bluuebunny/crossref_metadata_2025_split huggingface dataset:
Definition of functionally and structurally distinct repressive states in the nuclear receptor PPARγ
Authors: Heidari Zahra , Chrisman Ian M. , Nemetchek Michelle D. , Novick Scott J. , Blayo Anne-Laure , Patton Trey , Mendes Desiree E. , Diaz Philippe , Kamenecka Theodore M. , Griffin Patrick R. , Hughes Travis S. 
Published: December 2019

AbstractThe repressive states of nuclear receptors (i.e., apo or bound to antagonists or inverse agonists) are poorly defined, despite the fact that nuclear receptors are a major drug target. Most ligand bound structures of nuclear receptors, including peroxisome proliferator-activated receptor γ (PPARγ), are similar to the apo structure. Here we use NMR, accelerated molecular dynamics and hydrogen-deuterium exchange mass spectrometry to define the PPARγ structural ensemble. We find that the helix 3 charge clamp positioning varies widely in apo and is stabilized by efficacious ligand binding. We also reveal a previously undescribed mechanism for inverse agonism involving an omega loop to helix switch which induces disruption of a tripartite salt-bridge network. We demonstrate that ligand binding can induce multiple structurally distinct repressive states. One state recruits peptides from two different corepressors, while another recruits just one, providing structural evidence of ligand bias in a nuclear receptor.
Structural basis for Fullerene geometry in a human endogenous retrovirus capsid
Authors: Acton Oliver , Grant Tim , Nicastro Giuseppe , Ball Neil J. , Goldstone David C. , Robertson Laura E. , Sader Kasim , Nans Andrea , Ramos Andres , Stoye Jonathan P. , Taylor Ian A. , Rosenthal Peter B. 
Published: December 2019

AbstractThe HML2 (HERV-K) group constitutes the most recently acquired family of human endogenous retroviruses, with many proviruses less than one million years old. Many maintain intact open reading frames and provirus expression together with HML2 particle formation are observed in early stage human embryo development and are associated with pluripotency as well as inflammatory disease, cancers and HIV-1 infection. Here, we reconstruct the core structural protein (CA) of an HML2 retrovirus, assemble particles in vitro and employ single particle cryogenic electron microscopy (cryo-EM) to determine structures of four classes of CA Fullerene shell assemblies. These icosahedral and capsular assemblies reveal at high-resolution the molecular interactions that allow CA to form both pentamers and hexamers and show how invariant pentamers and structurally plastic hexamers associate to form the unique polyhedral structures found in retroviral cores.
Ultrastructure of the axonal periodic scaffold reveals a braid-like organization of actin rings
Authors: Vassilopoulos Stéphane , Gibaud Solène , Jimenez Angélique , Caillol Ghislaine , Leterrier Christophe 
Published: December 2019

AbstractRecent super-resolution microscopy studies have unveiled a periodic scaffold of actin rings regularly spaced by spectrins under the plasma membrane of axons. However, ultrastructural details are unknown, limiting a molecular and mechanistic understanding of these enigmatic structures. Here, we combine platinum-replica electron and optical super-resolution microscopy to investigate the cortical cytoskeleton of axons at the ultrastructural level. Immunogold labeling and correlative super-resolution/electron microscopy allow us to unambiguously resolve actin rings as braids made of two long, intertwined actin filaments connected by a dense mesh of aligned spectrins. This molecular arrangement contrasts with the currently assumed model of actin rings made of short, capped actin filaments. Along the proximal axon, we resolved the presence of phospho-myosin light chain and the scaffold connection with microtubules via ankyrin G. We propose that braided rings explain the observed stability of the actin-spectrin scaffold and ultimately participate in preserving the axon integrity.
RNF208, an estrogen-inducible E3 ligase, targets soluble Vimentin to suppress metastasis in triple-negative breast cancers
Authors: Pang Kyoungwha , Park Jinah , Ahn Sung Gwe , Lee Jihee , Park Yuna , Ooshima Akira , Mizuno Seiya , Yamashita Satoshi , Park Kyung-Soon , Lee So-Young , Jeong Joon , Ushijima Toshikazu , Yang Kyung-Min , Kim Seong-Jin 
Published: December 2019

