bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring the Wnt signaling pathway in schizophrenia and bipolar disorder
Authors: Hoseth Eva Z. , Krull Florian , Dieset Ingrid , Mørch Ragni H. , Hope Sigrun , Gardsjord Erlend S. , Steen Nils Eiel , Melle Ingrid , Brattbakk Hans-Richard , Steen Vidar M. , Aukrust Pål , Djurovic Srdjan , Andreassen Ole A. , Ueland Thor 
Published: March 2018

AbstractThe Wnt signaling pathway plays a crucial role in neurodevelopment and in regulating the function and structure of the adult nervous system. Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental disorders with evidence of subtle neurodevelopmental, structural and functional neuronal abnormalities. We aimed to elucidate the role of aberrant regulation of the Wnt system in these disorders by evaluating plasma levels of secreted Wnt modulators in patients (SCZ = 551 and BD = 246) and healthy controls (HCs = 639) using enzyme immune-assay. We also investigated the expression of 141 Wnt-related genes in whole blood in a subsample (SCZ = 338, BD = 241, and HCs = 263) using microarray analysis. Both SCZ and BD had dysregulated mRNA expression of Wnt-related genes favoring attenuated canonical (beta-catenin-dependent) signaling, and there were also indices of enhanced non-canonical Wnt signaling. In particular, FZD7, which may activate all Wnt pathways, but favors non-canonical signaling, and NFATc3, a downstream transcription factor and readout of the non-canonical Wnt/Ca2+ pathway, were significantly increased in SCZ and BD (p < 3 × 10−4). Furthermore, patients had lower plasma levels of soluble dickkopf 1 and sclerostin (p < 0.01) compared with HC. Our findings suggest that SCZ and BD are characterized by abnormal Wnt gene expression and plasma protein levels, and we propose that drugs targeting the Wnt pathway may have a role in the treatment of severe mental disorders.
Fear extinction requires infralimbic cortex projections to the basolateral amygdala
Authors: Bloodgood Daniel W. , Sugam Jonathan A. , Holmes Andrew , Kash Thomas L. 
Published: March 2018

AbstractFear extinction involves the formation of a new memory trace that attenuates fear responses to a conditioned aversive memory, and extinction impairments are implicated in trauma- and stress-related disorders. Previous studies in rodents have found that the infralimbic prefrontal cortex (IL) and its glutamatergic projections to the basolateral amygdala (BLA) and basomedial amygdala (BMA) instruct the formation of fear extinction memories. However, it is unclear whether these pathways are exclusively involved in extinction, or whether other major targets of the IL, such as the nucleus accumbens (NAc) also play a role. To address this outstanding issue, the current study employed a combination of electrophysiological and chemogenetic approaches in mice to interrogate the role of IL-BLA and IL-NAc pathways in extinction. Specifically, we used patch-clamp electrophysiology coupled with retrograde tracing to examine changes in neuronal activity of the IL and prelimbic cortex (PL) projections to both the BLA and NAc following fear extinction. We found that extinction produced a significant increase in the intrinsic excitability of IL-BLA projection neurons, while extinction appeared to reverse fear-induced changes in IL-NAc projection neurons. To establish a causal counterpart to these observations, we then used a pathway-specific Designer Receptors Exclusively Activated by Designer Drugs (DREADD) strategy to selectively inhibit PFC-BLA projection neurons during extinction acquisition. Using this approach, we found that DREADD-mediated inhibition of PFC-BLA neurons during extinction acquisition impaired subsequent extinction retrieval. Taken together, our findings provide further evidence for a critical contribution of the IL-BLA neural circuit to fear extinction.
DNAJC5 facilitates USP19-dependent unconventional secretion of misfolded cytosolic proteins
Authors: Xu Yue , Cui Lei , Dibello Anthony , Wang Lihui , Lee Juhyung , Saidi Layla , Lee Jin-Gu , Ye Yihong 
Published: March 2018

