window for neonatal immune system priming.
Cytoplasmic LIF reprograms invasive mode to enhance NPC dissemination through modulating YAP1-FAK/PXN signaling
Authors: Liu Shu-Chen , Hsu Tien , Chang Yu-Sun , Chung An-Ko , Jiang Shih Sheng , OuYang Chun-Nan , Yuh Chiou-Hwa , Hsueh Chuen , Liu Ya-Ping , Tsang Ngan-Ming
Published: November 2018

Metastasis remains a clinically unsolved issue in nasopharyngeal carcinoma. Here, we report that higher levels of cytoplasmic leukemia inhibitory factor (LIF) and LIF receptor are correlated with poorer metastasis/recurrence-free survival. Further, single nucleotide variations and signal peptide mutation of LIF are identified in NPC. Cytoplasmic LIF reprograms the invasive mode from collective to mesenchymal migration via acquisition of EMT and invadopodia-associated characteristics. Higher cytoplasmic LIF enhances cancer vascular dissemination and local invasion mechanistically through modulation of YAP1-FAK/PXN signaling. Immunohistochemical analyses of NPC biopsies reveal a positive correlation of cytoplasmic LIF expression with focal adhesion kinases. Pharmaceutical intervention with AZD0530 markedly reverses LIF-mediated cancer dissemination and local invasion through promotion of cytoplasmic accumulation of YAP1 and suppression of focal adhesion kinases. Given the significant role of LIF/YAP1-focal adhesion signaling in cancer dissemination, targeting of this pathway presents a promising opportunity to block metastasis.
Subcellular connectomic analyses of energy networks in striated muscle
Authors: Bleck Christopher K. E. , Kim Yuho , Willingham T. Bradley , Glancy Brian
Published: November 2018

Mapping biological circuit connectivity has revolutionized our understanding of structure-function relationships. Although connectomic analyses have primarily focused on neural systems, electrical connectivity within muscle mitochondrial networks was recently demonstrated to provide a rapid mechanism for cellular energy distribution. However, tools to evaluate organelle connectivity with high spatial fidelity within single cells are currently lacking. Here, we developed a framework to quantitatively assess mitochondrial network connectivity and interactions with cellular sites of energy storage, utilization, and calcium cycling in cardiac, oxidative, and glycolytic muscle. We demonstrate that mitochondrial network configuration, individual mitochondrial size and shape, and the junctions connecting mitochondria within each network are consistent with the differing contraction demands of each muscle type. Moreover, mitochondria-lipid droplet interaction analyses suggest that individual mitochondria within networks may play specialized roles regarding energy distribution and calcium cycling within the cell and reveal the power of connectomic analyses of organelle interactions within single cells.
Nitrogen physiology of contrasting genotypes of Chenopodium quinoa Willd. (Amaranthaceae)
Authors: Bascuñán-Godoy Luisa , Sanhueza Carolina , Pinto Katherine , Cifuentes Leonardo , Reguera María , Briones Vilbett , Zurita-Silva Andrés , Álvarez Rodrigo , Morales Andrea , Silva Herman
Published: November 2018

Quinoa has been highlighted as a promising crop to sustain food security. The selection of physiological traits that allow identification genotypes with high Nitrogen use efficiency (NUE) is a key factor to increase Quinoa cultivation. In order to unveil the underpinning mechanisms for N-stress tolerance in Quinoa, three genotypes with similar phenology, but different NUE were developed under high (HN) or low (LN) nitrogen conditions. N metabolism processes and photosynthetic performance were studied after anthesis and in correlation with productivity to identify principal traits related to NUE. We found that protein content, net photosynthesis and leaf dry-mass were determinant attributes for yield at both HN and LN conditions. Contrastingly, the enhancement of N related metabolites ($${{\rm{NH}}}_{4}^{+}$$

NH

4

+

, proline, betacyanins) and processes related with re-assimilation of $${{\rm{NH}}}_{4}^{+}$$

NH

4

+

, including an increment of glutamine synthetase activity and up-regulation of CqAMT1,1 transporter expression in leaves, were negatively correlated with grain yield at both N conditions. Biochemical aspects of photosynthesis and root biomass were traits exclusively associated with grain yield at LN. The impact of N supply on seed quality is discussed. These results provide new insights towards the understanding the N metabolism of Quinoa.
Episodic zircon age spectra mimic fluctuations in subduction
Authors: Domeier Mathew , Magni Valentina , Hounslow Mark W. , Torsvik Trond H.
Published: November 2018