AbstractThe development of triple-negative breast cancer (TNBC) negatively impacts both quality of life and survival in a high percentage of patients. Here, we show that RING finger protein 208 (RNF208) decreases the stability of soluble Vimentin protein through a polyubiquitin-mediated proteasomal degradation pathway, thereby suppressing metastasis of TNBC cells. RNF208 was significantly lower in TNBC than the luminal type, and low expression of RNF208 was strongly associated with poor clinical outcomes. Furthermore, RNF208 was induced by 17β-estradiol (E2) treatment in an estrogen receptor alpha (ΕRα)-dependent manner. Overexpression of RNF208 suppresses tumor formation and lung metastasis of TNBC cells. Mechanistically, RNF208 specifically polyubiquitinated the Lys97 residue within the head domain of Vimentin through interaction with the Ser39 residue of phosphorylated Vimentin, which exists as a soluble form, eventually facilitating proteasomal degradation of Vimentin. Collectively, our findings define RNF208 as a negative regulator of soluble Vimentin and a prognostic biomarker for TNBC cells.
Intestinal Neurod1 expression impairs paneth cell differentiation and promotes enteroendocrine lineage specification
Authors: Li Hui Joyce , Ray Subir K. , Pan Ning , Haigh Jody , Fritzsch Bernd , Leiter Andrew B. 
Published: December 2019

AbstractTranscription factor Neurod1 is required for enteroendocrine progenitor differentiation and maturation. Several earlier studies indicated that ectopic expression of Neurod1 converted non- neuronal cells into neurons. However, the functional consequence of ectopic Neurod1 expression has not been examined in the GI tract, and it is not known whether Neurod1 can similarly switch cell fates in the intestine. We generated a mouse line that would enable us to conditionally express Neurod1 in intestinal epithelial cells at different stages of differentiation. Forced expression of Neurod1 throughout intestinal epithelium increased the number of EECs as well as the expression of EE specific transcription factors and hormones. Furthermore, we observed a substantial reduction of Paneth cell marker expression, although the expressions of enterocyte-, tuft- and goblet-cell specific markers are largely not affected. Our earlier study indicated that Neurog3+ progenitor cells give rise to not only EECs but also Goblet and Paneth cells. Here we show that the conditional expression of Neurod1 restricts Neurog3+ progenitors to adopt Paneth cell fate, and promotes more pronounced EE cell differentiation, while such effects are not seen in more differentiated Neurod1+ cells. Together, our data suggest that forced expression of Neurod1 programs intestinal epithelial cells more towards an EE cell fate at the expense of the Paneth cell lineage and the effect ceases as cells mature to EE cells.
Dusp8 affects hippocampal size and behavior in mice and humans
Authors: Baumann Peter , Schriever Sonja C. , Kullmann Stephanie , Zimprich Annemarie , Feuchtinger Annette , Amarie Oana , Peter Andreas , Walch Axel , Gailus-Durner Valerie , Fuchs Helmut , Hrabě de Angelis Martin , Wurst Wolfgang , Tschöp Matthias H. , Heni Martin , Hölter Sabine M. , Pfluger Paul T. 
Published: December 2019

AbstractDual-specificity phosphatase 8 (Dusp8) acts as physiological inhibitor for the MAPKs Jnk, Erk and p38 which are involved in regulating multiple CNS processes. While Dusp8 expression levels are high in limbic areas such as the hippocampus, the functional role of Dusp8 in hippocampus morphology, MAPK-signaling, neurogenesis and apoptosis as well as in behavior are still unclear. It is of particular interest whether human carriers of a DUSP8 allelic variant show similar hippocampal alterations to mice. Addressing these questions using Dusp8 WT and KO mouse littermates, we found that KOs suffered from mildly impaired spatial learning, increased locomotor activity and elevated anxiety. Cell proliferation, apoptosis and p38 and Jnk phosphorylation were unaffected, but phospho-Erk levels were higher in hippocampi of the KOs. Consistent with a decreased hippocampus size in Dusp8 KO mice, we found reduced volumes of the hippocampal subregions subiculum and CA4 in humans carrying the DUSP8 allelic variant SNP rs2334499:C > T. Overall, aberrations in morphology and behavior in Dusp8 KO mice and a decrease in hippocampal volume of SNP rs2334499:C > T carriers point to a novel, translationally relevant role of Dusp8 in hippocampus function that warrants further studies on the role of Dusp8 within the limbic network.
Effectiveness of Renin-Angiotensin-Aldosterone System Blockade on Residual Kidney Function and Peritoneal Membrane Function in Peritoneal Dialysis Patients: A Network Meta-Analysis
Authors: Phatthanasobhon Sirayut , Nochaiwong Surapon , Thavorn Kednapa , Noppakun Kajohnsak , Panyathong Setthapon , Suteeka Yuttitham , Hutton Brian , Sood Manish M. , Knoll Greg A. , Ruengorn Chidchanok 
Published: December 2019