AbstractCell-to-cell transmission of misfolded proteins propagates proteotoxic stress in multicellular organisms when transmitted polypeptides serve as a seeding template to cause protein misfolding in recipient cells, but how misfolded proteins are released from cells to initiate this process is unclear. Misfolding-associated protein secretion (MAPS) is an unconventional protein-disposing mechanism that specifically exports misfolded cytosolic proteins including various neurodegenerative disease-causing proteins. Here we establish the HSC70 co-chaperone DNAJC5 as an essential mediator of MAPS. USP19, a previously uncovered MAPS regulator binds HSC70 and acts upstream of HSC70 and DNAJC5. We further show that as a membrane-associated protein localized preferentially to late endosomes and lysosomes, DNAJC5 can chaperone MAPS client proteins to the cell exterior. Intriguingly, upon secretion, misfolded proteins can be taken up through endocytosis and eventually degraded in the lysosome. Collectively, these findings suggest a transcellular protein quality control regulatory pathway in which a deubiquitinase-chaperone axis forms a “triaging hub”, transferring aberrant polypeptides from stressed cells to healthy ones for disposal.
Risk of nontyphoidal Salmonella bacteraemia in African children is modified by STAT4
Authors: Gilchrist James J. , Rautanen Anna , Fairfax Benjamin P. , Mills Tara C. , Naranbhai Vivek , Trochet Holly , Pirinen Matti , Muthumbi Esther , Mwarumba Salim , Njuguna Patricia , Mturi Neema , Msefula Chisomo L. , Gondwe Esther N. , MacLennan Jenny M. , Chapman Stephen J. , Molyneux Malcolm E. , Knight Julian C. , Spencer Chris C. A. , Williams Thomas N. , MacLennan Calman A. , Scott J. Anthony G. , Hill Adrian V. S. 
Published: March 2018

AbstractNontyphoidal Salmonella (NTS) is a major cause of bacteraemia in Africa. The disease typically affects HIV-infected individuals and young children, causing substantial morbidity and mortality. Here we present a genome-wide association study (180 cases, 2677 controls) and replication analysis of NTS bacteraemia in Kenyan and Malawian children. We identify a locus in STAT4, rs13390936, associated with NTS bacteraemia. rs13390936 is a context-specific expression quantitative trait locus for STAT4 RNA expression, and individuals carrying the NTS-risk genotype demonstrate decreased interferon-γ (IFNγ) production in stimulated natural killer cells, and decreased circulating IFNγ concentrations during acute NTS bacteraemia. The NTS-risk allele at rs13390936 is associated with protection against a range of autoimmune diseases. These data implicate interleukin-12-dependent IFNγ-mediated immunity as a determinant of invasive NTS disease in African children, and highlight the shared genetic architecture of infectious and autoimmune disease.
MYC-driven epigenetic reprogramming favors the onset of tumorigenesis by inducing a stem cell-like state
Authors: Poli Vittoria , Fagnocchi Luca , Fasciani Alessandra , Cherubini Alessandro , Mazzoleni Stefania , Ferrillo Sara , Miluzio Annarita , Gaudioso Gabriella , Vaira Valentina , Turdo Alice , Gaggianesi Miriam , Chinnici Aurora , Lipari Elisa , Bicciato Silvio , Bosari Silvano , Todaro Matilde , Zippo Alessio 
Published: March 2018

AbstractBreast cancer consists of highly heterogeneous tumors, whose cell of origin and driver oncogenes are difficult to be uniquely defined. Here we report that MYC acts as tumor reprogramming factor in mammary epithelial cells by inducing an alternative epigenetic program, which triggers loss of cell identity and activation of oncogenic pathways. Overexpression of MYC induces transcriptional repression of lineage-specifying transcription factors, causing decommissioning of luminal-specific enhancers. MYC-driven dedifferentiation supports the onset of a stem cell-like state by inducing the activation of de novo enhancers, which drive the transcriptional activation of oncogenic pathways. Furthermore, we demonstrate that the MYC-driven epigenetic reprogramming favors the formation and maintenance of tumor-initiating cells endowed with metastatic capacity. This study supports the notion that MYC-driven tumor initiation relies on cell reprogramming, which is mediated by the activation of MYC-dependent oncogenic enhancers, thus establishing a therapeutic rational for treating basal-like breast cancers.
Brain and eyes of Kerygmachela reveal protocerebral ancestry of the panarthropod head
Authors: Park Tae-Yoon S. , Kihm Ji-Hoon , Woo Jusun , Park Changkun , Lee Won Young , Smith M. Paul , Harper David A. T. , Young Fletcher , Nielsen Arne T. , Vinther Jakob 
Published: March 2018

