bluuebunny/crossref_metadata_2025 huggingface dataset:
Performance of five automated white matter hyperintensity segmentation methods in a multicenter dataset
Authors: Heinen Rutger , Steenwijk Martijn D. , Barkhof Frederik , Biesbroek J. Matthijs , van der Flier Wiesje M. , Kuijf Hugo J. , Prins Niels D. , Vrenken Hugo , Biessels Geert Jan , de Bresser Jeroen ,   TRACE-VCI study group, van den Berg E. , Biessels G. J. , Boomsma J. M. F. , Exalto L. G. , Ferro D. A. , Frijns C. J. M. , Groeneveld O. N. , Heinen R. , van Kalsbeek N. M. , Verwer J. H. , de Bresser J. , Kuijf H. J. , Emmelot-Vonk M. E. , Koek H. L. , Benedictus M. R. , Bremer J. , van der Flier W. M. , Leeuwis A. E. , Leijenaar J. , Prins N. D. , Scheltens P. , Tijms B. M. , Barkhof F. , Wattjes M. P. , Teunissen C. E. , Koene T. , Boomsma J. M. F. , Weinstein H. C. , Hamaker M. , Faaij R. , Pleizier M. , Prins M. , Vriens E.
Published: November 2019

White matter hyperintensities (WMHs) are a common manifestation of cerebral small vessel disease, that is increasingly studied with large, pooled multicenter datasets. This data pooling increases statistical power, but poses challenges for automated WMH segmentation. Although there is extensive literature on the evaluation of automated WMH segmentation methods, such evaluations in a multicenter setting are lacking. We performed WMH segmentations in sixty patients scanned on six different magnetic resonance imaging (MRI) scanners (10 patients per scanner) using five freely available and fully-automated WMH segmentation methods (Cascade, kNN-TTP, Lesion-TOADS, LST-LGA and LST-LPA). Different MRI scanner vendors and field strengths were included. We compared these automated WMH segmentations with manual WMH segmentations as a reference. Performance of each method both within and across scanners was assessed using spatial and volumetric correspondence with the reference segmentations by Dice’s similarity coefficient (DSC) and intra-class correlation coefficient (ICC) respectively. We found the best performance, both within and across scanners, for kNN-TTP, followed by LST-LPA and LST-LGA, with worse performance for Lesion-TOADS and Cascade. Our findings can serve as a guide for choosing a method and also highlight the importance to further improve and evaluate consistency of methods in a multicenter setting.
High-fat diet-mediated dysbiosis exacerbates NSAID-induced small intestinal damage through the induction of interleukin-17A
Authors: Sugimura Naoki , Otani Koji , Watanabe Toshio , Nakatsu Geicho , Shimada Sunao , Fujimoto Kosuke , Nadatani Yuji , Hosomi Shuhei , Tanaka Fumio , Kamata Noriko , Taira Koichi , Nagami Yasuaki , Tanigawa Tetsuya , Uematsu Satoshi , Fujiwara Yasuhiro
Published: November 2019

Non-steroidal anti-inflammatory drugs (NSAIDs) cause damage in the small intestine in a bacteria-dependent manner. As high-fat diet (HFD) is a potent inducer of gut dysbiosis, we investigated the effects of HFD on bacterial flora in the small intestine and NSAID-induced enteropathy. 16S rRNA gene analysis revealed that the population of Bifidobacterium spp. significantly decreased by fold change of individual operational taxonomic units in the small intestine of mice fed HFD for 8 weeks. HFD increased intestinal permeability, as indicated by fluorescein isothiocyanate-dextran absorption and serum lipopolysaccharide levels, accompanied by a decrease in the protein expressions of ZO-1 and occludin and elevated mRNA expression of interleukin (IL)-17A in the small intestine. HFD-fed mice exhibited increased susceptibility to indomethacin-induced damage in the small intestine; this phenotype was observed in normal diet-fed mice that received small intestinal microbiota from HFD-fed mice. Administration of neutralizing antibodies against IL-17A to HFD-fed mice reduced intestinal permeability and prevented exacerbation of indomethacin-induced damage. Thus, HFD-induced microbial dysbiosis in small intestine caused microinflammation through the induction of IL-17A and increase in intestinal permeability, resulting in the aggravation of NSAID-induced small intestinal damage.
The morpho-genetic and ecological niche analyses reveal the existence of climatically restricted Cycas zeylanica complex in Sri Lanka
Authors: Mudannayake Asanka , Ranaweera Lahiru , Samaraweera Preminda , Sooriyapathirana Suneth , Perera Anoma
Published: November 2019

