bluuebunny/crossref_metadata_2025 huggingface dataset:
Sulphur isotopes of alkaline magmas unlock long-term records of crustal recycling on Earth
Authors: Hutchison William , Babiel Rainer J. , Finch Adrian A. , Marks Michael A. W. , Markl Gregor , Boyce Adrian J. , Stüeken Eva E. , Friis Henrik , Borst Anouk M. , Horsburgh Nicola J.
Published: September 2019

Earth’s surface and mantle sulphur reservoirs are connected via subduction, crustal recycling and volcanism. Although oceanic hotspot lavas currently provide the best constraints on the deep sulphur cycle, their restricted age range (<200 Ma) means they cannot reveal temporal variations in crustal recycling over Earth history. Sulphur-rich alkaline magmas offer the solution because they are associated with recycled sources (i.e. metasomatized lithospheric mantle and plumes) and, crucially, are found throughout the geological record. Here, we present a detailed study of sulphur isotope fractionation in a Mesoproterozoic alkaline province in Greenland and demonstrate that an enriched subduction-influenced source (δ34S of +1 to +5‰) can be reconstructed. A global δ34S compilation reveals secular variation in alkaline magma sources which support changes in the composition of the lithospheric mantle and/or Ga timescales for deep crustal recycling. Thus, alkaline magmas represent a powerful yet underutilized repository for interrogating crustal recycling through geological time.
Derailing the aspartate pathway of Mycobacterium tuberculosis to eradicate persistent infection
Authors: Hasenoehrl Erik J. , Rae Sajorda Dannah , Berney-Meyer Linda , Johnson Samantha , Tufariello JoAnn M. , Fuhrer Tobias , Cook Gregory M. , Jacobs William R. , Berney Michael
Published: September 2019

A major constraint for developing new anti-tuberculosis drugs is the limited number of validated targets that allow eradication of persistent infections. Here, we uncover a vulnerable component of Mycobacterium tuberculosis (Mtb) persistence metabolism, the aspartate pathway. Rapid death of threonine and homoserine auxotrophs points to a distinct susceptibility of Mtb to inhibition of this pathway. Combinatorial metabolomic and transcriptomic analysis reveals that inability to produce threonine leads to deregulation of aspartate kinase, causing flux imbalance and lysine and DAP accumulation. Mtb’s adaptive response to this metabolic stress involves a relief valve-like mechanism combining lysine export and catabolism via aminoadipate. We present evidence that inhibition of the aspartate pathway at different branch-point enzymes leads to clearance of chronic infections. Together these findings demonstrate that the aspartate pathway in Mtb relies on a combination of metabolic control mechanisms, is required for persistence, and represents a target space for anti-tuberculosis drug development.
Repurposing DNA-binding agents as H-bonded organic semiconductors
Authors: Zhang Fengjiao , Lemaur Vincent , Choi Wookjin , Kafle Prapti , Seki Shu , Cornil Jérôme , Beljonne David , Diao Ying
Published: September 2019

Organic semiconductors are usually polycyclic aromatic hydrocarbons and their analogs containing heteroatom substitution. Bioinspired materials chemistry of organic electronics promises new charge transport mechanism and specific molecular recognition with biomolecules. We discover organic semiconductors from deoxyribonucleic acid topoisomerase inhibitors, featuring conjugated backbone decorated with hydrogen-bonding moieties distinct from common organic semiconductors. Using ellipticine as a model compound, we find that hydrogen bonds not only guide polymorph assembly, but are also critical to forming efficient charge transport pathways along π−conjugated planes when at a low dihedral angle by shortening the end-to-end distance of adjacent π planes. In the π−π stacking and hydrogen-bonding directions, the intrinsic, short-range hole mobilities reach as high as 6.5 cm2V−1s−1 and 4.2 cm2V−1s−1 measured by microwave conductivity, and the long-range apparent hole mobilities are up to 1.3 × 10–3 cm2V−1s−1 and 0.4 × 10–3 cm2V−1s−1 measured in field-effect transistors. We further demonstrate printed transistor devices and chemical sensors as potential applications.
The RNA-mediated estrogen receptor α interactome of hormone-dependent human breast cancer cell nuclei
Authors: Nassa Giovanni , Giurato Giorgio , Salvati Annamaria , Gigantino Valerio , Pecoraro Giovanni , Lamberti Jessica , Rizzo Francesca , Nyman Tuula A. , Tarallo Roberta , Weisz Alessandro
Published: September 2019

Estrogen Receptor alpha (ERα) is a ligand-inducible transcription factor that mediates estrogen signaling in hormone-responsive cells, where it controls key cellular functions by assembling in gene-regulatory multiprotein complexes. For this reason, interaction proteomics has been shown to represent a useful tool to investigate the molecular mechanisms underlying ERα action in target cells. RNAs have emerged as bridging molecules, involved in both assembly and activity of transcription regulatory protein complexes. By applying Tandem Affinity Purification (TAP) coupled to mass spectrometry (MS) before and after RNase digestion in vitro, we generated a dataset of nuclear ERα molecular partners whose association with the receptor involves RNAs. These data provide a useful resource to elucidate the combined role of nuclear RNAs and the proteins identified here in ERα signaling to the genome in breast cancer and other cell types.
Design, synthesis, and discovery of novel oxindoles bearing 3-heterocycles as species-specific and combinatorial agents in eradicating Staphylococcus species
Authors: Shin Jonghoon , Magar Krishna Bahadur Somai , Lee Jungwoon , Kim Kwang-sun , Lee Yong Rok
Published: September 2019

