bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic CD138 surface expression regulates switch between myeloma growth and dissemination
Authors: Akhmetzyanova Ilseyar , McCarron Mark J. , Parekh Samir , Chesi Marta , Bergsagel P. Leif , Fooksman David R. 
Published: August 2019

Abstract
The canonical plasma cell marker CD138 (syndecan-1) is highly expressed on the myeloma cell surface, but its functional role in vivo is unclear, as well as the ontogeny of CD138-high and CD138-negative (neg) myeloma cells. In this study we used an in vivo murine Vk*MYC myeloma model where CD138 is heterogeneously expressed depending on tumor size. We find that in comparison to CD138-neg myeloma cells, the CD138-high subset of myeloma cells is highly proliferative, less apoptotic, and enhanced IL-6R signaling, which is known to promote survival. In addition CD138-high myeloma engrafts better than its CD138-neg counterpart. In contrast, CD138-neg cells are more motile both in vitro and in vivo, and more readily disseminate and spread to other bones in vivo than CD138-high subset. Neutralizing CD138 rapidly triggers migration of myeloma cells in vivo and leads to intravasation, which results in increased dissemination to other bones. Both murine and human myeloma cells can rapidly recycle CD138 surface expression through endocytic trafficking, in response to serum levels. Blocking CD138 enhances myeloma sensitivity to bortezomib chemotherapy and significantly reduces tumor size compared to bortezomib treatment alone. Thus, our data show that CD138 surface expression dynamically regulates a switch between growth vs. dissemination for myeloma, in response to nutrient conditions.
Crystal structure and substrate-induced activation of ADAMTS13
Authors: Petri Anastasis , Kim Hyo Jung , Xu Yaoxian , de Groot Rens , Li Chan , Vandenbulcke Aline , Vanhoorelbeke Karen , Emsley Jonas , Crawley James T. B. 
Published: August 2019

AbstractPlatelet recruitment to sites of blood vessel damage is highly dependent upon von Willebrand factor (VWF). VWF platelet-tethering function is proteolytically regulated by the metalloprotease ADAMTS13. Proteolysis depends upon shear-induced conformational changes in VWF that reveal the A2 domain cleavage site. Multiple ADAMTS13 exosite interactions are involved in recognition of the unfolded A2 domain. Here we report through kinetic analyses that, in binding VWF, the ADAMTS13 cysteine-rich and spacer domain exosites bring enzyme and substrate into proximity. Thereafter, binding of the ADAMTS13 disintegrin-like domain exosite to VWF allosterically activates the adjacent metalloprotease domain to facilitate proteolysis. The crystal structure of the ADAMTS13 metalloprotease to spacer domains reveals that the metalloprotease domain exhibits a latent conformation in which the active-site cleft is occluded supporting the requirement for an allosteric change to enable accommodation of the substrate. Our data demonstrate that VWF functions as both the activating cofactor and substrate for ADAMTS13.
Sp1-regulated expression of p11 contributes to motor neuron degeneration by membrane insertion of TASK1
Authors: García-Morales Victoria , Rodríguez-Bey Guillermo , Gómez-Pérez Laura , Domínguez-Vías Germán , González-Forero David , Portillo Federico , Campos-Caro Antonio , Gento-Caro Ángela , Issaoui Noura , Soler Rosa M. , Garcera Ana , Moreno-López Bernardo 
Published: August 2019

AbstractDisruption in membrane excitability contributes to malfunction and differential vulnerability of specific neuronal subpopulations in a number of neurological diseases. The adaptor protein p11, and background potassium channel TASK1, have overlapping distributions in the CNS. Here, we report that the transcription factor Sp1 controls p11 expression, which impacts on excitability by hampering functional expression of TASK1. In the SOD1-G93A mouse model of ALS, Sp1-p11-TASK1 dysregulation contributes to increased excitability and vulnerability of motor neurons. Interference with either Sp1 or p11 is neuroprotective, delaying neuron loss and prolonging lifespan in this model. Nitrosative stress, a potential factor in human neurodegeneration, stimulated Sp1 expression and human p11 promoter activity, at least in part, through a Sp1-binding site. Disruption of Sp1 or p11 also has neuroprotective effects in a traumatic model of motor neuron degeneration. Together our work suggests the Sp1-p11-TASK1 pathway is a potential target for treatment of degeneration of motor neurons.
Nucleosome and ubiquitin position Set2 to methylate H3K36
Authors: Bilokapic Silvija , Halic Mario 
Published: August 2019