Taxonomy and phylogenesis of Sri Lankan cycad species of the subsection Rumphiae has not been fully resolved and therefore, we conducted an island-wide survey of cycads of the subsection to assess their morphological or genetic variations while exploring the phylogenetic relationship between Sri Lankan Rumphiae and other world cycad species. Further, we assessed the possible distribution of the species in the region through climatic profiling, using maximum entropy modeling approach. We analyzed 21 variable morphological features in collected specimens and used the polymorphism of trnH-psbA locus to understand the phylogeny. The distance tree drawn from the principal component analysis revealed a significant variation in female reproductive structures. The maximum likelihood tree separated Sri Lankan Cycas zeylanica to a well-supported unigeneric clade (bootstrap = 96, posterior probability = 100) with shallow divergence. Ecological niche modeling supported the existence of Cycas zeylanica in South East Asia and in southern Western Ghats in India in addition to the Wet Zone of Sri Lanka. We rename the taxa as Cycas zeylanica complex based on the observed high morphological diversity of female reproductive structures which might have ascended due to multiple introductions of South East Asian cycads by long distance dispersal of seeds through sea currents.
PGC-1β Induces Susceptibility To Acetaminophen-Driven Acute Liver Failure
Authors: Piccinin Elena , Ducheix Simon , Peres Claudia , Arconzo Maria , Vegliante Maria Carmela , Ferretta Anna , Bellafante Elena , Villani Gaetano , Moschetta Antonio
Published: November 2019

Acetaminophen (APAP) is a worldwide commonly used painkiller drug. However, high doses of APAP can lead to acute hepatic failure and, in some cases, death. Previous studies indicated that different factors, including life-style and metabolic diseases, could predispose to the risk of APAP-induced liver failure. However, the molecular process that could favor APAP hepatotoxicity remains understood. Here, we reported that a short-term high fat-enriched diet worsens APAP-induced liver damage, by promoting liver accumulation of lipids that induces the activation of peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC-1β). Therefore, we challenged mice with hepatic-specific PGC-1β overexpression on a chow diet with a subtoxic dose of APAP and we found that PGC-1β overexpression renders the liver more sensitive to APAP damage, mainly due to intense oxidative stress, finally ending up with liver necrosis and mice death. Overall, our results indicated that during high fat feeding, PGC-1β adversely influences the ability of the liver to overcome APAP toxicity by orchestrating different metabolic pathways that finally lead to fatal outcome.
Fecal microbiome signatures of pancreatic cancer patients
Authors: Half Elizabeth , Keren Nirit , Reshef Leah , Dorfman Tatiana , Lachter Ishai , Kluger Yoram , Reshef Naama , Knobler Hilla , Maor Yaakov , Stein Assaf , Konikoff Fred M. , Gophna Uri
Published: November 2019

Pancreatic cancer (PC) is a leading cause of cancer-related death in developed countries, and since most patients have incurable disease at the time of diagnosis, developing a screening method for early detection is of high priority. Due to its metabolic importance, alterations in pancreatic functions may affect the composition of the gut microbiota, potentially yielding biomarkers for PC. However, the usefulness of these biomarkers may be limited if they are specific for advanced stages of disease, which may involve comorbidities such as biliary obstruction or diabetes. In this study we analyzed the fecal microbiota of 30 patients with pancreatic adenocarcinoma, 6 patients with pre-cancerous lesions, 13 healthy subjects and 16 with non-alcoholic fatty liver disease, using amplicon sequencing of the bacterial 16S rRNA gene. Fourteen bacterial features discriminated between PC and controls, and several were shared with findings from a recent Chinese cohort. A Random Forest model based on the microbiota classified PC and control samples with an AUC of 82.5%. However, inter-subject variability was high, and only a small part of the PC-associated microbial signals were also observed in patients with pre-cancerous pancreatic lesions, implying that microbiome-based early detection of such lesions will be challenging.
Shrub cover homogenizes small mammals’ activity and perceived predation risk
Authors: Loggins Anne A. , Shrader Adrian M. , Monadjem Ara , McCleery Robert A.
Published: November 2019