A series of new functionalized 3-indolylindolin-2-ones, 3-(1-methylpyrrol-2-yl)indolin-2-ones, and 3-(thiophen-2-yl)indolin-2-ones were synthesized by using novel indium (III)-catalysed reaction of various 3-diazoindolin-2-ones with indoles, 1-methylpyrrole, or thiophene via one-pot procedure. The newly synthesized compounds were characterized and screened for their in vitro antibacterial activity against various Staphylococcus species, including methicillin-resistant Staphylococcus aureus. results revealed that five compounds KS15, KS16, KS17, KS19, and KS20 exhibited potent and specific antibacterial activity against Staphylococcus species albeit inactive against Gram-negative bacteria. Especially, compounds exhibited superior antibacterial potency against Staphylococcus epidermidis compared to the reference drug streptomycin. The most potential compound KS16 also increased the susceptibility of Staphylococcus aureus to ciprofloxacin, gentamicin, kanamycin, and streptomycin. Among them, KS16 was found to be a synergistic compound with gentamicin and kanamycin. Furthermore, the cellular level of autolysin protein was increased from the KS16-treated Staphylococcus aureus cells. Finally, in vitro CCK-8 assays showed that KS16 exhibited no cytotoxicity at the minimum inhibitory concentrations used for killing Staphylococcus species. From all our results, novel oxindole compounds directly have lethal action or boost existing antibiotic power with the reduction of doses and toxicity in the treatment of multidrug-resistant Staphylococcus species.
Levosimendan pretreatment improves survival of septic rats after partial hepatectomy and suppresses iNOS induction in cytokine-stimulated hepatocytes
Authors: Sakaguchi Tatsuma , Hashimoto Yuki , Matsushima Hideyuki , Hishikawa Hidehiko , Nishizawa Mikio , Okumura Tadayoshi , Kaibori Masaki
Published: September 2019

We evaluated the survival effects and biochemical profiles of levosimendan in septic rats after partial hepatectomy and investigated its effects in cultured hepatocytes. Thirty-two rats underwent 70% hepatectomy and were randomised equally into four groups, followed by lipopolysaccharide (LPS) injection (250 µg/kg, i.v.) after 48 h. Levosimendan was given (i.p.) 1 h before LPS injection [group (A) levosimendan 2 mg/kg; (B) 1; (C) 0.5; (D) vehicle]. Survival at 7 days was increased significantly in group A compared with that in group D [A: 63%; B: 38%; C: 13%; D: 0%]. In serum, levosimendan decreased the level of tumour necrosis factor-α, interleukin (IL)-1β, IL-6 and nitric oxide (NO). In remnant livers, levosimendan inhibited inducible nitric oxide synthase (iNOS) gene expression. In primary cultured rat hepatocytes stimulated by IL-1β, levosimendan suppressed NO production by inhibiting iNOS promoter activity and stability of its mRNA.
Cigarette smoke preparations, not moist snuff, impair expression of genes involved in immune signaling and cytolytic functions
Authors: Liu Gang , Arimilli Subhashini , Savage Evan , Prasad G. L.
Published: September 2019

Cigarette smoke-induced chronic inflammation is associated with compromised immune responses. To understand how tobacco products impact immune responses, we assessed transcriptomic profiles in peripheral blood mononuclear cells (PBMCs) pretreated with Whole Smoke-Conditioned Medium (WS-CM) or Smokeless Tobacco Extracts (STE), and stimulated with lipopolysaccharide, phorbol myristate and ionomycin (agonists). Gene expression profiles from PBMCs treated with low equi-nicotine units (0.3 μg/mL) of WS-CM and one high dose of STE (100 μg/mL) were similar to those from untreated controls. Cells treated with medium and high doses of WS-CM (1.0 and 3.0 μg/mL) exhibited significantly different gene expression profiles compared to the low WS-CM dose and STE. Pre-treatment with higher doses of WS-CM inhibited the expression of several pro-inflammatory genes (IFNγ, TNFα, and IL-2), while CSF1-R and IL17RA were upregulated. Pre-treatment with high doses of WS-CM abolished agonist-stimulated secretion of IFNγ, TNF and IL-2 proteins. Pathway analyses revealed that higher doses of WS-CM inhibited NF-ĸB signaling, immune cell differentiation and inflammatory responses, and increased apoptotic pathways. Our results show that pre-treatment of PBMCs with higher doses of WS-CM inhibits immune activation and effector cytokine expression and secretion, resulting in a reduced immune response, whereas STE exerted minimal effects.
Differential Impacts of Yeasts on Feeding Behavior and Development in Larval Drosophila suzukii (Diptera:Drosophilidae)
Authors: Lewis Margaret T. , Hamby Kelly A.
Published: September 2019

Larval Drosophila encounter and feed on a diverse microbial community within fruit. In particular, free-living yeast microbes provide a source of dietary protein critical for development. However, successional changes to the fruit microbial community may alter host quality through impacts on relative protein content or yeast community composition. For many species of Drosophila, fitness benefits from yeast feeding vary between individual yeast species, indicating differences in yeast nutritional quality. To better understand these associations, we evaluated how five species of yeast impacted feeding preference and development in larval Drosophila suzukii. Larvae exhibited a strong attraction to the yeast Hanseniaspora uvarum in pairwise yeast feeding assays. However, larvae also performed most poorly on diets containing H. uvarum, a mismatch in preference and performance that suggests differences in yeast nutritional quality are not the primary factor driving larval feeding behavior. Together, these results demonstrate that yeast plays a critical role in D. suzukii’s ecology and that larvae may have developed specific yeast associations. Further inquiry, including systematic comparisons of Drosophila larval yeast associations more broadly, will be necessary to understand patterns of microbial resource use in larvae of D. suzukii and other frugivorous species.
Anti-tumor activity of BET inhibitors in androgen-receptor-expressing triple-negative breast cancer
Authors: Park In Hae , Yang Han Na , Jeon Su Yeon , Hwang Jung-Ah , Kim Min Kyeong , Kong Sun-Young , Shim Sung Hoon , Lee Keun Seok
Published: September 2019