Decades of geochronological work have shown the temporal distribution of zircon ages to be episodic on billion-year timescales and seemingly coincident with the lifecycle of supercontinents, but the physical processes behind this episodicity remain contentious. The dominant, end-member models of fluctuating magmatic productivity versus selective preservation of zircon during times of continental assembly have important and very different implications for long-term, global-scale phenomena, including the history of crustal growth, the initiation and evolution of plate tectonics, and the tempo of mantle outgassing over billions of years. Consideration of this episodicity has largely focused on the Precambrian, but here we analyze a large collection of Phanerozoic zircon ages in the context of global, full-plate tectonic models that extend back to the mid-Paleozoic. We scrutinize two long-lived and relatively simple active margins, and show that along both, a relationship between the regional subduction flux and zircon age distribution is evident. In both cases, zircon age peaks correspond to intervals of high subduction flux with a ~10–30 Ma time lag (zircons trailing subduction), illuminating a possibly intrinsic delay in the subduction-related magmatic system. We also show that subduction fluxes provide a stronger correlation to zircon age distributions than subduction lengths do, implying that convergence rates play a significant role in regulating the volume of melting in subduction-related magmatic systems, and thus crustal growth.
Causes of volcanic unrest at Mt. Spurr in 2004–2005 inferred from repeated tomography
Authors: Koulakov I. , Smirnov S. Z. , Gladkov V. , Kasatkina E. , West M. , El Khrepy S. , Al-Arifi N.
Published: November 2018

Mt. Spurr is the largest active volcano in Alaska of high explosive potential. The most recent activity, including two recent magmatic eruptions in 1953 and 1992, has occurred via the flanking Crater Peak. From 2004 to 2006, strong seismicity, gas flux, and heating were observed in the summit area, which had remained inactive for more than 5 Ka. To understand the cause of this reactivation, we performed repeated tomography inversions that clearly imaged the magma reservoir beneath Mt. Spurr and showed temporal changes in its shape and intensity. During the two years preceding the unrest, we observed ascension of the upper limit of the reservoir-related anomaly from a depth of 5 to 3 km below the surface, accompanied by strong seismicity. During the following years, the shape of the anomaly remained unchanged, but its intensity weakened. These observations may indicate the release of fluids from the ductile reservoir and fast upward ascent through the brittle cover that caused intensive seismicity and gas flux during the unrest from 2004 to 2006. The origin of this zone will possibly cause a resumption of explosive eruptions in the summit area of Mt. Spurr.
Computational Investigation of the Morphology, Efficiency, and Properties of Silver Nano Wires Networks in Transparent Conductive Film
Authors: Han Fei , Maloth Thirupathi , Lubineau Gilles , Yaldiz Recep , Tevtia Amit
Published: November 2018

Random networks of silver nano wires have been considered for use in transparent conductive films as an alternative to Indium Tin Oxide (ITO), which is unsuitable for flexible devices. However, the random distribution of nano wires makes such conductive films non-uniform. As electrical conductivity is achieved through a percolation process, understanding the scale-dependency of the macroscopic properties (like electrical conductivity) and the exact efficiency of the network (the proportion of nano wires that participate in electrical conduction) is essential for optimizing the design. In this paper, we propose a computational method for identifying the representative volume element (RVE) of nano wire networks. This defines the minimum pixel size in devices using such transparent electrodes. The RVE is used to compute the macroscopic properties of films and to quantify the electrically conducting efficiency of networks. Then, the sheet resistance and transparency of networks are calculated based on the predicted RVEs, in order to analyze the effects of nano wire networks on the electrical and optical properties of conductive films. The results presented in this paper provide insights that help optimizing random nano wire networks in transparent conductive films for achieving better efficiencies.
Magnetotransport and conductivity mechanisms in Cu2ZnSnxGe1−xS4 single crystals
Authors: Lähderanta Erkki , Hajdeu-Chicarosh Elena , Guc Maxim , Shakhov Mikhail A. , Zakharchuk Ivan , Bodnar Ivan V. , Arushanov Ernest , Lisunov Konstantin G.
Published: November 2018

Resistivity, ρ(T), and magnetoresistance (MR) are investigated in the Cu2ZnSnxGe1−xS4 single crystals, obtained by the chemical vapor transport method, between x = 0–0.70, in the temperature range of T ~ 50–300 K in pulsed magnetic field of B up to 20 T. The Mott variable-range hopping (VRH) conductivity is observed within broad temperature intervals, lying inside that of T ~ 80–180 K for different x. The nearest-neighbor hopping conductivity and the charge transfer, connected to activation of holes into the delocalized states of the acceptor band, are identified above and below the Mott VRH conduction domain, respectively. The microscopic electronic parameters, including width of the acceptor band, the localization radius and the density of the localized states at the Fermi level, as well as the acceptor concentration and the critical concentration of the metal-insulator transition, are obtained with the analysis of the ρ(T) and MR data. All the parameters above exhibit extremums near x = 0.13, which are attributable mainly to the transition from the stannite crystal structure at x = 0 to the kesterite-like structure near x = 0.13. The detailed analysis of the activation energy in the low-temperature interval permitted estimations of contributions from different crystal phases of the border compounds into the alloy structure at different compositions.
The central exons of the human MUC2 and MUC6 mucins are highly repetitive and variable in sequence between individuals
Authors: Svensson Frida , Lang Tiange , Johansson Malin E. V. , Hansson Gunnar C.
Published: November 2018