AbstractRecent discoveries of fossil nervous tissue in Cambrian fossils have allowed researchers to trace the origin and evolution of the complex arthropod head and brain based on stem groups close to the origin of the clade, rather than on extant, highly derived members. Here we show that Kerygmachela from Sirius Passet, North Greenland, a primitive stem-group euarthropod, exhibits a diminutive (protocerebral) brain that innervates both the eyes and frontal appendages. It has been surmised, based on developmental evidence, that the ancestor of vertebrates and arthropods had a tripartite brain, which is refuted by the fossil evidence presented here. Furthermore, based on the discovery of eyes in Kerygmachela, we suggest that the complex compound eyes in arthropods evolved from simple ocelli, present in onychophorans and tardigrades, rather than through the incorporation of a set of modified limbs.
Agreement between hospital and primary care on diagnostic labeling for COPD and heart failure in Toronto, Canada: a cross-sectional observational study
Authors: Greiver Michelle , Sullivan Frank , Kalia Sumeet , Aliarzadeh Babak , Sharma Deepak , Bernard Steven , Meaney Christopher , Moineddin Rahim , Eisen David , Rahman Navid , D’Urzo Tony 
Published: March 2018

AbstractPatients with chronic obstructive pulmonary disease (COPD) or heart failure (HF) are frequently cared for in hospital and in primary care settings. We studied labeling agreement for COPD and HF for patients seen in both settings in Toronto, Canada. This was a retrospective observational study using linked hospital-primary care electronic data from 70 family physicians. Patients were 20 years of age or more and had at least one visit in both settings between 1 January 2012 and 31 December 2014. We recorded labeling concordance and associations with clinical factors. We used capture-recapture models to estimate the size of the populations. COPD concordance was 34%; the odds ratios (ORs) of concordance increased with aging (OR 1.84 for age 75+ vs. <65, 95% CI 0.92–3.69) and more inpatient admissions (OR 2.89 for 3+ visits vs. 0 visits, 95% CI 1.59–5.26). HF concordance was 33%; the ORs of concordance decreased with aging (OR 0.39 for 75+ vs. <65, 95% CI 0.18–0.86) and increased with more admissions (OR = 2.39; 95% CI 1.33–4.30 for 3+ visits vs. 0 visits). Based on capture-recapture models, 21–24% additional patients with COPD and 18–20% additional patients with HF did not have a label in either setting. The primary care prevalence was estimated as 748 COPD patients and 834 HF patients per 100,000 enrolled adult patients. Agreement levels for COPD and HF were low and labeling was incomplete. Further research is needed to improve labeling for these conditions.
Numerical investigation of gapped edge states in fractional quantum Hall-superconductor heterostructures
Authors: Repellin Cécile , Cook Ashley M. , Neupert Titus , Regnault Nicolas 
Published: March 2018

AbstractFractional quantum Hall-superconductor heterostructures may provide a platform towards non-abelian topological modes beyond Majoranas. However their quantitative theoretical study remains extremely challenging. We propose and implement a numerical setup for studying edge states of fractional quantum Hall droplets with a superconducting instability. The fully gapped edges carry a topological degree of freedom that can encode quantum information protected against local perturbations. We simulate such a system numerically using exact diagonalization by restricting the calculation to the quasihole-subspace of a (time-reversal symmetric) bilayer fractional quantum Hall system of Laughlin ν = 1/3 states. We show that the edge ground states are permuted by spin-dependent flux insertion and demonstrate their fractional 6π Josephson effect, evidencing their topological nature and the Cooper pairing of fractionalized quasiparticles. The versatility and efficiency of our setup make it a well suited method to tackle wider questions of edge phases and phase transitions in fractional quantum Hall systems.
Author Correction: Volcanic influence on centennial to millennial Holocene Greenland temperature change
Authors: Kobashi Takuro , Menviel Laurie , Jeltsch-Thömmes Aurich , Vinther Bo M. , Box Jason E. , Muscheler Raimund , Nakaegawa Toshiyuki , Pfister Patrik L. , Döring Michael , Leuenberger Markus , Wanner Heinz , Ohmura Atsumu 
Published: March 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Publisher Correction: Quaternary history, population genetic structure and diversity of the cold-adapted Alpine newt Ichthyosaura alpestris in peninsular Italy
Authors: Chiocchio Andrea , Bisconti Roberta , Zampiglia Mauro , Nascetti Giuseppe , Canestrelli Daniele 
Published: March 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Increased intracellular activity of MP1102 and NZ2114 against Staphylococcus aureus in vitro and in vivo
Authors: Wang Xiao , Wang Xiumin , Teng Da , Mao Ruoyu , Hao Ya , Yang Na , Li Zhanzhan , Wang Jianhua 
Published: March 2018