AbstractHistone H3 lysine 36 methylation (H3K36me) is a conserved histone modification deposited by the Set2 methyltransferases. Recent findings show that over-expression or mutation of Set2 enzymes promotes cancer progression, however, mechanisms of H3K36me are poorly understood. Set2 enzymes show spurious activity on histones and histone tails, and it is unknown how they obtain specificity to methylate H3K36 on the nucleosome. In this study, we present 3.8 Å cryo-EM structure of Set2 bound to the mimic of H2B ubiquitinated nucleosome. Our structure shows that Set2 makes extensive interactions with the H3 αN, the H3 tail, the H2A C-terminal tail and stabilizes DNA in the unwrapped conformation, which positions Set2 to specifically methylate H3K36. Moreover, we show that ubiquitin contributes to Set2 positioning on the nucleosome and stimulates the methyltransferase activity. Notably, our structure uncovers interfaces that can be targeted by small molecules for development of future cancer therapies.
B1 oligomerization regulates PML nuclear body biogenesis and leukemogenesis
Authors: Li Yuwen , Ma Xiaodan , Chen Zhiming , Wu Haiyan , Wang Pengran , Wu Wenyu , Cheng Nuo , Zeng Longhui , Zhang Hao , Cai Xun , Chen Sai-Juan , Chen Zhu , Meng Guoyu 
Published: August 2019

AbstractProMyelocyticLeukemia (PML) protein can polymerize into a mega-Dalton nuclear assembly of 0.1–2 μm in diameter. The mechanism of PML nuclear body biogenesis remains elusive. Here, PMLRBCC is successfully purified. The gel filtration and ultracentrifugation analysis suggest a previously unrecognized sequential oligomerization mechanism via PML monomer, dimer, tetramer and N-mer. Consistently, PML B1-box structure (2.0 Å) and SAXS characterization reveal an unexpected networking by W157-, F158- and SD1-interfaces. Structure-based perturbations in these B1 interfaces not only impair oligomerization in vitro but also abolish PML sumoylation and nuclear body biogenesis in HeLaPml-/- cell. More importantly, as demonstrated by in vivo study using transgenic mice, PML-RARα (PR) F158E precludes leukemogenesis. In addition, single cell RNA sequencing analysis shows that B1 oligomerization is an important regulator in PML-RARα-driven transactivation. Altogether, these results not only define a previously unrecognized B1-box oligomerization in PML, but also highlight oligomerization as an important factor in carcinogenesis.
Aeolian transport of viable microbial life across the Atacama Desert, Chile: Implications for Mars
Authors: Azua-Bustos Armando , González-Silva Carlos , Fernández-Martínez Miguel Ángel , Arenas-Fajardo Cristián , Fonseca Ricardo , Martín-Torres F. Javier , Fernández-Sampedro Maite , Fairén Alberto G. , Zorzano María-Paz 
Published: August 2019

AbstractHere we inspect whether microbial life may disperse using dust transported by wind in the Atacama Desert in northern Chile, a well-known Mars analog model. By setting a simple experiment across the hyperarid core of the Atacama we found that a number of viable bacteria and fungi are in fact able to traverse the driest and most UV irradiated desert on Earth unscathed using wind-transported dust, particularly in the later afternoon hours. This finding suggests that microbial life on Mars, extant or past, may have similarly benefited from aeolian transport to move across the planet and find suitable habitats to thrive and evolve.
A Ca2+/CaM-regulated transcriptional switch modulates stomatal development in response to water deficit
Authors: Yoo Chan Yul , Mano Noel , Finkler Aliza , Weng Hua , Day Irene S. , Reddy Anireddy S. N. , Poovaiah B. W. , Fromm Hillel , Hasegawa Paul M. , Mickelbart Michael V. 
Published: August 2019