Triple-negative breast cancer (TNBC) is a heterogeneous disease comprising several subtypes. Androgen-receptor (AR) signaling has been targeted by several investigational agents in luminal AR subtype TNBCs. Bromodomain (BRD) and extra-terminal motif (BET) protein inhibitors have been shown to attenuate AR signaling in metastatic castration-resistant prostate cancer and to overcome enzalutamide resistance. We demonstrated potent anti-tumor effects of the BET inhibitor JQ1 against AR-positive TNBC cell lines using cell viability and cell cycle analysis. To reveal the mechanisms of JQ1 effects, multiplex gene expression analysis and immunoblotting assays were used. We examined in vivo effects of JQ1 in a xenograft model of AR expressing TNBC. JQ1 exhibited its anti-proliferative activity by inducing apoptosis and cell cycle arrest. JQ1 activity was not mediated by MYC downregulation. Instead, JQ1 blocked the interactions among the ATPase-family AAA-domain-containing 2 protein (ATAD2), BRD2, BRD4, and AR; effectively suppressing the expression of AR associated targets. In addition, JQ1 showed significant anti-tumor activity in vivo in TNBC xenograft mouse models as a monotherapy and in combination with anti-AR therapy. Taken together, our results showed that the BET inhibitor JQ1 is a promising therapeutic agent for the treatment of AR-positive TNBC.
Largest Cretaceous lizard track assemblage, new morphotypes and longest trackways comprise diverse components of an exceptional Korean Konservat-Lagerstätten ichnofauna
Authors: Kim Kyung Soo , Lim Jong Deock , Lockley Martin G. , Hee Kim Dong , Piñuela Laura , Yoo Jae Sang
Published: September 2019

A newly discovered assemblage of lizard tracks from the Lower Cretaceous Jinju Formation (Sindong Group, Gyeongsang Basin) Korea is the largest yet reported from the Cretaceous. It consists of at least 95 tracks comprising five trackways, including a meter-long trackway (T1) with 50 footprints assigned to the new ichnotaxon Neosauroides innovatus ichnosp. nov. Two other trackways (T2 and T3) are designated N. innovatus paratypes characterized by strong heteropody, relatively wide trackways and small narrow manus tracks. These morphological characteristics distinguish Neosauroides innovatus from the previously reported lizard trackways Sauripes hadongensis from the Hasandong Formation and Neosauroides koreaensis from the Haman Formation, both also from the Gyeongsang Basin. These three lizard track assemblages from the Korean Cretaceous constitute the entire global lizard track record for this period. The Mesozoic record of lizard tracksites is more localized than the lizard body fossil record. This limited distribution suggests bias in the track record and the fossil record more generally. However, due to deposition of fine-grained substrates, suitable for high definition track registration, the Jinju Formation is increasingly well known as an ichnological window on small tetrapod activity and based on diversity, abundance and high-quality preservation, is regarded as an exceptional Konservat-Lagerstätten.
Spaceflight influences gene expression, photoreceptor integrity, and oxidative stress-related damage in the murine retina
Authors: Overbey Eliah G. , da Silveira Willian Abraham , Stanbouly Seta , Nishiyama Nina C. , Roque-Torres Gina D. , Pecaut Michael J. , Zawieja David Carl , Wang Charles , Willey Jeffrey S. , Delp Michael D. , Hardiman Gary , Mao Xiao Wen
Published: September 2019

Extended spaceflight has been shown to adversely affect astronaut visual acuity. The purpose of this study was to determine whether spaceflight alters gene expression profiles and induces oxidative damage in the retina. Ten week old adult C57BL/6 male mice were flown aboard the ISS for 35 days and returned to Earth alive. Ground control mice were maintained on Earth under identical environmental conditions. Within 38 (+/−4) hours after splashdown, mice ocular tissues were collected for analysis. RNA sequencing detected 600 differentially expressed genes (DEGs) in murine spaceflight retinas, which were enriched for genes related to visual perception, the phototransduction pathway, and numerous retina and photoreceptor phenotype categories. Twelve DEGs were associated with retinitis pigmentosa, characterized by dystrophy of the photoreceptor layer rods and cones. Differentially expressed transcription factors indicated changes in chromatin structure, offering clues to the observed phenotypic changes. Immunofluorescence assays showed degradation of cone photoreceptors and increased retinal oxidative stress. Total retinal, retinal pigment epithelium, and choroid layer thickness were significantly lower after spaceflight. These results indicate that retinal performance may decrease over extended periods of spaceflight and cause visual impairment.
Hypoxia Activates the PTHrP –MEF2C Pathway to Attenuate Hypertrophy in Mesenchymal Stem Cell Derived Cartilage
Authors: Browe David C. , Coleman Cynthia M. , Barry Frank P. , Elliman Stephen J.
Published: September 2019