Altered disturbance regimes, increasing atmospheric CO2, and other processes have increased woody cover and homogenized vegetation in savannas across the planet. African savannas with extensive versus minimal woody cover often have vastly different animal communities. However, we lack a clear mechanistic understanding of why animal communities are changing with vegetation structure. Our goal for this study was to understand how vegetation structure in an African savanna shaped the perceived predation risk of small mammals, hence affecting their activity. Using a reciprocal measure of standard giving-up-densities, amount of food eaten, we found sharp declines in rodents’ perceived predation risk and increased rodent activity underneath shrub cover. This response was consistent across species; however, species showed subtle differences in their responses to grassy vegetation. Our findings suggest that areas of minimal or extensive shrub cover (shrub encroachment) may be homogenizing rodents’ perceptions of predation risk and thus shaping their use of space.
Multiple genome analyses reveal key genes in Vitamin C and Vitamin D synthesis and transport pathways are shared
Authors: Dong Wei , Tian Cheng , Jiao Yan , Blackwell Savannah , Lou Ge , Postlethwaite Arnold , Gu Weikuan , Sun Dianjun
Published: November 2019

Vitamin C (VC) and vitamin D (VD) have been widely used as the dietary supplements and in treatment of diseases both independently and in combination. Whether there is a connection between their pathways is critical for their therapeutic applications. Using whole-genome expression profiles, we performed multiple measures of associations, networks, eQTL mappings and expressions of key genes of interest in VC and VD functions. Several key genes in their pathways were found to be associated. Gc and Rgn play important roles connecting VC and VD pathways in mice. The r values of expression levels between Gc and Rgn in mouse spleen, liver, lung, and kidney are 0.937, 0.558, 0.901, and 0.617, respectively. The expression QTLs of Gc and Rgn are mapped onto the same locations, i.e., 68–76 MB in chromosome 7 and 26–36 MB in chromosome 9. In humans, there are positive correlations between CYP27B1 and SLC23A1 expression levels in kidney (r = 0.733) and spleen (r = 0.424). SLC23A2 and RXRA are minimally associated in both mouse and human. These data indicate that pathways of VC and VD are not independent but affect each other, and this effect is different between mice and humans during VC and VD synthesis and transportation.
Duration of stunting impacts compensatory growth and carcass quality of farmed milkfish, Chanos chanos (Forsskal, 1775) under field conditions
Authors: Lingam Somu Sunder , Sawant Paramita Banerjee , Chadha Narinder Kumar , Prasad Kurcheti Pani , Muralidhar A. P. , Syamala Karthireddy , Xavier K. A. Martin
Published: November 2019

An 18-months field trial was performed to explore the effect of duration of stunting on growth, digestive enzymes and carcass quality in Chanos chanos. Milkfish fry (weight of 1.25 ± 0.03 g and length of 5.53 ± 0.03 cm) were stocked in earthen ponds of 0.02 ha, in triplicate, for different duration of stunting, viz., 4 months (Treatment-1; T4), 8 months (Treatment-2; T8) and 12 months (Treatment-3; T12) and a normal seed (Control; C) separately. In the stunting phase, fish were stocked at higher stocking density (0.2 million/ha) and fed de-oiled rice bran at sub-optimal level. Post-stunting or re-feeding phase commenced immediately after completion of respective stunting duration and fish were reared for the rest of the period to complete the total rearing period of 18 months. In post-stunting, fish stocking density was adjusted to (5000 pieces/ha) and fed at an optimum level (3%). At the end of stunting phase, the study found a significant reduction in growth, survival, digestive enzymes activity, except protease in the T4 group, and carcass nutrients composition of stunted fish. However, in the initial phase of post-stunting, T8 group exhibited an elevated specific growth rate (5.00 ± 0.092%/day), body weight gain (80.82 ± 1.28 g), amylase (0.585 ± 0.021 U/mg protein), protease (5.48 ± 0.13 U/mg protein), and lipase activity (7.92 ± 0.32 U/mg protein). All stunted fish groups displayed a compensatory growth response in post-stunting, but a complete growth compensation was observed in T8 group, which resulted in better feed conversion ratio (3.03 ± 0.04) feed efficiency ratio (0.33 ± 0.01), protein efficiency ratio (1.91 ± 0.03), survival (91.38 ± 0.07%) and digestive enzyme activities. Similarly, at the end of post-stunting, carcass analysis revealed a complete restoration of nutrients in stunted fish and significantly higher protein content in T8 group. Further, the study found lower meat and higher bone contents in normally reared fish than the post-stunted fish which revealed the carcass quality improvement in post-stunted fish thus indicates superiority of the stunting process over normal rearing. Overall, the study suggests that stunting of milkfish, for 8 months (T8), positively affects its growth, survival, digestive enzyme activities and carcass quality which in turn, shall help to overcome the contemporary challenges in milkfish culture.
PRAS40 suppresses atherogenesis through inhibition of mTORC1-dependent pro-inflammatory signaling in endothelial cells
Authors: Zhang Kevin Sun , Schecker Johannes , Krull Alexandros , Riechert Eva , Jürgensen Lonny , Kamuf-Schenk Verena , Burghaus Jana , Kiper Leon , Cao Ho Thanh , Wöltje Kerstin , Stangl Verena , Katus Hugo A. , Stangl Karl , Völkers Mirko , Althoff Till F.
Published: November 2019