The DNA sequence of the two human mucin genes MUC2 and MUC6 have not been completely resolved due to the repetitive nature of their central exon coding for Proline, Threonine and Serine rich sequences. The exact nucleotide sequence of these exons has remained unknown for a long time due to limitations in traditional sequencing techniques. These are still very poorly covered in new whole genome sequencing projects with the corresponding protein sequences partly missing. We used a BAC clone containing both these genes and third generation sequencing technology, SMRT sequencing, to obtain the full-length contiguous MUC2 and MUC6 tandem repeat sequences. The new sequences span the entire repeat regions with good coverage revealing their length, variation in repeat sequences and their internal organization. The sequences obtained were used to compare with available sequences from whole genome sequencing projects indicating variation in number of repeats and their internal organization between individuals. The lack of these sequences has limited the association of genetic alterations with disease. The full sequences of these mucins will now allow such studies, which could be of importance for inflammatory bowel diseases for MUC2 and gastric ulcer diseases for MUC6 where deficient mucus protection is assumed to play an important role.
Improved Kerogen Models for Determining Thermal Maturity and Hydrocarbon Potential of Shale
Authors: Agrawal Vikas , Sharma Shikha
Published: November 2018

Kerogen is the insoluble component of organic-rich shales that controls the type and amount of hydrocarbons generated in conventional and unconventional reservoirs. Significant progress has recently been made in developing structural models of kerogen. However, there is still a large gap in understanding the evolution of the molecular components of kerogen with thermal maturation and their hydrocarbon (HC) generative potential. Here, we determine the variations in different molecular fragments of kerogen from a Marcellus Shale maturity series (with VRo ranging from 0.8 to 3) using quantitative 13C MultiCP/MAS NMR and MultiCP NMR/DD (dipolar dephasing). These molecular variations provide insight into the (1) evolution of the molecular structure of kerogen with increasing thermal maturity and, (2) the primary molecular contributors to HC generation. Our results also indicate that old model equations based on structural parameters of kerogen underestimate the thermal maturity and overestimate the HC generation potential of Marcellus Shale samples. This could primarily be due to the fact that the kerogen samples used to reconstruct old models were mostly derived from immature shales (VRo <1) acquired from different basins with varying depositional environments. We utilized the kerogen molecular parameters determined from the Marcellus maturity series samples to develop improved models for determining thermal maturity and HC potential of Marcellus Shale. The models generated in this study could also potentially be applied to other shales of similar maturity range and paleo-depositional environments.
Modified VEGF-A mRNA induces sustained multifaceted microvascular response and accelerates diabetic wound healing
Authors: Sun Naidi , Ning Bo , Hansson Kenny M. , Bruce Anthony C. , Seaman Scott A. , Zhang Chenchu , Rikard Michaela , DeRosa Christopher A. , Fraser Cassandra L. , Wågberg Maria , Fritsche-Danielson Regina , Wikström Johannes , Chien Kenneth R. , Lundahl Anna , Hölttä Mikko , Carlsson Leif G. , Peirce Shayn M. , Hu Song
Published: November 2018

Capable of mediating efficient transfection and protein production without eliciting innate immune responses, chemically modified mRNA holds great potential to produce paracrine factors at a physiologically beneficial level, in a spatiotemporally controlled manner, and with low toxicity. Although highly promising in cardiovascular medicine and wound healing, effects of this emerging therapeutic on the microvasculature and its bioactivity in disease settings remain poorly understood. Here, we longitudinally and comprehensively characterize microvascular responses to AZD8601, a modified mRNA encoding vascular endothelial growth factor A (VEGF-A), in vivo. Using multi-parametric photoacoustic microscopy, we show that intradermal injection of AZD8601 formulated in a biocompatible vehicle results in pronounced, sustained and dose-dependent vasodilation, blood flow upregulation, and neovessel formation, in striking contrast to those induced by recombinant human VEGF-A protein, a non-translatable variant of AZD8601, and citrate/saline vehicle. Moreover, we evaluate the bioactivity of AZD8601 in a mouse model of diabetic wound healing in vivo. Using a boron nanoparticle-based tissue oxygen sensor, we show that sequential dosing of AZD8601 improves vascularization and tissue oxygenation of the wound bed, leading to accelerated re-epithelialization during the early phase of diabetic wound healing.
Interplay between nitrogen fertilizer and biological nitrogen fixation in soybean: implications on seed yield and biomass allocation
Authors: Tamagno Santiago , Sadras Victor O. , Haegele Jason W. , Armstrong Paul R. , Ciampitti Ignacio A.
Published: November 2018

