bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Management and Prognosis of Facial and Scalp Angiosarcoma
Authors: Alqumber Nedhal A. , Choi Jong-Woo , Kang Min-kyu 
Published: June 2019

Background
Angiosarcomas are extremely aggressive malignant tumors that arise from vascular endothelial cells. The risk factors, etiology, prognostic factors, and optimal management strategies for angiosarcomas are as yet unknown.

Methods
We retrospectively analyzed data from 15 patients who were treated in Asan Medical Center, Seoul, Republic of Korea, in the past 12 years, to assess the effect of different treatment modalities and reconstructive methods on the locoregional recurrence, metastasis, and overall survival.

Results
A total of 15 patients were identified (median age at diagnosis, 72 years; range, 61–82 years). Median tumor size was 6 cm. Median follow-up was 287 days. The median overall survival was 14.96 months; a total of 13 (87%) patients had died by the end of the study.
The median locoregional recurrence, metastasis, and overall survival were 7.3, 6.5, and 16.7 months, respectively. On univariate analysis, the use of adjuvant therapy after surgery (vs surgery without adjuvant therapy) was associated with delayed median time to detection of recurrence (7.9 months vs 3.1 months, respectively; P = 0.825), delayed median time to metastasis (8.7 months vs 3.1 months, respectively; P = 0.191), and better median overall survival (7.3 months vs 3.1 months, respectively; P = 0.078).
The use of flap versus skin graft as a reconstructive method was associated with delayed median recurrence (8.75 vs 7.32 months, respectively; P = 0.274) and earlier median metastasis (3.75 vs 6.53 months, respectively; P = 0.365), but the same median overall survival of 16.7 months (P value: 0.945) and tumor smaller or bigger than 5 cm show earlier median time to detection of recurrence (4.17-7.32 months; P = 0.41), earlier median time to metastasis (3.75-6.53 months; P = 0.651), but better median overall survival of 18.21 versus 16.7 months, respectively (P = 0.111).

Conclusions
Multimodal treatment that combines surgery with adjuvant therapy is the best management strategy that influences survival positively in patients with angiosarcoma. The study shows that the reconstructive method does not affect the prognosis in these patients. So it is better to choose the simplest suitable resection and reconstructive method with the least complications and to avoid unnecessary procedures.
Tracing Autism Traits in Large Multiplex Families to Identify Endophenotypes of the Broader Autism Phenotype
Authors: Trevis Krysta J , Brown Natasha J , Green Cherie , Lockhart Paul , Hickey Peter , Fanjul-Fernández Miriam , Bromhead Catherine , Desai Tarishi , Vick Tanya , Gillies Greta , Mountford Hayley , Fitzpatrick Elizabeth , Gordon Lavinia , Hewson Peter , Anderson Vicki , Delatycki Martin B , Scheffer Ingrid E , Wilson Sarah J 
Published: June 2019

AbstractFamilies comprising many individuals with Autism Spectrum Disorder (ASD) may carry a dominant predisposing mutation. Our aim was to use rigorous phenotyping of the ‘Broader Autism Phenotype’ (BAP) in large multiplex ASD families to identify endophenotypes of the BAP for future genetic studies. We evaluated ASD/BAP features using standardised tests and a semi-structured interview to assess social, intellectual, executive and adaptive functioning in 109 individuals, including two large multiplex families (Family A: 30; Family B: 34) and an independent sample of small families (n=45). Our protocol identified four psychological endophenotypes of the BAP that were evident in both samples, and showed high sensitivity (97%) and specificity (82%) for individuals classified with the BAP. The patterns of inheritance of these endophenotypes varied in the two large families, supporting their utility for identifying genes in autism.
Cannabinoid Receptor 2 (CB2) Signals via G-alpha-s and Induces IL-6 and IL-10 Cytokine Secretion in Human Primary Leukocytes
Authors: Saroz Yurii , Kho Dan T. , Glass Michelle , Graham Euan Scott , Grimsey Natasha Lillia 
Published: June 2019