AbstractCalcium (Ca2+) signals are decoded by the Ca2+-sensor protein calmodulin (CaM) and are transduced to Ca2+/CaM-binding transcription factors to directly regulate gene expression necessary for acclimation responses in plants. The molecular mechanisms of Ca2+/CaM signal transduction processes and their functional significance remains enigmatic. Here we report a novel Ca2+/CaM signal transduction mechanism that allosterically regulates DNA-binding activity of GT2-LIKE 1 (GTL1), a transrepressor of STOMATAL DENSITY AND DISTRIBUTION 1 (SDD1), to repress stomatal development in response to water stress. We demonstrated that Ca2+/CaM interaction with the 2nd helix of the GTL1 N-terminal trihelix DNA-binding domain (GTL1N) destabilizes a hydrophobic core of GTL1N and allosterically inhibits 3rd helix docking to the SDD1 promoter, leading to osmotic stress-induced Ca2+/CaM-dependent activation (de-repression) of SDD1 expression. This resulted in GTL1-dependent repression of stomatal development in response to water-deficit stress. Together, our results demonstrate that a Ca2+/CaM-regulated transcriptional switch on a trihelix transrepressor directly transduces osmotic stress to repress stomatal development to improve plant water-use efficiency as an acclimation response.
The ESA Swarm mission to help ionospheric modeling: a new NeQuick topside formulation for mid-latitude regions
Authors: Pezzopane M. , Pignalberi A. 
Published: August 2019

AbstractThe ionospheric topside representation made by the NeQuick model is improved by correcting the H0 parameter used by the model to calculate the topside scale height. The task is accomplished by fitting the NeQuick topside analytical function through two anchor points: the F2-layer absolute electron density maximum; the electron density value as measured by Swarm satellites from December 2013 to September 2018. Specifically, two-dimensional grids of H0 as a function of foF2 and hmF2 are obtained, one by employing data from Swarm A and Swarm C, both flying at about 460 km of altitude, and the other one by employing data from Swarm B, flying at about 520 km of altitude. These two grids are used to calculate corrected values of H0, which allows a more reliable description of the topside region. The new NeQuick formulation is statistically validated by comparing corresponding modeled vertical total electron content values to those derived from COSMIC/FORMOSAT-3 measured Radio Occultation profiles, and those measured by Swarm satellites. The results show that the proposed formulation significantly improves the topside description made by the NeQuick model at mid latitudes, for both high and low solar activities. The International Reference Ionosphere model might benefit of its inclusion.
Crystal structures of cholera toxin in complex with fucosylated receptors point to importance of secondary binding site
Authors: Heim Joel B. , Hodnik Vesna , Heggelund Julie E. , Anderluh Gregor , Krengel Ute 
Published: August 2019

AbstractCholera is a life-threatening diarrhoeal disease caused by the human pathogen Vibrio cholerae. Infection occurs after ingestion of the bacteria, which colonize the human small intestine and secrete their major virulence factor – the cholera toxin (CT). The GM1 ganglioside is considered the primary receptor of the CT, but recent studies suggest that also fucosylated receptors such as histo-blood group antigens are important for cellular uptake and toxicity. Recently, a special focus has been on the histo-blood group antigen Lewisx (Lex), however, where and how the CT binds to Lex remains unclear. Here we report the high-resolution crystal structure (1.5 Å) of the receptor-binding B-subunits of the CT bound to the Lex trisaccharide, and complementary quantitative binding data for CT holotoxins. Lex, and also l-fucose alone, bind to the secondary binding site of the toxin, distinct from the GM1 binding site. In contrast, fucosyl-GM1 mainly binds to the primary binding site due to high-affinity interactions of its GM1 core. Lex is the first histo-blood group antigen of non-secretor phenotype structurally investigated in complex with CT. Together with the quantitative binding data, this allows unique insight into why individuals with non-secretor phenotype are more prone to severe cholera than so-called ‘secretors’.
Living bridges using aerial roots of ficus elastica – an interdisciplinary perspective
Authors: Ludwig Ferdinand , Middleton Wilfrid , Gallenmüller Friederike , Rogers Patrick , Speck Thomas 
Published: August 2019