AbstractTreatment of Staphylococcus aureus infections remains very difficult due to its capacity to survive intracellularly and its multidrug resistance. In this study, the extracellular/intracellular activities of plectasin derivatives-MP1102/NZ2114 were investigated against three methicillin-susceptible/-resistant S. aureus (MSSA/MRSA) strains in RAW 264.7 macrophages and mice to overcome poor intracellular activity. Antibacterial activities decreased 4–16-fold under a mimic phagolysosomal environment. MP1102/NZ2114 were internalized into the cells via clathrin-mediated endocytosis and macropinocytosis and distributed in the cytoplasm; they regulated tumor necrosis factor-α, interleukin-1β and interleukin-10 levels. The extracellular maximal relative efficacy (Emax) values of MP1102/NZ2114 towards the three S. aureus strains were >5-log decrease in colony forming units (CFU). In the methicillin-resistant and virulent strains, MP1102/NZ2114 exhibited intracellular bacteriostatic efficacy with an Emax of 0.42–1.07-log CFU reduction. In the MSSA ATCC25923 mouse peritonitis model, 5 mg/kg MP1102/NZ2114 significantly reduced the bacterial load at 24 h, which was superior to vancomycin. In MRSA ATCC43300, their activity was similar to that of vancomycin. The high virulent CVCC546 strain displayed a relatively lower efficiency, with log CFU decreases of 2.88–2.91 (total), 3.41–3.50 (extracellular) and 2.11–2.51 (intracellular) compared with vancomycin (3.70). This suggests that MP1102/NZ2114 can be used as candidates for treating intracellular S. aureus.
High-affinity ligands of the colchicine domain in tubulin based on a structure-guided design
Authors: Bueno Oskía , Estévez Gallego Juan , Martins Solange , Prota Andrea E. , Gago Federico , Gómez-SanJuan Asier , Camarasa María-José , Barasoain Isabel , Steinmetz Michel O. , Díaz J. Fernando , Pérez-Pérez María-Jesús , Liekens Sandra , Priego Eva-María 
Published: March 2018

AbstractMicrotubule-targeting agents that bind at the colchicine-site of tubulin are of particular interest in antitumoral therapy due to their dual mechanism of action as antimitotics and vascular disrupting agents. Cyclohexanediones derivatives have been described as a new family of colchicine-domain binders with an association constant to tubulin similar to that of colchicine. Here, the high-resolution structures of tubulin in complex with cyclohexanediones TUB015 and TUB075 were solved by X-ray crystallography. A detailed analysis of the tubulin-TUB075 interaction by means of computational affinity maps allowed the identification of two additional regions at the binding site that were addressed with the design and synthesis of a new series of cyclohexanediones with a distal 2-substituted benzofurane. These new compounds showed potent antiproliferative activity with IC50 values in the nM range, arrested cell cycle progression at the G2/M phase and induced apoptosis at sub μM concentrations. Moreover, they caused the destruction of a preformed vascular network in vitro and inhibited the migration of endothelial cells at non-toxic concentrations. Finally, these compounds displayed high affinity for tubulin as substantiated by a K
b
value of 2.87 × 108 M−1 which, to the best of our knowledge, represents the highest binding constant measured to date for a colchicine-domain ligand.
Intensify3D: Normalizing signal intensity in large heterogenic image stacks
Authors: Yayon Nadav , Dudai Amir , Vrieler Nora , Amsalem Oren , London Michael , Soreq Hermona 
Published: March 2018

AbstractThree-dimensional structures in biological systems are routinely evaluated using large image stacks acquired from fluorescence microscopy; however, analysis of such data is muddled by variability in the signal across and between samples. Here, we present Intensify3D: a user-guided normalization algorithm tailored for overcoming common heterogeneities in large image stacks. We demonstrate the use of Intensify3D for analyzing cholinergic interneurons of adult murine brains in 2-Photon and Light-Sheet fluorescence microscopy, as well as of mammary gland and heart tissues. Beyond enhancement in 3D visualization in all samples tested, in 2-Photon in vivo images, this tool corrected errors in feature extraction of cortical interneurons; and in Light-Sheet microscopy, it enabled identification of individual cortical barrel fields and quantification of somata in cleared adult brains. Furthermore, Intensify3D enhanced the ability to separate signal from noise. Overall, the universal applicability of our method can facilitate detection and quantification of 3D structures and may add value to a wide range of imaging experiments.
A Facile Approach to Prepare Multiple Heteroatom-Doped Carbon Materials from Imine-Linked Porous Organic Polymers
Authors: Yang Juan , Xu Min , Wang Jingyu , Jin Shangbin , Tan Bien 
Published: March 2018