Endothelial pro-inflammatory activation plays a pivotal role in atherosclerosis, and many pro-inflammatory and atherogenic signals converge upon mechanistic target of rapamycin (mTOR). Inhibitors of mTOR complex 1 (mTORC1) reduced atherosclerosis in preclinical studies, but side effects including insulin resistance and dyslipidemia limit their clinical use in this context. Therefore, we investigated PRAS40, a cell type-specific endogenous modulator of mTORC1, as alternative target. Indeed, we previously found PRAS40 gene therapy to improve metabolic profile; however, its function in endothelial cells and its role in atherosclerosis remain unknown. Here we show that PRAS40 negatively regulates endothelial mTORC1 and pro-inflammatory signaling. Knockdown of PRAS40 in endothelial cells promoted TNFα-induced mTORC1 signaling, proliferation, upregulation of inflammatory markers and monocyte recruitment. In contrast, PRAS40-overexpression blocked mTORC1 and all measures of pro-inflammatory signaling. These effects were mimicked by pharmacological mTORC1-inhibition with torin1. In an in vivo model of atherogenic remodeling, mice with induced endothelium-specific PRAS40 deficiency showed enhanced endothelial pro-inflammatory activation as well as increased neointimal hyperplasia and atherosclerotic lesion formation. These data indicate that PRAS40 suppresses atherosclerosis via inhibition of endothelial mTORC1-mediated pro-inflammatory signaling. In conjunction with its favourable effects on metabolic homeostasis, this renders PRAS40 a potential target for the treatment of atherosclerosis.
Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis
Authors: Saw Wuan-Geok , Wu Mu-Lu , Ragunathan Priya , Biuković Goran , Lau Aik-Meng , Shin Joon , Harikishore Amaravadhi , Cheung Chen-Yi , Hards Kiel , Sarathy Jickky Palmae , Bates Roderick W. , Cook Gregory M. , Dick Thomas , Grüber Gerhard
Published: November 2019

The dynamic interaction of the N- and C-terminal domains of mycobacterial F-ATP synthase subunit ε is proposed to contribute to efficient coupling of H+-translocation and ATP synthesis. Here, we investigate crosstalk between both subunit ε domains by introducing chromosomal atpC missense mutations in the C-terminal helix 2 of ε predicted to disrupt inter domain and subunit ε-α crosstalk and therefore coupling. The ε mutant εR105A,R111A,R113A,R115A (ε4A) showed decreased intracellular ATP, slower growth rates and lower molar growth yields on non-fermentable carbon sources. Cellular respiration and metabolism were all accelerated in the mutant strain indicative of dysregulated oxidative phosphorylation. The ε4A mutant exhibited an altered colony morphology and was hypersusceptible to cell wall-acting antimicrobials suggesting defective cell wall biosynthesis. In silico screening identified a novel mycobacterial F-ATP synthase inhibitor disrupting ε’s coupling activity demonstrating the potential to advance this regulation as a new area for mycobacterial F-ATP synthase inhibitor development.
Improved power and precision with whole genome sequencing data in genome-wide association studies of inflammatory biomarkers
Authors: Höglund Julia , Rafati Nima , Rask-Andersen Mathias , Enroth Stefan , Karlsson Torgny , Ek Weronica E. , Johansson Åsa
Published: November 2019