AbstractCannabinoid receptor 2 (CB2) is a promising therapeutic target for immunological modulation. There is, however, a deficit of knowledge regarding CB2signaling and function in human primary immunocompetent cells. We applied an experimental paradigm which closely models thein situstate of human primary leukocytes (PBMC; peripheral blood mononuclear cells) to characterize activation of a number of signaling pathways in response to a CB2-selective ligand (HU308). We observed a “lag” phase of unchanged cAMP concentration prior to development of classically-expected Gαi-mediated inhibition of cAMP synthesis. Application of G protein inhibitors revealed that this apparent lag was a result of counteraction of Gαieffects by concurrent Gαsactivation. Monitoring downstream signaling events, activation of p38 was mediated by Gαiwhereas ERK1/2 and Akt phosphorylation were mediated by Gαi-coupled βγ. Activation of CREB integrated multiple components; Gαsand βγ mediated ∼85% of the response, while ∼15% was attributed to Gαi. Responses to HU308 had an important functional outcome – secretion of interleukins 6 (IL-6) and 10 (IL-10). IL-2, IL-4, IL-12, IL-13, IL-17A, MIP-1α, and TNF-α were unaffected. IL-6/IL-10 induction had a similar G protein coupling profile to CREB activation. All response potencies were consistent with that expected for HU308 acting via CB2. Additionally, signaling and functional effects were completely blocked by a CB2-selective inverse agonist, giving additional evidence for CB2involvement. This work expands the current paradigm regarding cannabinoid immunomodulation and reinforces the potential utility of CB2ligands as immunomodulatory therapeutics.Significance statementCannabinoid receptor 2 (CB2) is a G protein-coupled receptor which plays a complex role in immunomodulation and is a promising target in a range of disorders with immune system involvement. However, to date the majority of the studies in this field have been performed on cell lines, rodent models, or stimulated primary cells. Here we provide a detailed account of CB2-mediated signaling in primary human immune cells under conditions which closely mimic theirin vivostate. We reveal a complex signaling system involving an unprecedented CB2 signaling pathway and leading to immunomodulatory functional outcomes. This work provides not only a critical foundation impacting CB2-targeted drug discovery, but reveals important wider considerations for GPCR signaling studies and model validity.Table of Contents Summary Figure
Effects of arm weight support on neuromuscular activation during reaching in chronic stroke patients
Authors: Runnalls Keith D , Ortega-Auriol Pablo , McMorland Angus J C , Anson Greg , Byblow Winston D 
Published: June 2019

AbstractTo better understand how arm weight support (WS) can be used to alleviate upper limb impairment after stroke, we investigated the effects of WS on muscle activity, muscle synergy expression, and corticomotor excitability (CME) in 13 chronic stroke patients and 6 age-similar healthy controls. For patients, lesion location and corticospinal tract integrity were assessed using magnetic resonance imaging. Upper limb impairment was assessed using the Fugl-Meyer upper extremity assessment with patients categorised as either mild or moderate-severe. Three levels of WS were examined: low=0, medium=50 and high=100 % of full support. Surface EMG was recorded from 8 upper limb muscles, and muscle synergies were decomposed using non-negative matrix factorisation from data obtained during reaching movements to an array of 14 targets using the paretic or dominant arm. Interactions between impairment level and WS were found for the number of targets hit, and EMG measures. Overall, greater WS resulted in lower EMG levels, although the degree of modulation between WS levels was less for patients with moderate-severe compared to mild impairment. Healthy controls expressed more synergies than patients with moderate-severe impairment. Healthy controls and patients with mild impairment showed more synergies with high compared to low weight support. Transcranial magnetic stimulation was used to elicit motor-evoked potentials (MEPs) to which stimulus-response curves were fitted as a measure of corticomotor excitability (CME). The effect of WS on CME varied between muscles and across impairment level. These preliminary findings demonstrate that WS has direct and indirect effects on muscle activity, synergies, and CME and warrants further study in order to reduce upper limb impairment after stroke.
Early Life Supraphysiological Levels of Oxygen Exposure Permanently Impairs Hippocampal Mitochondrial Function
Authors: Ramani Manimaran , Miller Kiara , Kumar Ranjit , Kadasamy Jegen , McMahon Lori , Ballinger Scott , Ambalavanan Namasivayam 
Published: June 2019