AbstractIn this paper, we proposed a new strategy to prepare multiple heteroatom doped (N,P-doped) porous carbon materials with high surface area of ~1,535 m2g−1simply by pyrolysis of imine-linked porous organic polymers (POPs) synthesizedviaSchiff base condensation. The strategy is simple without any post-processing and various heteroatoms could be involved. Scanning electron microscopy, Raman spectra, Nitrogen gas adsorption-desorption, X-ray photoelectron spectroscopy have been used to characterize the morphology, the structure and the composition of the materials. The multiple heteroatom doped porous carbon materials also display high electrocatalytic performance as exampled by the application in oxygen reduction, which showed the catalyst favors 4-electron transfer during the process, along with superior stability and higher tolerance to methanol as compared to the Pt/C. These results indicate the present method is promising for the preparation of multi-heteroatom doped carbon materials in the application of electrocatalysis.
Reactive oxygen species stress increases accumulation of tyrosyl-DNA phsosphodiesterase 1 within mitochondria
Authors: Fam Hok Khim , Choi Kunho , Fougner Lauren , Lim Chinten James , Boerkoel Cornelius F. 
Published: March 2018

AbstractTyrosyl-DNA phosphodiesterase 1 (Tdp1) is a nuclear and mitochondrial protein that in nuclei and in vitro repairs blocked 3′ DNA termini such as 3′ phosphotyrosine conjugates resulting from stalling of topoisomerase I-DNA intermediates. Its mutation also causes spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1). Because Tdp1 colocalizes with mitochondria following oxidative stress, we hypothesized that Tdp1 repairs mitochondrial DNA (mtDNA) and that mtDNA damage mediates entry of Tdp1 into the mitochondria. To test this, we used S. cerevisiae mutants, cultured mouse and human cells, and a Tdp1 knockout mouse. H2O2- and rotenone-induced cellular and intramitochondrial reactive oxygen species (ROS) activated oxidant-responsive kinases P38 and ERK1, and the translocation of Tdp1 from the nucleus to the mitochondria via the TIM/TOM complex. This translocation occurred independently of mtDNA. Within the mitochondria, Tdp1 interacted with Ligase III and reduced mtDNA mutations. Tdp1-deficient tissues had impaired mitochondrial respiration and decreased viability. These observations suggest that Tdp1 maintains mtDNA integrity and support the hypothesis that mitochondrial dysfunction contributes to the pathology of SCAN1.
The dose-response analysis between BMI and common chronic diseases in northeast China
Authors: Yu Jianxing , Tao Yuchun , Dou Jing , Ye Junsen , Yu Yaqin , Jin Lina 
Published: March 2018

AbstractHigh body mass index (BMI) predisposes to several chronic diseases, but a large-scale systematic and detailed study of dose-response relationship between BMI and chronic diseases has not been reported previously. In this study, we aimed to investigate the relationship between BMI and 3 chronic diseases (hypertension, dyslipidemia and MetS) in northeast China. A sample of 16412 participants aged 18~79 years old were included in Jilin province in 2012. The lambda-mu-sigma (LMS) method was applied to examine the trend of BMI by age, and the restricted cubic splines were used to investigate the non-linear associations (dose-response curve) between BMI and chronic diseases. It was pointed out that BMI increased rapidly when young, then kept steady in middle age, and finally declined slowly in old age, and accordingly age was divided into 3 segments, which were different by gender. The odds ratios (ORs) of BMI for the chronic diseases increased relatively slowly when young, then increased dramatically in middle-age and old population, especially for men. Further, the ORs of BMI among non-smokers were lower than those among smokers, and the same trend was shown to be more apparent among drinkers and non-drinkers. The risk of BMI for common chronic diseases increased dramatically in middle-aged, especially for men with drinking and smoking habits.
Identifying temporal patterns in patient disease trajectories using dynamic time warping: A population-based study
Authors: Giannoula Alexia , Gutierrez-Sacristán Alba , Bravo Álex , Sanz Ferran , Furlong Laura I. 
Published: March 2018

AbstractTime is a crucial parameter in the assessment of comorbidities in population-based studies, as it permits to identify more complex disease patterns apart from the pairwise disease associations. So far, it has been, either, completely ignored or only, taken into account by assessing the temporal directionality of identified comorbidity pairs. In this work, a novel time-analysis framework is presented for large-scale comorbidity studies. The disease-history vectors of patients of a regional Spanish health dataset are represented as time sequences of ordered disease diagnoses. Statistically significant pairwise disease associations are identified and their temporal directionality is assessed. Subsequently, an unsupervised clustering algorithm, based on Dynamic Time Warping, is applied on the common disease trajectories in order to group them according to the temporal patterns that they share. The proposed methodology for the temporal assessment of such trajectories could serve as the preliminary basis of a disease prediction system.