Articular cartilage lacks an intrinsic repair capacity and due to the ability of mesenchymal stem cells (MSCs) to differentiate into chondrocytes, MSCs have been touted as a cellular source to regenerate damaged cartilage. However, a number of prevailing concerns for such a treatment remain. Generally, administration of MSCs into a cartilage defect results in poor regeneration of the damaged cartilage with the repaired cartilage consisting primarily of fibro-cartilage rather than hyaline cartilage. Methods that improve the chondrogenic potential of transplanted MSCs in vivo may be advantageous. In addition, the proclivity of MSC-derived cartilage to undergo hypertrophic differentiation or form bone in vivo also remains a clinical concern. If MSC-derived cartilage was to undergo hypertrophic differentiation in vivo, this would be deleterious in a clinical setting. This study focuses on establishing a mechanism of action by which hypoxia or low oxygen tension can be used to both enhance chondrogenesis and attenuate hypertrophic differentiation of both MSC and ATDC5 derived chondrocytes. Having elucidated a novel mechanism of action, the subsequent goals of this study were to develop an in vitro culture regime to mimic the beneficial effects of physiological low oxygen tension in a normoxic environment.
Early Life Supraphysiological Levels of Oxygen Exposure Permanently Impairs Hippocampal Mitochondrial Function
Authors: Ramani Manimaran , Miller Kiara , Brown Jamelle , Kumar Ranjit , Kadasamy Jegen , McMahon Lori , Ballinger Scott , Ambalavanan Namasivayam
Published: September 2019

Preterm infants requiring prolonged oxygen therapy often develop cognitive dysfunction in later life. Previously, we reported that 14-week-old young adult mice exposed to hyperoxia as newborns had spatial and learning deficits and hippocampal shrinkage. We hypothesized that the underlying mechanism was the induction of hippocampal mitochondrial dysfunction by neonatal hyperoxia. C57BL/6J mouse pups were exposed to 85% oxygen or room air from P2–P14. Hippocampal proteomic analysis was performed in young adult mice (14 weeks). Mitochondrial bioenergetics were measured in neonatal (P14) and young adult mice. We found that hyperoxia exposure reduced mitochondrial ATP-linked oxygen consumption and increased state 4 respiration linked proton leak in both neonatal and young adult mice while complex I function was decreased at P14 but increased in young adult mice. Proteomic analysis revealed that hyperoxia exposure decreased complex I NDUFB8 and NDUFB11 and complex IV 7B subunits, but increased complex III subunit 9 in young adult mice. In conclusion, neonatal hyperoxia permanently impairs hippocampal mitochondrial function and alters complex I function. These hippocampal mitochondrial changes may account for cognitive deficits seen in children and adolescents born preterm and may potentially be a contributing mechanism in other oxidative stress associated brain disorders.
Fourier transforms for fast and quantitative Laser Speckle Imaging
Authors: Buijs J. , Gucht J. van der , Sprakel J.
Published: September 2019

Laser speckle imaging is a powerful imaging technique that visualizes microscopic motion within turbid materials. At current two methods are widely used to analyze speckle data: one is fast but qualitative, the other quantitative but computationally expensive. We have developed a new processing algorithm based on the fast Fourier transform, which converts raw speckle patterns into maps of microscopic motion and is both fast and quantitative, providing a dynamnic spectrum of the material over a frequency range spanning several decades. In this article we show how to apply this algorithm and how to measure a diffusion coefficient with it. We show that this method is quantitative and several orders of magnitude faster than the existing quantitative method. Finally we harness the potential of this new approach by constructing a portable laser speckle imaging setup that performs quantitative data processing in real-time on a tablet.
A robust method for automatic identification of landmarks on surface models of the pelvis
Authors: Fischer Maximilian C. M. , Krooß Felix , Habor Juliana , Radermacher Klaus
Published: September 2019

The recognition of bony landmarks of the pelvis is a required operation in patient-specific orthopedics, subject-specific biomechanics or morphometrics. A fully automatic detection is preferable to a subjective and time-consuming manual identification. In this paper, a new approach, called the iterative tangential plane (ITP) method, for fully automatic identification of landmarks on surface models of the pelvis is introduced. The method includes the landmarks to construct the two most established anatomical reference frames of the pelvis: the anterior pelvic plane (APP) coordinate system and superior inferior spine plane (SISP) coordinate system. The ITP method proved to be robust against the initial alignment of the pelvis in space. A comparison to a manual identification was performed that showed minor but significant (p < 0.05) median differences below 3 mm for the position of the landmarks and below 1° for the orientation of the APP coordinate system. Whether these differences are acceptable, has to be evaluated for each specific use case. There were no significant differences for the orientation of the SISP coordinate system recommended by the International Society of Biomechanics.
Oceanic mantle reflections in deep seismic profiles offshore Sumatra are faults or fakes
Authors: Sibuet Jean-Claude , He Enyuan , Zhao Minghui , Pang Xinming , Klingelhoefer Frauke
Published: September 2019

In the late 90’s, some faults identified within oceanic crust were demonstrated to be artifacts arising from out-of-plane scattering along linear sediment-buried fault scarps. Symmetrical mantle reflections observed southwest northern Sumatra on seismic reflection profiles have been identified as faults cutting through the upper mantle down to unprecedented depths reaching ~45 km. Seawater being conveyed along sub-vertical re-activated fracture zones (FZs) to the upper mantle, the mantle portions of FZs are serpentinized and act as mirrors for seismic rays. We suggest that the mantle features are not faults but artifacts resulting from out-of-plane reflections on these mirrors. Two perpendicular seismic profiles crossing the same FZ display two dipping features down to 30 km, which cannot be explained as faults from recent tectonic and structural constraints but merely as out-of-plane reflections on this FZ. This result confirms that most of mantle reflections observed southwest northern Sumatra are fakes rather than faults.
CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer
Authors: Kim Min Joo , Sun Hyun Jin , Song Young Shin , Yoo Seong-Keun , Kim Young A , Seo Jeong-Sun , Park Young Joo , Cho Sun Wook
Published: September 2019