AbstractPreterm infants requiring prolonged oxygen therapy often develop cognitive dysfunction later life. Previously, we reported that 14-week-old young adult mice exposed to hyperoxia as newborns had spatial memory 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 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. Following hyperoxia exposure, complex I function was decreased at P14 but increased in young adult mice. Proteomic analysis revealed that neonatal 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 changes may account for memory deficits seen in preterm survivors following prolonged oxygen supplementation and may potentially be a contributing mechanism in other oxidative stress associated cognitive disorders.
Mast cells are mediators of fibrosis and effector cell recruitment in dermal chronic graft-versus-host disease
Authors: Strattan Ethan , Palaniyandi Senthilnathan , Kumari Reena , Du Jing , Hakim Natalya , Huang Timothy , Kesler Melissa V. , Jennings C. Darrell , Sturgill Jamie L. , Hildebrandt Gerhard C. 
Published: June 2019

AbstractAllogeneic hematopoietic stem cell transplant (allo-HSCT) is often used to treat acute leukemia or defects of hematopoiesis. Its widespread use is hampered by graft-versus-host disease (GVHD), which has high morbidity and mortality in both acute and chronic subtypes. Chronic GVHD (cGVHD) occurs most frequently in skin and often is characterized by pathogenic fibrosis. Mast cells (MCs) are known to be involved in the pathogenesis of other fibrotic diseases. In a murine model of cGVHD after allo-HSCT, C57BL/6J recipients of allogeneic LP/J donor cells develop sclerodermatous dermal cGVHD which is significantly decreased in mast cell-deficient B6.Cg-KitW-sh/HNihrJaeBsmGlliJ recipients. MCs survive conditioning and are associated with fibrosis, chemokine production, and recruitment of GVHD effector cells to the skin. Chemokine production by MCs is blocked by drugs used to treat cGVHD. The importance of MCs in skin cGVHD is mirrored by increased MCs in the skin of patients with dermal cGVHD. We show for the first time a role for MCs in skin cGVHD that may be targetable for preventive and therapeutic intervention in this disease.
Telophase correction refines division orientation in stratified epithelia
Authors: Lough Kendall J. , Byrd Kevin M. , Descovich Carlos P. , Spitzer Danielle C. , Bergman Abby J. , Beaudoin Gerard M. , Reichardt Louis F. , Williams Scott E. 
Published: June 2019

ABSTRACTDuring organogenesis, precise control of spindle orientation ensures a proper balance of proliferation and differentiation. In the developing murine epidermis, planar and perpendicular divisions yield symmetric and asymmetric fate outcomes, respectively. Classically, division axis specification involves centrosome migration and spindle rotation, events that occur early in mitosis. Here, we identify a previously uncharacterized orientation mechanism that occurs during telophase, correcting erroneous oblique orientations that unexpectedly persist into anaphase. The directionality of reorientation—towards either planar or perpendicular—correlates with the maintenance or loss of basal contact by the apical daughter. While the conserved scaffolding protein Pins/LGN is believed to function primarily through initial spindle positioning, we now show it also functions actively during telophase to reorient oblique divisions toward perpendicular. The ability to undergo telophase correction is also critically dependent upon an LGN-independent pathway involving the tension-sensitive adherens junction proteins vinculin, a-catenin and afadin, and correction directionality is influenced by local cell density. Failure of this reorientation mechanism impacts tissue architecture, as excessive oblique divisions induce precocious differentiation. The division orientation plasticity provided by telophase correction may provide a means for progenitors to dynamically respond to extrinsic cues provided by neighboring cells in order to adapt to local tissue needs.
A TetR-family protein activates transcription from a new promoter motif associated with essential genes for autotrophic growth in acetogens
Authors: de Souza Pinto Lemgruber Renato , Valgepea Kaspar , Garcia Ricardo Axayacatl Gonzalez , de Bakker Christopher , Palfreyman Robin William , Tappel Ryan , Köpke Michael , Simpson Séan Dennis , Nielsen Lars Keld , Marcellin Esteban 
Published: June 2019