Genome-wide association studies (GWAS) have identified associations between thousands of common genetic variants and human traits. However, common variants usually explain a limited fraction of the heritability of a trait. A powerful resource for identifying trait-associated variants is whole genome sequencing (WGS) data in cohorts comprised of families or individuals from a limited geographical area. To evaluate the power of WGS compared to imputations, we performed GWAS on WGS data for 72 inflammatory biomarkers, in a kinship-structured cohort. When using WGS data, we identified 18 novel associations that were not detected when analyzing the same biomarkers with genotyped or imputed SNPs. Five of the novel top variants were low frequency variants with a minor allele frequency (MAF) of <5%. Our results suggest that, even when applying a GWAS approach, we gain power and precision using WGS data, presumably due to more accurate determination of genotypes. The lack of a comparable dataset for replication of our results is a limitation in our study. However, this further highlights that there is a need for more genetic epidemiological studies based on WGS data.
An Improved Free Energy Perturbation FEP+ Sampling Protocol for Flexible Ligand-Binding Domains
Authors: Fratev Filip , Sirimulla Suman
Published: November 2019

Recent improvements to the free energy perturbation (FEP) calculations, especially FEP+ , established their utility for pharmaceutical lead optimization. Herein, we propose a modified version of the FEP/REST (i.e., replica exchange with solute tempering) sampling protocol, based on detail studies on several targets by probing a large number of perturbations with different sampling schemes. Improved FEP+ binding affinity predictions for regular flexible-loop motions and considerable structural changes can be obtained by extending the prior to REST (pre-REST) sampling time from 0.24 ns/λ to 5 ns/λ and 2 × 10 ns/λ, respectively. With this new protocol, much more precise ∆∆G values of the individual perturbations, including the sign of the transformations and decreased error were obtained. We extended the REST simulations from 5 ns to 8 ns to achieve reasonable free energy convergence. Implementing REST to the entire ligand as opposed to solely the perturbed region, and also some important flexible protein residues (pREST region) in the ligand binding domain (LBD) has considerably improved the FEP+ results in most of the studied cases. Preliminary molecular dynamics (MD) runs were useful for establishing the correct binding mode of the compounds and thus precise alignment for FEP+ . Our improved protocol may further increase the FEP+ accuracy.
The first comprehensive phylogenetic and biochemical analysis of NADH diphosphatases reveals that the enzyme from Tuber melanosporum is highly active towards NAD+
Authors: García-Saura Antonio Ginés , Zapata-Pérez Rubén , Martínez-Moñino Ana Belén , Hidalgo José Francisco , Morte Asunción , Pérez-Gilabert Manuela , Sánchez-Ferrer Álvaro
Published: November 2019

Nudix (for nucleoside diphosphatases linked to other moieties, X) hydrolases are a diverse family of proteins capable of cleaving an enormous variety of substrates, ranging from nucleotide sugars to NAD+-capped RNAs. Although all the members of this superfamily share a common conserved catalytic motif, the Nudix box, their substrate specificity lies in specific sequence traits, which give rise to different subfamilies. Among them, NADH pyrophosphatases or diphosphatases (NADDs) are poorly studied and nothing is known about their distribution. To address this, we designed a Prosite-compatible pattern to identify new NADDs sequences. In silico scanning of the UniProtKB database showed that 3% of Nudix proteins were NADDs and displayed 21 different domain architectures, the canonical architecture (NUDIX-like_zf-NADH-PPase_NUDIX) being the most abundant (53%). Interestingly, NADD fungal sequences were prominent among eukaryotes, and were distributed over several Classes, including Pezizomycetes. Unexpectedly, in this last fungal Class, NADDs were found to be present from the most common recent ancestor to Tuberaceae, following a molecular phylogeny distribution similar to that previously described using two thousand single concatenated genes. Finally, when truffle-forming ectomycorrhizal Tuber melanosporum NADD was biochemically characterized, it showed the highest NAD+/NADH catalytic efficiency ratio ever described.
Assessing cross-species transmission of hemoplasmas at the wild-domestic felid interface in Chile using genetic and landscape variables analysis
Authors: Sacristán I. , Acuña F. , Aguilar E. , García S. , López M. J. , Cevidanes A. , Cabello J. , Hidalgo-Hermoso E. , Johnson W. E. , Poulin E. , Millán J. , Napolitano C.
Published: November 2019