Although various chemokines have pro-tumorigenic actions in cancers, the effects of CXCL16 remain controversial. The aim of this study was to investigate the molecular characteristics of CXCL16-expressing papillary thyroid cancers (PTCs). CXCL16 expressions were significantly higher in PTCs than benign or normal thyroid tissues. In the TCGA dataset for PTCs, a higher CXCL16 expression was associated with M2 macrophage- and angiogenesis-related genes and poor prognostic factors including a higher TNM staging and the BRAFV600E mutation. PTCs with a higher expression of 3-gene panel including CXCL16, AHNAK2, and THBS2 showed poor recurrence-free survivals than that of the lower expression group. Next, shCXCL16 was introduced into BHP10-3SCp cells to deplete the endogenous CXCL16, and then, the cells were subcutaneously injected to athymic mice. Tumors from the BHP10-3SCpshCXCL16 exhibited a delayed tumor growth with decreased numbers of ERG+ endothelial cells and F4/80+ macrophages than those from the BHP10-3SCpcontrol. CXCL16-related genes including AHNAK2 and THBS2 were downregulated in the tumors from the BHP10-3SCpshCXCL16 compared with that from the BHP10-3SCpcontrol. In conclusion, a higher CXCL16 expression was associated with macrophage- and angiogenesis-related genes and aggressive phenotypes in PTC. Targeting CXCL16 may be a good therapeutic strategy for advanced thyroid cancer.
CED-4 CARD domain residues can modulate non-apoptotic neuronal regeneration functions independently from apoptosis
Authors: Wang Guoqiang , Sun Lin , Reina Christopher P. , Song Isaac , Gabel Christopher V. , Driscoll Monica
Published: September 2019

A major challenge in regenerative medicine is the repair of injured neurons. Regeneration of laser-cut C. elegans neurons requires early action of core apoptosis activator CED-4/Apaf1 and CED-3/caspase. While testing models for CED-4 as a candidate calcium-sensitive activator of repair, we unexpectedly discovered that amino acid substitutions affecting alpha-helix-6 within the CED-4 caspase recruitment domain (CARD) confer a CED-4 gain-of-function (gf) activity that increases axonal regrowth without disrupting CED-4 apoptosis activity. The in vivo caspase reporter CA-GFP reveals a rapid localized increase in caspase activity upon axotomy, which is absent in ced-4 and ced-3 loss-of-function mutants but present in the ced-4(gf) mutant. The ced-3 loss-of-function mutation can significantly suppress the axonal regrowth of the ced-4(gf) mutant, indicating that CED-4(gf) regeneration depends on CED-3 caspase. Thus, we identified a subdomain within the CED-4 CARD that regulates the dynamic and controlled caspase activity required for efficient regeneration.
Wakeful rest compared to vigilance reduces intrusive but not deliberate memory for traumatic videos
Authors: Hørlyck Lone D. , Bisby James A. , King John A. , Burgess Neil
Published: September 2019

Intrusive memories are prominent features of post-traumatic stress disorder, but the mechanisms supporting their development, and their relationship to deliberate memories, are subject to competing theories. Are they strengthened examples of a unitary memory system, or fragmented representations lacking aspects of healthy memories? Given the importance of post-encoding processing in memory consolidation, we investigated the effects of a brief wakeful rest compared to a vigilance task immediately after the encoding of traumatic material on subsequent intrusive and deliberate memory. Across two experiments, participants watched emotionally negative film clips immediately followed by a brief wakeful rest or a simple vigilance (0-back) task. Brief wakeful rest had distinct effects on memory compared to the 0-back task, reducing intrusive memory frequency but not changing deliberate memory performance. These differential effects suggest that intrusive memory and deliberate memory reflect dissociable systems, arguing against unitary accounts. Our findings highlight the importance of post-encoding processing in the consolidation of traumatic material and the development of intrusive memories and provide a new perspective for interpreting mechanisms of therapeutic intervention.
Platelet P-selectin triggers rapid surface exposure of tissue factor in monocytes
Authors: Ivanov Ivelin I. , Apta Bonita H. R. , Bonna Arkadiusz M. , Harper Matthew T.
Published: September 2019

Tissue factor (TF) plays a central role in haemostasis and thrombosis. Following vascular damage, vessel wall TF initiates the extrinsic coagulation cascade. TF can also be exposed by monocytes. Inflammatory or infectious stimuli trigger synthesis of new TF protein by monocytes over the course of hours. It has also been suggested that monocytes can expose TF within minutes when stimulated by activated platelets. Here, we have confirmed that monocytes rapidly expose TF in whole blood and further demonstrate that platelet P-selectin exposure is necessary and sufficient. Monocyte TF exposure increased within five minutes in response to platelet activation by PAR1-AP, PAR4-AP or CRP-XL. PAR1-AP did not trigger TF exposure on isolated monocytes unless platelets were also present. In whole blood, PAR1-AP-triggered TF exposure required P-selectin and PGSL-1. In isolated monocytes, although soluble recombinant P-selectin had no effect, P-selectin coupled to 2 µm beads triggered TF exposure. Cycloheximide did not affect rapid TF exposure, indicating that de novo protein synthesis was not required. These data show that P-selectin on activated platelets rapidly triggers TF exposure on monocytes. This may represent a mechanism by which platelets and monocytes rapidly contribute to intravascular coagulation.
Regulation of VEGFR2 trafficking and signaling by Rab GTPase-activating proteins
Authors: Xie Ye , Mansouri Maysam , Rizk Aurélien , Berger Philipp
Published: September 2019