AbstractWe performed a network meta-analysis of randomised controlled trials (RCTs) and non-randomised studies in adult peritoneal dialysis patients to evaluate the effects of specific renin-angiotensin aldosterone systems (RAAS) blockade classes on residual kidney function and peritoneal membrane function. Key outcome parameters included the following: residual glomerular filtration rate (rGFR), urine volume, anuria, dialysate-to-plasma creatinine ratio (D/P Cr), and acceptability of treatment. Indirect treatment effects were compared using random-effects model. Pooled standardised mean differences (SMDs) and odd ratios (ORs) were estimated with 95% confidence intervals (CIs). We identified 10 RCTs (n = 484) and 10 non-randomised studies (n = 3,305). Regarding changes in rGFR, RAAS blockade with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) were more efficacious than active control (SMD 0.55 [0.06–1.04] and 0.62 [0.19–1.04], respectively) with the protective effect on rGFR observed only after usage ≥12 months, and no differences among ACEIs and ARBs. Compared with active control, only ACEIs showed a significantly decreased risk of anuria (OR 0.62 [0.41–0.95]). No difference among treatments for urine volume and acceptability of treatment were observed, whereas evidence for D/P Cr is inconclusive. The small number of randomised studies and differences in outcome definitions used may limit the quality of the evidence.
Transcriptional plasticity buffers genetic variation in zinc homeostasis
Authors: Pita-Barbosa Alice , Ricachenevsky Felipe K. , Wilson Michael , Dottorini Tania , Salt David E. 
Published: December 2019

AbstractIn roots of Arabidopsis thaliana, Zn can be either loaded into the xylem for translocation to the shoot or stored in vacuoles. Vacuolar storage is achieved through the action of the Zn/Cd transporter HMA3 (Heavy Metal Atpase 3). The Col-0 accession has an HMA3 loss-of-function allele resulting in high shoot Cd, when compared to accession CSHL-5 which has a functional allele and low shoot Cd. Interestingly, both Col-0 and CSHL-5 have similar shoot Zn concentrations. We hypothesize that plants sense changes in cytosolic Zn that are due to variation in HMA3 function, and respond by altering expression of genes related to Zn uptake, transport and compartmentalisation, in order to maintain Zn homeostasis. The expression level of genes known to be involved in Zn homeostasis were quantified in both wild-type Col-0 and Col-0::HMA3CSHL-5 plants transformed with the functional CSHL-5 allele of HMA3. We observed significant positive correlations between expression of HMA3 and of genes known to be involved in Zn homeostasis, including ZIP3, ZIP4, MTP1, and bZIP19. The results support our hypothesis that alteration in the level of function of HMA3 is counterbalanced by the fine regulation of the Zn homeostasis gene network in roots of A. thaliana.
Sea anemone and clownfish microbiota diversity and variation during the initial steps of symbiosis
Authors: Roux Natacha , Lami Raphaël , Salis Pauline , Magré Kévin , Romans Pascal , Masanet Patrick , Lecchini David , Laudet Vincent 
Published: December 2019

AbstractClownfishes and sea anemones form an intriguing long-term association, but the mechanism underlying this symbiosis is not well understood. Since clownfishes seem to cover themselves with sea anemone mucus, we investigated the microbiomes of the two partners to search for possible shifts in their compositions. We used a 16S rRNA gene sequencing strategy to study the dynamics of the microbiota during the association between the clownfishAmphiprion ocellarisand its hostHeteractis magnificaunder laboratory conditions. The experiment conducted in aquaria revealed that both clownfish and sea anemone mucus had specific signatures compared to artificial sea water. The microbiomes of both species were highly dynamic during the initiation of the symbiosis and for up to seven days after contact. Three families of bacteria (Haliangiaceae, Pseudoalteromonadacae, Saprospiracae) were shared between the two organisms after symbiosis. Once the symbiosis had been formed, the clownfishes and sea anemone then shared some communities of their mucus microbiota. This study paves the way for further investigations to determine if similar microbial signatures exist in natural environments, whether such microbial sharing can be beneficial for both organisms, and whether the microbiota is implicated in the mechanisms that protect the clownfish from sea anemone stinging.
The Urinary Excretion of Uromodulin is Regulated by the Potassium Channel ROMK
Authors: Schiano Guglielmo , Glaudemans Bob , Olinger Eric , Goelz Nadine , Müller Michael , Loffing-Cueni Dominique , Deschenes Georges , Loffing Johannes , Devuyst Olivier 
Published: December 2019