AbstractAcetogens can fix carbon (CO or CO2) into acetyl-CoA via the Wood-Ljungdahl pathway (WLP) that also makes them attractive cell factories for the production of fuels and chemicals from waste feedstocks. Although most biochemical details of the WLP are well understood and systems-level characterisation of acetogen metabolism has recently improved, key transcriptional features such as promoter motifs and transcriptional regulators are still unknown in acetogens. Here, we use differential RNA-sequencing to identify a previously undescribed promoter motif associated with essential genes for autotrophic growth of the model-acetogen Clostridium autoethanogenum. RNA polymerase was shown to bind to the new promoter motif using a DNA-binding protein assay and proteomics enabled the discovery of four candidates to potentially function directly in control of transcription of the WLP and other key genes of C1 fixation metabolism. Next, in vivo experiments showed that a TetR-family transcriptional regulator (CAETHG_0459) and the housekeeping sigma factor (σA) activate expression of a reporter protein (GFP) in-frame with the new promoter motif from a fusion vector in E. coli. Lastly, a protein-protein interaction assay with the RNA polymerase (RNAP) shows that CAETHG_0459 directly binds to the RNAP. Together, the data presented here advance the fundamental understanding of transcriptional regulation of C1 fixation in acetogens and provide a strategy for improving the performance of gas-fermenting bacteria by genetic engineering.
A Refined Open State of the Glycine Receptor Obtained Via Molecular Dynamics Simulations
Authors: Dämgen Marc A. , Biggin Philip C. 
Published: June 2019

AbstractFast neurotransmission is mediated by pentameric ligand-gated ion channels. Glycine receptors are chloride-selective members of this receptor family that mediate inhibitory synaptic transmission and are implicated in neurological disorders including autism and hyperekplexia. They have been structurally characterized by both X-ray crystallography and cryo electron microscopy studies, with the latter giving rise to what was proposed as a possible open state. However, recent work has questioned the physiological relevance of this open state structure, since it rapidly collapses in molecular dynamics simulations. Here, we show that the collapse can be avoided by a careful equilibration protocol that reconciles the more problematic regions of the original electron-density map and gives a stable open state that shows frequent selective chloride permeation. The protocol developed in this work provides a means to refine open-like structures of the whole pentameric ligand-gated ion channel superfamily and reconciles the previous issues with the cryo-EM structure.
Activity subspaces in medial prefrontal cortex distinguish states of the world
Authors: Maggi Silvia , Humphries Mark D. 
Published: June 2019

AbstractMedial prefrontal cortex (mPfC) activity represents information about the state of the world, including present behaviour, such as decisions, and the immediate past, such as short-term memory. Unknown is whether information about different states of the world are represented in the same mPfC neural population and, if so, how they are kept distinct. To address this, we analyse here mPfC population activity of rats learning rules in a Y-maze, with self-initiated choice trials to an arm-end followed by a self-paced return during the inter-trial interval (ITI). We find that trial and ITI population activity from the same population fall into different low-dimensional subspaces. These subspaces encode different states of the world: multiple features of the task can be decoded from both trial and ITI activity, but the decoding axes for the same feature are roughly orthogonal between the two task phases, and the decodings are predominantly of features of the present during the trial but features of the preceding trial during the ITI. These subspace distinctions are carried forward into sleep, where population activity is preferentially reactivated in post-training sleep, but differently for activity from the trial and ITI subspaces. Our results suggest that the problem of interference when representing different states of the world is solved in mPfC by population activity occupying different subspaces for the world states, which can be independently decoded by downstream targets and independently addressed by upstream inputs.Significance statementActivity in the medial prefrontal cortex plays a roles in representing the current and past states of the world. We show that during a maze task the activity of a single population in medial prefrontal cortex represents at least two different states of the world. These representations were sequential and sufficiently distinct that a downstream population could separately read out either state from that activity. Moreover, the activity representing different states is differently reactivated in sleep. Different world states can thus be represented in the same medial prefrontal cortex population, but in such a way that prevents potentially catastrophic interference between them.
The tapeworm interactome: inferring confidence scored protein-protein interactions from the proteome of Hymenolepis microstoma
Authors: James Katherine , Olson Peter D. 
Published: June 2019