AbstractHere we report on a pilot study of the Living Root Bridges (LRBs) in the Indian State Meghalaya, which are grown with aerial roots ofFicus elastica, a facultative hemiepiphyte developing abundant aerial roots. Locals use these aerial roots to build living bridges, which strengthen themselves over time due to adaptive secondary growth and their capacity to form a mechanically stable structure via inosculations. An extensive inventory of LRBs in Meghalaya including data of location, altitude, approximate age and bridge length was performed in field studies. Root morphology was characterised by measurements of cross-sectional area and shape-related parameters and analysed in relation to the orientation of the roots. LRBs are found to occur mainly in the mountainous limestone rainforests whereF. elasticamay be native or traditionally cultivated. They cover an altitude range of 57–1211 m a.m.s.l. and display a length of 2 to 52.7 m. Some bridges are several hundreds of years old. Horizontally and vertically trained roots differ significantly in shape and cross-sectional area when approximately even-aged roots are compared. The results are discussed from an interdisciplinary perspective, considering the adaptive traits in the natural life cycle ofF. elasticaand possible applications in living architecture (Baubotanik).
Linkage of CD8+ T cell exhaustion with high-fat diet-induced tumourigenesis
Authors: Kado Tomonobu , Nawaz Allah , Takikawa Akiko , Usui Isao , Tobe Kazuyuki 
Published: August 2019

AbstractObesity increases the risk of cancer. Increased levels of hormones (such as oestrogen, insulin, insulin-like growth factor, and leptin), free fatty acid-induced production of reactive oxygen species, an altered intestinal microbiome and chronic inflammation are known to be associated with an increased cancer risk in obese subjects. However, the mechanism underlying the connection between obesity and cancer development remains elusive. Here, we show that a high-fat diet (HFD) promotes tumour initiation/progression and induces a phenotypic switch from PD-1− CD8+non-exhausted T cells to PD-1+ CD8+exhausted T cells in a murine breast cancer model. While PD-1− CD8+non-exhausted T cells predominated in the mammary glands of normal diet (ND)-fed mice, PD-1+ CD8+exhausted T cells accumulated in the developing tumours of HFD-fed mice. Gene expression profiles indicated that PD-1+ CD8+ T cells expressed higher levels of the tumour-trophic gene Opn and lower levels of the cytotoxic genes Ifng and Gzmb than did PD-1− CD8+ T cells. Our study provides a possible mechanistic linkage between obesity and cancer.
A biomimetic 3D model of hypoxia-driven cancer progression
Authors: Liverani Chiara , De Vita Alessandro , Minardi Silvia , Kang Yibin , Mercatali Laura , Amadori Dino , Bongiovanni Alberto , La Manna Federico , Ibrahim Toni , Tasciotti Ennio 
Published: August 2019

AbstractThe fate of tumors depends both on the cancer cells’ intrinsic characteristics and on the environmental conditions where the tumors reside and grow. Engineered in vitro models have led to significant advances in cancer research, allowing the investigation of cells in physiological environments and the study of disease mechanisms and processes with enhanced relevance. Here we present a biomimetic cancer model based on a collagen matrix synthesized through a biologically inspired process. We compared in this environment the responses of two breast tumor lineages characterized by different molecular patterns and opposite clinical behaviors: MCF-7 that belong to the luminal A subtype connected to an indolent course, and basal-like MDA-MB-231 connected to high-grade and aggressive disease. Cancer cells in the biomimetic matrix recreate a hypoxic environment that affects their growth dynamics and phenotypic features. Hypoxia induces apoptosis and the selection of aggressive cells that acquire expression signatures associated with glycolysis, angiogenesis, cell-matrix interaction, epithelial to mesenchymal transition and metastatic ability. In response to hypoxia MDA-MB-231 migrate on the collagen fibrils and undergo cellular senescence, while MCF-7 do not exhibit these behaviors. Our biomimetic model mimics the evolution of tumors with different grade of aggressiveness fostered by a hypoxic niche and provides a relevant technology to dissect the events involved in cancer progression.
BK channels regulate extracellular Tat-mediated HIV-1 LTR transactivation
Authors: Khan Nabab , Lakpa Koffi L. , Halcrow Peter W. , Afghah Zahra , Miller Nicole M. , Geiger Jonathan D. , Chen Xuesong 
Published: August 2019