Vascular endothelial growth factor receptor-2 (VEGFR2) and its ligands (VEGFs) are crucial players in vasculogenesis and angiogenesis. General blocking of this signaling system with antibodies or small molecule inhibitors is an established strategy to treat cancer and age-related macular degeneration. Nevertheless, the activated receptor can signal to discrete downstream signaling pathways and the equilibrium between these pathways is modulated by coreceptors and distinct isoforms of VEGF. Here we investigated the influence of Rab GTPase activating proteins (RabGAPs) on VEGFR2 signaling, tube formation, and migration of endothelial cells. We demonstrate that members of the TBC1D10 subfamily of RabGAPs have opposite effects. Whereas TBC1D10A leads to increased Erk1/2 signaling, TBC1D10B lowered Erk1/2 and p38 signaling and reduced tube formation in vitro. TBC1D10A is a RabGAP acting on RAB13 that was shown before to play a role in angiogenesis and we could indeed show colocalization of these two proteins with VEGFR2 in activated cells. In addition, we observed that cells expressing TBC1D10B show lower expression of VEGFR2 and NRP1 on filopodia of activated cells. Taken together, our systematic analysis of influence of RabGAPs on VEGFR2 signaling identifies the TBC1D10 subfamily members as modulators of angiogenesis.
Adipocytes promote ovarian cancer chemoresistance
Authors: Yang Jiang , Zaman Munir M. , Vlasakov Iliyan , Roy Roopali , Huang Lan , Martin Camilia R. , Freedman Steven D. , Serhan Charles N. , Moses Marsha A.
Published: September 2019

Ovarian cancer (OvCa), while accounting for only 3% of all women’s cancer, is the fifth leading cause of cancer death among women. One of the most significant obstacles to successful OvCa treatment is chemoresistance. The current lack of understanding of the driving mechanisms underlying chemoresistance hinders the development of effective therapeutics against this obstacle. Adipocytes are key components of the OvCa microenvironment and have been shown to be involved in OvCa cell proliferation, however, little is known about their impact on OvCa chemoresistance. In the current study, we found that adipocytes, of both subcutaneous and visceral origin, secrete factors that enhance the resistance of OvCa cells against chemotherapeutic drugs by activating the Akt pathway. Importantly, we have demonstrated that secreted lipids mediate adipocyte-induced chemoresistance. Through a comprehensive lipidomic analysis, we have identified this chemo-protective lipid mediator as arachidonic acid (AA). AA acts on OvCa cells directly, not through its downstream derivatives such as prostaglandins, to activate Akt and inhibit cisplatin-induced apoptosis. Taken together, our study has identified adipocytes and their secreted AA as important mediators of OvCa chemoresistance. Strategies that block the production of AA from adipocytes or block its anti-apoptotic function may potentially inhibit chemoresistance in OvCa patients.
Realization of efficient quantum gates with a superconducting qubit-qutrit circuit
Authors: Bækkegaard T. , Kristensen L. B. , Loft N. J. S. , Andersen C. K. , Petrosyan D. , Zinner N. T.
Published: September 2019

Building a quantum computer is a daunting challenge since it requires good control but also good isolation from the environment to minimize decoherence. It is therefore important to realize quantum gates efficiently, using as few operations as possible, to reduce the amount of required control and operation time and thus improve the quantum state coherence. Here we propose a superconducting circuit for implementing a tunable system consisting of a qutrit coupled to two qubits. This system can efficiently accomplish various quantum information tasks, including generation of entanglement of the two qubits and conditional three-qubit quantum gates, such as the Toffoli and Fredkin gates. Furthermore, the system realizes a conditional geometric gate which may be used for holonomic (non-adiabatic) quantum computing. The efficiency, robustness and universality of the presented circuit makes it a promising candidate to serve as a building block for larger networks capable of performing involved quantum computational tasks.
Comprehensive proteomic profiling of plasma-derived Extracellular Vesicles from dementia with Lewy Bodies patients
Authors: Gámez-Valero Ana , Campdelacreu Jaume , Reñé Ramón , Beyer Katrin , Borràs Francesc E.
Published: September 2019

Proteins and nucleic acids contained in extracellular vesicles (EVs) are considered a feasible source of putative biomarkers for physiological and pathological conditions. Within the nervous system, not only neurons but also other brain cells are able to produce EVs, which have been involved in their physiological processes and also in the development and course of several neurodegenerative diseases. Among these, dementia with Lewy bodies (DLB) is the second cause of dementia worldwide, though most cases are missed or misdiagnosed as Alzheimer’s disease (AD) due to the important clinical and pathological overlap between both diseases. In an attempt to find reliable biomarkers for DLB diagnosis, our group characterized the proteome of plasma-derived EVs from DLB patients compared to aged-matched healthy controls (HCs) using two different proteomic LC-MS/MS approaches. Remarkably, we found that gelsolin and butyrylcholinesterase were differentially identified between DLB and HCs. Further validation of these results using conventional ELISA techniques, and including an additional group of AD patients, pointed to decreased levels of gelsolin in plasma-EVs from DLB compared to HCs and to AD samples. Thus, gelsolin may be considered a possible biomarker for the differentiation between DLB and AD.
The reduction of miR146b-5p in monocytes and T cells could contribute to the immunopathogenesis of hepatitis C virus infection
Authors: Kondo Yasuteru , Kogure Takayuki , Ninomiya Masashi , Fukuda Ryo , Monma Norikazu , Ikeo Kazuho , Tanaka Yasuhito
Published: September 2019