The co-occurrence of domestic cats (Felis silvestris catus) and wild felids in rural landscapes can facilitate pathogen transmission. However, in the relatively-isolated regions of southern South America there have been no comprehensive studies to assess disease transmission risks between domestic cats and forest-dwelling wild felids such as guigna (Leopardus guigna). We evaluated hemoplasma infection and the possibility of transmission between domestic cats and guignas by comparing spatial and phylogenetic patterns of pathogen prevalence. Blood/spleen samples were collected from 102 wild guignas and 262 co-occurring rural domestic cats across the entire distribution range of guigna in Chile. Hemoplasma infection was assessed by direct sequencing of the 16S RNA gene. Infection with hemoplasmas was common and geographically widespread across different bioclimatic areas for both species. The most common felineMycoplasmaspecies in guigna and domestic cats wereCandidatusM. haemominutum (CMhm) (15.7% guigna; 10.3% domestic cat) andMycoplasma haemofelis(Mhf) (9.8% guigna, 6.1% domestic cat). A previously undescribedMycoplasmasp. sequence was found in two guignas and one cat. Continuous forest-landscapes were associated with higher hemoplasma-prevalence in guignas. Shared hemoplasma nucleotide sequence types between guigna and domestic cats were rare, suggesting that cross-species transmission between guignas and domestic cats may occur, but is probably uncommon. Ectoparasites, which have been linked with hemoplasma transmission, were not found on guignas and were infrequent on domestic cats. Our results suggest that transmission pathways vary among hemoplasma species and, contrary to our predictions, domestic cats did not appear to be the main driver of hemoplasma infection in guignas in these human-dominated landscapes.
Data-driven spectral analysis for coordinative structures in periodic human locomotion
Authors: Fujii Keisuke , Takeishi Naoya , Kibushi Benio , Kouzaki Motoki , Kawahara Yoshinobu
Published: November 2019

Living organisms dynamically and flexibly operate a great number of components. As one of such redundant control mechanisms, low-dimensional coordinative structures among multiple components have been investigated. However, structures extracted from the conventional statistical dimensionality reduction methods do not reflect dynamical properties in principle. Here we regard coordinative structures in biological periodic systems with unknown and redundant dynamics as a nonlinear limit-cycle oscillation, and apply a data-driven operator-theoretic spectral analysis, which obtains dynamical properties of coordinative structures such as frequency and phase from the estimated eigenvalues and eigenfunctions of a composition operator. Using segmental angle series during human walking as an example, we first extracted the coordinative structures based on dynamics; e.g. the speed-independent coordinative structures in the harmonics of gait frequency. Second, we discovered the speed-dependent time-evolving behaviours of the phase by estimating the eigenfunctions via our approach on the conventional low-dimensional structures. We also verified our approach using the double pendulum and walking model simulation data. Our results of locomotion analysis suggest that our approach can be useful to analyse biological periodic phenomena from the perspective of nonlinear dynamical systems.
The positive correlation of TIPRL with LC3 and CD133 contributes to cancer aggressiveness: potential biomarkers for early liver cancer
Authors: Jun Soo Young , Jeon Su-Jin , Yoon Ji-Yong , Lee Jeong-Ju , Yoon Hyang Ran , Choi Min-Hyuk , Halder Debasish , Lee Kwangho , Kim Nam-Soon
Published: November 2019