AbstractUromodulin, the most abundant protein in normal urine, is produced by cells lining the thick ascending limb (TAL) of the loop of Henle. Uromodulin regulates the activity of the potassium channel ROMK in TAL cells. Common variants in KCNJ1, the gene encoding ROMK, are associated with urinary levels of uromodulin in population studies. Here, we investigated the functional link between ROMK and uromodulin in Kcnj1 knock-out mouse models, in primary cultures of mouse TAL (mTAL) cells, and in patients with Bartter syndrome due to KCNJ1 mutations. Both global and kidney-specific Kcnj1 knock-out mice showed reduced urinary levels of uromodulin paralleled by increased levels in the kidney, compared to wild-type controls. Pharmacological inhibition and genetic deletion of ROMK in mTAL cells caused a reduction in apical uromodulin excretion, reflected by cellular accumulation. In contrast, NKCC2 inhibition showed no effect on uromodulin processing. Patients with Bartter syndrome type 2 showed reduced urinary uromodulin levels compared to age and gender matched controls. These results demonstrate that ROMK directly regulates processing and release of uromodulin by TAL cells, independently from NKCC2. They support the functional link between transport activity and uromodulin in the TAL, relevant for blood pressure control and urinary concentrating ability.
Impact of Biophysical Mechanisms on Urban Heat Island Associated with Climate Variation and Urban Morphology
Authors: Fitria Ressy , Kim Daeun , Baik Jongjin , Choi Minha 
Published: December 2019

AbstractThe rapid development of urban areas can potentially alter hydro-meteorological fluxes and lead to the Urban Heat Island (UHI) phenomenon. In this study, UHI intensity and its driving factors were estimated using the Community Land Model (CLM) in cities of Tokyo, Phoenix, Bandung, and Quito, with different landscapes and climates, as a step in risk assessment of urbanization phenomena. The UHI magnitude increased along with the ratio of the height to width (H/W) of urban canyons in cities with the same latitude, especially during the daytime, when Quito (Tokyo) had a higher UHI than Bandung (Phoenix). El Niño-Southern Oscillation (ENSO) events, such as El Niño and La Niña, contributed to UHI variability, during which the cities in the western (eastern) part of Pacific Ocean experienced a higher UHI during El Niño (La Niña). The UHI differences from total biophysical drivers between these events were highest in Tokyo during the daytime as a result of convection process, and in Phoenix during the nighttime due to the hot arid climate of the city. Our results suggest the need to consider climate variation beyond local site characteristics when mitigating heat stress and making decisions regarding urban development.
Prolactin and its receptor as therapeutic targets in glioblastoma multiforme
Authors: Asad Antonela Sofía , Nicola Candia Alejandro Javier , Gonzalez Nazareno , Zuccato Camila Florencia , Abt Araceli , Orrillo Santiago Jordi , Lastra Yael , De Simone Emilio , Boutillon Florence , Goffin Vincent , Seilicovich Adriana , Pisera Daniel Alberto , Ferraris María Jimena , Candolfi Marianela 
Published: December 2019

AbstractAlthough prolactin (PRL) and its receptor (PRLR) have been detected in glioblastoma multiforme (GBM), their role in its pathogenesis remains unclear. Our aim was to explore their contribution in GBM pathogenesis. We detected PRL and PRLR in all GBM cell lines tested. PRLR activation or overexpression using plasmid transfection increased proliferation, viability, clonogenicity, chemoresistance and matrix metalloproteinase activity in GBM cells, while PRLR antagonist ∆1–9-G129R-hPRL reduced their proliferation, viability, chemoresistance and migration. Meta-analysis of transcriptomic data indicated that PRLR was expressed in all grade II-III glioma (GII-III) and GBM samples. PRL was upregulated in GBM biopsies when compared to GII-III. While in the general population tumour PRL/PRLR expression did not correlate with patient survival, biological sex-stratified analyses revealed that male patients with PRL+/PRLRHIGH GBM performed worse than PRL+/PRLRLOW GBM. In contrast, all male PRL+/PRLRHIGH GII-III patients were alive whereas only 30% of PRL+/PRLRLOW GII-III patients survived after 100 months. Our study suggests that PRLR may be involved in GBM pathogenesis and could constitute a therapeutic target for its treatment. Our findings also support the notion that sexual dimorphism should be taken into account to improve the care of GBM patients.
De novo Assembly of the Brugia malayi Genome Using Long Reads from a Single MinION Flowcell
Authors: Fauver Joseph R. , Martin John , Weil Gary J. , Mitreva Makedonka , Fischer Peter U. 
Published: December 2019