AbstractReference genome and transcriptome assemblies of helminths have reached a level of completion whereby secondary analyses that rely on accurate gene estimation or syntenic relationships can be now conducted with a high level of confidence. Recent public release of the v.3 assembly of the mouse bile-duct tapeworm, Hymenolepis microstoma, provides chromosome-level characterisation of the genome and a stabilised set of protein coding gene models underpinned by both bioinformatic and empirical data. However, interactome data have not been produced. Conserved protein-protein interactions in other organisms, termed interologs, can be used to transfer interactions between species, allowing systems-level analysis in non-model organisms. Here, we describe a probabilistic, integrated network of interologs for the H. microstoma proteome, based on conserved protein interactions found in eukaryote model species. Almost a third of the 10,139 gene models in the v.3 assembly could be assigned interaction data and assessment of the resulting network indicates that topologically-important proteins are related to essential cellular pathways, and that the network clusters into biologically meaningful components. Moreover, network parameters are similar to those of single-species interaction networks that we constructed in the same way for S. cerevisiae, C. elegans and H. sapiens, demonstrating that information-rich, system-level analyses can be conducted even on species separated by a large phylogenetic distance from the major model organisms from which most protein interaction evidence is based. Using the interolog network, we then focused on sub-networks of interactions assigned to discrete suites of genes of interest, including signalling components and transcription factors, germline ‘multipotency’ genes, and differentially-expressed genes between larval and adult worms. These analyses not only showed an expected bias toward highly-conserved proteins, such as components of intracellular signal transduction, but in some cases predicted interactions with transcription factors that aid in identifying their target genes. With the completion of key helminth genomes, such systems level analyses can provide an important predictive framework to guide basic and applied research on helminths and will become increasingly informative as protein-protein interaction data accumulate.
Optimization of insect odorant receptor trafficking and functional expression via transient transfection in HEK293 cells
Authors: Miazzi Fabio , Hoyer Carolin , Sachse Silke , Knaden Markus , Wicher Dieter , Hansson Bill S. , Lavista-Llanos Sofia 
Published: June 2019

AbstractInsect odorant receptors show a limited functional expression in various heterologous expression systems including insect and mammalian cells. This may be in part due to the absence of key components driving the release of these proteins from the endoplasmic reticulum and directing them to the plasma membrane. In order to mitigate this problem we took advantage of small export signals within the human HCN1 and Rhodopsin that have been shown to promote protein release from the endoplasmic reticulum and the trafficking of post-Golgi vesicles, respectively. Moreover, we designed a new vector based on a bidirectional expression cassette to drive the functional expression of the insect odorant receptor co-receptor (Orco) and an odor-binding odorant receptor, simultaneously. We show that this new method can be used to reliably express insect odorant receptors in HEK293 cells via transient transfection and that is highly suitable for downstream applications using automated and high-throughput imaging platforms.
The organizer of chromatin topology RIF1 ensures cellular resilience to DNA replication stress
Authors: Ribeyre Cyril , Lebdy Rana , Patouillard Julie , Larroque Marion , Abou-Merhi Raghida , Larroque Christian , Constantinou Angelos 
Published: June 2019

AbstractEukaryotic genomes are duplicated from thousands of replication origins that fire sequentially forming a defined spatiotemporal pattern of replication clusters. The temporal order of DNA replication is determined by chromatin architecture and, more specifically, by chromatin contacts that are stabilized by RIF1. Here we show that RIF1 localizes in close proximity to newly synthesized DNA. In cells exposed to the DNA replication inhibitor aphidicolin, suppression of RIF1 markedly decreased the efficacy of protein isolation on nascent DNA (iPOND), suggesting that the iPOND procedure is biased by chromatin topology. RIF1 was required to limit the accumulation of DNA lesions induced by aphidicolin treatment and promoted the recruitment of cohesins in the vicinity of nascent DNA. Collectively, the data suggest that the stabilization of chromatin topology by RIF1 limits replication-associated genomic instability.