It has been reported that various kinds of miRNAs could affect the pathogenesis of hepatitis C virus infection. Recently, our group reported that deep-sequencing analysis was useful to detect disease-specific miRNAs. The aim of this study is to identify the HCV-specific miRNAs that could contribute to the immunopathogenesis of HCV by using clinical samples and in vitro analysis. Five miRNAs (hsa-miR181a-2-3p, hsa-miR-374a-3p, hsa-miR374a-5p, hsa-miR-204-5p and hsa-miR146b-5p) were shown to be significantly downregulated in CH-C by deep sequence analysis. The average ratio (PBMCs miRNAs/serum miRNAs) of hsa-miR146b-5p was highest among all the miRNAs. Moreover, serum hsa-miR146b-5p was significantly down-regulated in CH-C patients in comparison to CH-B patients and healthy subjects. The expression of hsa-miR146b-5p in CD3+ T cells and CD14+ monocytes of CH-C patients was significantly lower than that of the other groups. The hsa-miR146b-5p expression in CD14+ monocytes of SVR patients treated with Peg-IFN/RBV was significantly higher than in those of non-SVR patients treated with Peg IFN/RBV. However, the hsa-miR146b-5p expression in CD14+ monocytes of SVR patients treated with DCV and ASV was comparable to that in monocytes of non-SVR patients treated with DCV and ASV. Moreover, the expression levels of hsa-miR146b-5p in CD14+ monocytes were significantly increased after achieving SVR and 1(OH)Vitamin D3 treatment. Further, the expression of HCV-Core could suppress miR146b-5p expression in immune cells and affect the expression of various kinds of cytokines by affecting the NF-κB signaling. In conclusion, the reduction of miR146b-5p in monocytes and T cells could contribute to the immunopathogenesis of hepatitis C virus infection.
Study of vertebral fracture and Scanographic Bone Attenuation Coefficient in rheumatoid arthritis and ankylosing spondylitis vs. controls
Authors: Fauny Marine , Albuisson Eliane , Bauer Elodie , Perrier-Cornet Julia , Chary-Valckenaere Isabelle , Loeuille Damien
Published: September 2019

The objective of this study is to identify the prevalence of vertebral fractures (VFs) and to measure the scanographic bone attenuation coefficient of the first lumbar vertebra (SBAC-L1) based CT-scan, a biomarker of bone fragility in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) and in a control group. This monocentric and retrospective study included patients with RA and AS, based on ACR/EULAR or New-York criteria, respectively. A control group was constituted. All of the patients received a CT-scan. VFs were determined via CT-scans according to the Genant classification, and the SBAC-L1 was measured in Hounsfield units (HU). SBAC-L1 ≤145 HU (fracture threshold) defined patients at risk of VFs. 244 patients were included (105 RA, 83 AS, 56 controls). Of the 4.365 vertebrae studied, 66 osteoporotic VFs were found in 36 patients: 18 (17.1%) RA, 13 (15.7%) AS and 5 (8.9%) controls. The mean SBAC-L1 was 142.2 (±48.4) HU for RA, 142.8 (±48.2) for AS, both of which were significantly lower than that of the control group (161.8 (±42.7) HU). Of the 36 patients with VFs and rheumatism, 28% had a T-score ≤−2.5 SD and 71.4% a SBAC-L1 ≤145 HU. A T-score ≤−2.5 SD and a SBAC-L1 ≤145 HU were associated with VF (OR = 3.07 (CI 95%: 1.07; 8.81), and 2.31 (CI 95%: 1.06; 5.06)), respectively. The SBAC-L1 was significantly lower in the RA and AS groups than in the control group. Furthermore, SBAC-L1 ≤145 HU was associated with a higher risk of VFs, with an odds ratio similar to that of a DXA.
Comparing Remote Sensing Methods for Monitoring Karst Rocky Desertification at Sub-pixel Scales in a Highly Heterogeneous Karst Region
Authors: Qi Xiangkun , Zhang Chunhua , Wang Kelin
Published: September 2019

Rugged karst terrain relief that creates shadows in satellite imagery, combined with high karst landscape heterogeneity stand in the way of fractional cover retrieval on karst rocky desertification (KRD) monitoring. In this study, we explored the feasibility of applying multispectral high spatial resolution Advanced Land Observing Satellite (ALOS) imagery for the fractional cover extraction of rocky outcrops. Dimidiate pixel model (DPM) and spectral mixture analysis (SMA) approaches (including simple endmember spectral mixture analysis and multiple endmember spectral mixture analysis) were selected to explore their feasibility for KRD monitoring through accuracy improvement for fraction estimation. Results showed fractional cover retrievals at the sub-pixel scale is essential in highly heterogeneous karst landscapes. Indeed, mixed pixels accounted for 93.7% of the study area in southwest China. Multiple endmember spectral mixture analysis achieved high overall accuracy (80.5%) in monitoring the percentage of rocky outcrop land cover. Furthermore, the predicted exposed bedrock coverage via spectral mixture analysis were similar in sunlit and shadow areas for the same surface types. This reflected that SMA methods could effectively reduce topographic effects of satellite imagery to improve the accuracy of fractional cover extraction at sub-pixel level in heterogeneous and rugged landscapes.
Interactive Studies on Synthetic Nanopolymer decorated with Edible Biopolymer and its Selective Electrochemical determination of L-Tyrosine
Authors: Dhananjayan Nathiya , Jeyaraj Wilson , Karuppasamy Gurunathan
Published: September 2019