AbstractFilarial nematode infections cause a substantial global disease burden. Genomic studies of filarial worms can improve our understanding of their biology and epidemiology. However, genomic information from field isolates is limited and available reference genomes are often discontinuous. Single molecule sequencing technologies can reduce the cost of genome sequencing and long reads produced from these devices can improve the contiguity and completeness of genome assemblies. In addition, these new technologies can make generation and analysis of large numbers of field isolates feasible. In this study, we assessed the performance of the Oxford Nanopore Technologies MinION for sequencing and assembling the genome of Brugia malayi, a human parasite widely used in filariasis research. Using data from a single MinION flowcell, a 90.3 Mb nuclear genome was assembled into 202 contigs with an N50 of 2.4 Mb. This assembly covered 96.9% of the well-defined B. malayi reference genome with 99.2% identity. The complete mitochondrial genome was obtained with individual reads and the nearly complete genome of the endosymbiotic bacteria Wolbachia was assembled alongside the nuclear genome. Long-read data from the MinION produced an assembly that approached the quality of a well-established reference genome using comparably fewer resources.
Assessment of platelet-rich fibrin in the maintenance and recovery of cell viability of the periodontal ligament
Authors: Navarro Lorena Bortolini , Barchiki Fabiane , Navarro Junior Wilson , Carneiro Everdan , da Silva Neto Ulisses Xavier , Westphalen Vânia Portela Ditzel 
Published: December 2019

AbstractThis study analyzed the efficacy of autologous platelet-rich fibrin (PRF) in maintaining and recovering cell viability of the periodontal ligament (PDL). The PDL cells were isolated from 45 extracted teeth randomly distributed among 6 groups: 5 min, 1 h, 2 h, PRF 30 min, PRF 1 h and PRF 2 h. In the groups 5 min, 1 h and 2 h (n = 5), the teeth were kept dry in extra-alveolar times of 5 min, 1 h and 2 h respectively. The teeth of the groups PRF 30 min, PRF 1 h and PRF 2 h (n = 10) were kept dry at extra-alveolar times of 30 min, 1 and 2 h followed by immersion in PRF for 45 min. PDL cells were isolated by enzymatic digestion with type II collagenase and dispase, counted and analyzed for viability with Trypan blue vital dye in Neubauer chamber. The variables total number of cells and cell viability demonstrated that in the 5 min, 1 h and 2 h groups there was a decrease after the extra-alveolar dry times of 1 and 2 h. In comparison with the total number of cells, group 1 h, considered immediate reimplantation, did not present statistical difference when compared to the groups PRF 30 min, PRF 1 h and 2 h, a result that demonstrates that PRF assists in cell maintenance and recovery. PRF provided increased cell viability in relation to the different dry extra-alveolar times analyzed (p < 0.001). Autologous PRF presented effectiveness in maintaining and recovering PDL cells from extracted teeth and kept dry for up to 2 h.
Prostate Cancer Detection using Deep Convolutional Neural Networks
Authors: Yoo Sunghwan , Gujrathi Isha , Haider Masoom A. , Khalvati Farzad 
Published: December 2019

AbstractProstate cancer is one of the most common forms of cancer and the third leading cause of cancer death in North America. As an integrated part of computer-aided detection (CAD) tools, diffusion-weighted magnetic resonance imaging (DWI) has been intensively studied for accurate detection of prostate cancer. With deep convolutional neural networks (CNNs) significant success in computer vision tasks such as object detection and segmentation, different CNN architectures are increasingly investigated in medical imaging research community as promising solutions for designing more accurate CAD tools for cancer detection. In this work, we developed and implemented an automated CNN-based pipeline for detection of clinically significant prostate cancer (PCa) for a given axial DWI image and for each patient. DWI images of 427 patients were used as the dataset, which contained 175 patients with PCa and 252 patients without PCa. To measure the performance of the proposed pipeline, a test set of 108 (out of 427) patients were set aside and not used in the training phase. The proposed pipeline achieved area under the receiver operating characteristic curve (AUC) of 0.87 (95$${\boldsymbol{ \% }}$$% Confidence Interval (CI): 0.84–0.90) and 0.84 (95$${\boldsymbol{ \% }}$$% CI: 0.76–0.91) at slice level and patient level, respectively.