Legumes rely on soil mineral nitrogen (N) and biological N fixation (BNF). The interplay between these two sources is biologically interesting and agronomically relevant as the crop can accommodate the cost of BNF by five non-mutually exclusive mechanisms, whereby BNF: reduces shoot growth and seed yield, or maintains shoot growth and seed yield by enhanced photosynthesis, or reduced root:shoot ratio, or maintains shoot growth but reduces seed yield by reducing the fraction of shoot biomass allocated to seed (harvest index), or reducing concentration of oil and protein in seed. We explore the impact of N application on the seasonal dynamics of BNF, and its consequences for seed yield with emphasis on growth and shoot allocation mechanisms. Trials were established in 23 locations across the US Midwest under four N conditions. Fertilizer reduced the peak of BNF up to 16% in applications at the full flowering stage. Seed yield declined 13 kg ha−1per % increase in RAUR6. Harvest index accounted for the decline in seed yield with increasing BNF. This indicates the cost of BNF was met by a relative change in dry matter allocation against the energetically rich seed, and in favor of energetically cheaper vegetative tissue.
Prenatal retinoic acid exposure reveals candidate genes for craniofacial disorders
Authors: Berenguer Marie , Darnaudery Muriel , Claverol Stéphane , Bonneu Marc , Lacombe Didier , Rooryck Caroline
Published: November 2018

Syndromes that display craniofacial anomalies comprise a major class of birth defects. Both genetic and environmental factors, including prenatal retinoic acid (RA) exposure, have been associated with these syndromes. While next generation sequencing has allowed the discovery of new genes implicated in these syndromes, some are still poorly characterized such as Oculo-Auriculo-Vertebral Spectrum (OAVS). Due to the lack of clear diagnosis for patients, developing new strategies to identify novel genes involved in these syndromes is warranted. Thus, our study aimed to explore the link between genetic and environmental factors. Owing to a similar phenotype of OAVS reported after gestational RA exposures in humans and animals, we explored RA targets in a craniofacial developmental context to reveal new candidate genes for these related disorders. Using a proteomics approach, we detected 553 dysregulated proteins in the head region of mouse embryos following their exposure to prenatal RA treatment. This novel proteomic approach implicates changes in proteins that are critical for cell survival/apoptosis and cellular metabolism which could ultimately lead to the observed phenotype. We also identified potential molecular links between three major environmental factors known to contribute to craniofacial defects including maternal diabetes, prenatal hypoxia and RA exposure. Understanding these links could help reveal common key pathogenic mechanisms leading to craniofacial disorders. Using both in vitro and in vivo approaches, this work identified two new RA targets, Gnai3 and Eftud2, proteins known to be involved in craniofacial disorders, highlighting the power of this proteomic approach to uncover new genes whose dysregulation leads to craniofacial defects.
Lactobacillus reuteri HCM2 protects mice against Enterotoxigenic Escherichia coli through modulation of gut microbiota
Authors: Wang Tianwei , Teng Kunling , Liu Gang , Liu Yayong , Zhang Jie , Zhang Xin , Zhang Min , Tao Yong , Zhong Jin
Published: November 2018

Enterotoxigenic Escherichia coli (ETEC) is a leading cause of infectious diarrhea in children and postweaning piglets. ETEC infection results in induced pro-inflammatory responses in intestinal epithelial cells and dysbiosis of intestinal microbiota. Here, a Lactobacillus reuteri strain, HCM2, isolated from a healthy piglet showed a high survival rate in the harsh gastrointestinal tract environment and inhibited the growth of ETEC and its adherence to intestinal epithelial cells. Pre-supplementation with L. reuteri HCM2 for 14 days reduced the ETEC load in the jejunum of ETEC-infected mice and prevented the disruption of intestinal morphology by ETEC. The colonic microbiota of mice with or without HCM2 pre-supplementation were analyzed, and this analysis revealed that HCM2 could prevent dysbiosis caused by ETEC infection by stabilizing the relative abundance of dominant bacteria. These results indicate that L. reuteri HCM2 has the potential to attenuate the effect of ETEC on the colonic microbiota in infected mice.