AbstractHIV-1 Tat is essential for HIV-1 replication and plays an important role in latent HIV-1 infection, HIV-1 associated neurological complication, and other HIV-1 comorbidities. Secreted from HIV-1 infected or transfected cells, Tat can be up-taken into cells by receptor-mediated endocytosis and internalized into endolysosomes. To reach nucleus where it can facilitate HIV-1 viral replication, exogenous Tat has to escape the degradation by endolysosomes. Because of findings that endolysosome de-acidification with, for example, the weak-base anti-malarial drug chloroquine prevents exogenous Tat degradation and enhances the amount of Tat available to activate HIV-1 LTR, we hypothesize that acidifying endolysosomes may enhance Tat degradation in endolysosomes and restrict LTR transactivation. Here, we determined the involvement of endolysosome-resident transient receptor potential mucolipin 1 channel (TRPML1) and the big conductance Ca2+-activated potassium (BK) channel in regulating endolysosome pH, as well as Tat-mediated HIV-1 LTR transactivation in U87MG cells stably integrated with HIV-1 LTR luciferase reporter. Activating TRPML1 channels with ML-SA1 acidified endolysosomes and restricted Tat-mediated HIV-1 LTR transactivation. These effects of ML-SA1 appeared to be mediated through activation of BK channels, because the effects of ML-SA1 on Tat-mediated HIV-1 LTR transactivation were blocked using pharmacological inhibitors or shRNA knock-down of BK channels. On the other hand, activating TRPML1 and BK channels enhanced cellular degradation of exogenous Tat. These results suggest that acidifying endolysosomes by activating TRPML1 or BK channels may provide therapeutic benefit against latent HIV-1 infection, HIV-1 associated neurocognitive disorders, and other HIV-1 comorbidities.
Vocabulary Growth From 18 to 24 Months of Age in Children With and Without Repaired Cleft Palate
Authors: Eshghi Marziye , Adatorwovor Reuben , Preisser John S. , Crais Elizabeth R. , Zajac David J. 
Published: August 2019

PurposeThis study investigated vocabulary growth from 18 to 24 months of age in young children with repaired cleft palate (CP), children with otitis media, and typically developing (TD) children. In addition, the contributions of factors such as hearing level, middle ear status, size of consonant inventory, maternal education level, and gender to the development of expressive vocabulary were explored.MethodVocabulary size of 40 children with repaired CP, 29 children with otitis media, and 25 TD children was measured using the parent report on MacArthur–Bates Communicative Development Inventories: Words and Sentences (Fenson et al., 2007) at 18 and 24 months of age. All participants underwent sound field audiometry at 12 months of age and tympanometry at 18 months of age. A multiple linear regression with and without covariates was used to model vocabulary growth from 18 to 24 months of age across the 3 groups.ResultsChildren with CP produced a significantly smaller number of words at 24 months of age and showed significantly slower rate of vocabulary growth from 18 to 24 months of age when compared to TD children (p< .05). Although middle ear status was found to predict vocabulary growth from 18 to 24 months of age across the 3 groups (p< .05), the confidence interval was large, suggesting the effect should be interpreted with caution.ConclusionsChildren with CP showed slower expressive vocabulary growth relative to their age-matched TD peers. Middle ear status may be associated with development of vocabulary skills for some children.
Advanced energy management system based on PV and load forecasting for load smoothing and optimized peak shaving of islanded power systems
Authors: Iliadis Petros , Domalis Stefanos , Nesiadis Athanasios , Atsonios Konstantinos , Chapaloglou Spyridon , Nikolopoulos Nikos , Grammelis Panagiotis 
Published: August 2019

Photovoltaic (PV) systems constitute one of the most promising renewable energy sources, especially for warm and sunny regions like the southern-European islands. In such isolated systems, it is important to utilize clean energy in an optimal way in order to achieve high renewable penetration.
In this operational strategy, a Battery Energy Storage System (BESS) is most often used to transfer an amount of the stored renewable energy to the peak hours. This study presents an integrated energy management methodology for a PV-BESS energy system targeting to make the load curve of the conventional fuel based units as smooth as possible. The presented methodology includes prediction modules for short-term load and PV production forecasting using artificial neural, and a novel, optimized peak shaving algorithm capable of performing each day’s maximum amount of peak shaving and smoothing level simultaneously.
The algorithm is coupled with the overall system model in the Modelica environment, on the basis of which dynamic simulations are performed. The simulation results are compared with the previous version of the algorithm that had been developed in CERTH, and it is revealed that the system’s performance is drastically improved. The overall approach proves that in such islanding systems, a PV-BESS is a suitable option to flatten the load of the conventional fuel based units, achieve steadier operation and increase the share of renewable energy penetration to the grid.