Herein, an edible biopolymer amine Modified Gum Acacia (MGA), successfully encumbered with Electron Beam irradiated Polypyrrole Nanospheres (EB-PPy NSs), was investigated for the effective role in L-Tyrosine (Tyr) biosensing application. The morphology of EB-PPy NSs decorated MGA (EB-PPy/MGA) hybrid nanobiocomposite has been studied by Scanning electron microscopy and its affirmed interactions were characterized by X-ray diffraction, Raman, FT-IR spectroscopy, UV-Visible spectroscopy, Thermo Gravimetric Analysis and Vibrating Sample Magnetometer. The hybrid nanobiocomposite manifested diamagnetic behavior with reduced saturation magnetization (Ms = 1.412 × 10−4 emu/g) to produce more adhesive surface. Amine chains in EB-PPy NSs and hydroxyl groups of MGA contributed to effective immobilization, thus enabling suitable orientation for Tyr determination. The electrochemical analysis illustrated that the proposed nanobiocomposite based sensor exhibited an excellent electrocatalytic activity toward selective determination of Tyr in the linear range of 0.4 to 600 µM with a lower detection limit of 85 nM, low oxidation potential of 0.72 V and good selectivity. Finally, the reliability of the constructed EB-PPy/MGA for Tyr detection was demonstrated in real samples.
Hemoperfusion leads to impairment in hemostasis and coagulation process in patients with acute pesticide intoxication
Authors: Park Samel , Islam Md-Imtiazul , Jeong Ji-Hun , Cho Nam-Jun , Song Ho-yeon , Lee Eun-Young , Gil Hyo-Wook
Published: September 2019

Hemoperfusion (HP) is one of the important treatment modalities in extracorporeal therapy for patients with acute intoxication. Its use has declined during the past 20 years despite its efficacy, because of its side effects, especially an increased risk of bleeding. Mechanisms of hemostasis impairment have not been clearly elucidated and studies demonstrating the mechanism are lacking. It is not clear which step of the hemostatic process is impaired during HP, and whether it leads to an increased risk of bleeding. We performed both in vivo and in vitro studies to elucidate the mechanism of impairment in the hemostatic process. In patients with acute pesticide intoxication who underwent HP, the platelet count decreased rapidly during the first 30 minutes from 242.4 ± 57.7 × 103/μL to 184.8 ± 49.6 × 103/μL, then gradually decreased even lower to 145.4 ± 61.2 × 103/μL over time (p < 0.001). As markers of platelet activation, platelet distribution width increased continuously during HP from 41.98 ± 9.28% to 47.69 ± 11.18% (p < 0.05), however, mean platelet volume did not show significant change. In scanning electron microscopy, activated platelets adhered to modified charcoal were observed, and delayed closure time after HP in PFA-100 test suggested platelet dysfunction occurred during HP. To confirm these conflicting results, changes of glycoprotein expression on the platelet surface were evaluated when platelets were exposed to modified charcoal in vitro. Platelet expression of CD61, fibrinogen receptor, significantly decreased from 95.2 ± 0.9% to 73.9 ± 1.6%, while those expressing CD42b, von Willebrand factor receptor, did not show significant change. However, platelet expression of CD49b, collagen receptor, significantly increased from 24.6 ± 0.7% to 51.9 ± 2.3%. Thrombin-antithrombin complex, a marker for thrombin generation, appeared to decrease, however, it was not statistically significant. Fibrin degradation products and d-dimers, markers for fibrinolysis, increased significantly during HP. Taken together, our data suggests that hemoperfusion leads to impairment of platelet aggregation with incomplete platelet activation, which was associated with reduced thrombin generation, accompanied by increased fibrinolysis.
Lineage specific conservation of cis-regulatory elements in Cytokinin Response Factors
Authors: Powell Rachel V. , Willett Cipher R. , Goertzen Leslie R. , Rashotte Aaron M.
Published: September 2019

Expression patterns of genes are controlled by short regions of DNA in promoter regions known as cis-regulatory elements. How expression patterns change due to alterations in cis-regulatory elements in the context of gene duplication are not well studied in plants. Over 300 promoter sequences from a small, well-conserved family of plant transcription factors known as Cytokinin Response Factors (CRFs) were examined for conserved motifs across several known clades present in Angiosperms. General CRF and lineage specific motifs were identified. Once identified, significantly enriched motifs were then compared to known transcription factor binding sites to elucidate potential functional roles. Additionally, presence of similar motifs shows that levels of conservation exist between different CRFs across land plants, likely occurring through processes of neo- or sub-functionalization. Furthermore, significant patterns of motif conservation are seen within and between CRF clades suggesting cis-regulatory regions have been conserved throughout CRF evolution.
Role of protein conformation and weak interactions on γ-gliadin liquid-liquid phase separation
Authors: Sahli Line , Renard Denis , Solé-Jamault Véronique , Giuliani Alexandre , Boire Adeline
Published: September 2019

Wheat storage proteins, gliadins, were found to form in vitro condensates in 55% ethanol/water mixture by decreasing temperature. The possible role of this liquid-liquid phase separation (LLPS) process on the in vivo gliadins storage is elusive and remains to be explored. Here we use γ-gliadin as a model of wheat proteins to probe gliadins behavior in conditions near physiological conditions. Bioinformatic analyses suggest that γ-gliadin is a hybrid protein with N-terminal domain predicted to be disordered and C-terminal domain predicted to be ordered. Spectroscopic data highlight the disordered nature of γ-gliadin. We developed an in vitro approach consisting to first solubilize γ-gliadin in 55% ethanol (v/v) and to progressively decrease ethanol ratio in favor of increased aqueous solution. Our results show the ability of γ-gliadin to self-assemble into dynamic droplets through LLPS, with saturation concentrations ranging from 25.9 µM ± 0.85 µM (35% ethanol (v/v)) to 3.8 µM ± 0.1 µM (0% ethanol (v/v)). We demonstrate the importance of the predicted ordered C-terminal domain of γ-gliadin in the LLPS by highlighting the protein condensates transition from a liquid to a solid state under reducing conditions. We demonstrate by increasing ionic strength the role displayed by electrostatic interactions in the phase separation. We also show the importance of hydrogen bonds in this process. Finally, we discuss the importance of gliadins condensates in their accumulation and storage in the wheat seed.