Studies have reported dysregulation of TIPRL, LC3 and CD133 in liver cancer tissues. However, their respective relationships to liver cancer and roles as biomarkers for prognosis and diagnosis of liver cancer have never been studied. Here we report that the level of TIPRL is significantly correlated with levels of LC3 (Spearman r = 0.9) and CD133 (r = 0.7) in liver cancer tissues. We observed significant upregulations of TIPRL, LC3 and CD133 in hepatocellular carcinomas (HCCs) compared with adjacent normal tissues. Importantly, TIPRL, tested among additional variables, showed a significant impact on the prognosis of HCC patients. TIPRL knockdown significantly reduced expressions of LC3, CD133, stemness-related genes, as well as viability and stemness of liver cancer cell-lines, which were promoted by ectopic TIPRL expression. Either alone or as a combination, TIPRL, LC3 and CD133 showed significant values of area under the curve (AUC) and sensitivity/specificity in early liver cancer tissues. Furthermore, the statistical association and the diagnostic efficacies of TIPRL, LC3 and CD133 in HCC tissues were confirmed in a different IHC cohort. This data demonstrates that the complex involvement of TIPRL/LC3/CD133 in liver cancer aggressiveness can together or individually serve as potential biomarkers for the early detection of liver cancer.
Hemophilia A ameliorated in mice by CRISPR-based in vivo genome editing of human Factor VIII
Authors: Chen Hainan , Shi Mi , Gilam Avital , Zheng Qi , Zhang Yin , Afrikanova Ivka , Li Jinling , Gluzman Zoya , Jiang Ruhong , Kong Ling-Jie , Chen-Tsai Ruby Yanru
Published: November 2019

Hemophilia A is a monogenic disease with a blood clotting factor VIII (FVIII) deficiency caused by mutation in the factor VIII (F8) gene. Current and emerging treatments such as FVIII protein injection and gene therapies via AAV-delivered F8 transgene in an episome are costly and nonpermanent. Here, we describe a CRISPR/Cas9-based in vivo genome editing method, combined with non-homologous end joining, enabling permanent chromosomal integration of a modified human B domain deleted-F8 (BDD-F8) at the albumin (Alb) locus in liver cells. To test the approach in mice, C57BL/6 mice received tail vein injections of two vectors, AAV8-SaCas9-gRNA, targeting Alb intron 13, and AAV8-BDD-F8. This resulted in BDD-F8 insertion at the Alb locus and FVIII protein expression in the liver of vector-, but not vehicle-, treated mice. Using this approach in hemophilic mice, BDD-F8 was expressed in liver cells as functional human FVIII, leading to increased plasma levels of FVIII and restoration of blood clotting properties in a dose-dependent manor for at least 7 months, with no detectable liver toxicity or meaningful off-target effects. Based on these findings, our BDD-F8 genome editing approach may offer an efficacious, long-term and safe treatment for patients with hemophilia A.
Engineering a Virus-Like Particle as an Antigenic Platform for a Pfs47-Targeted Malaria Transmission-Blocking Vaccine
Authors: Yenkoidiok-Douti Lampouguin , Williams Adeline E. , Canepa Gaspar E. , Molina-Cruz Alvaro , Barillas-Mury Carolina
Published: November 2019

We recently characterized Pfs47, a protein expressed on the surface of sexual stages and ookinetes of Plasmodium falciparum, as a malaria transmission-blocking vaccine (TBV) target. Mice immunization induced antibodies that conferred strong transmission-reducing activity (TRA) at a concentration of 200 μg/mL. Here, we sought to optimize the Pfs47 vaccine to elicit higher titers of high-affinity antibodies, capable of inducing strong TRA at a lower concentration. We report the development and evaluation of a Pfs47-based virus-like particle (VLP) vaccine generated by conjugating our 58 amino acid Pfs47 antigen to Acinetobacter phage AP205-VLP using the SpyCatcher:SpyTag adaptor system. AP205-Pfs47 complexes (VLP-P47) formed particles of ~22 nm diameter that reacted with polyclonal anti-Pfs47 antibodies, indicating that the antigen was accessible on the surface of the particle. Mice immunized with VLP-P47 followed by a boost with Pfs47 monomer induced significantly higher antibody titers, with higher binding affinity to Pfs47, than mice that received two immunizations with either VLP-P47 (VLP-P47/VLP-P47) or the Pfs47 monomer (P47/P47). Purified IgG from VLP-P47/P47 mice had strong TRA (83–98%) at concentrations as low as 5 μg/mL. These results indicate that conjugating the Pfs47 antigen to AP205-VLP significantly enhanced antigenicity and confirm the potential of Pfs47 as a TBV candidate.
Two Hybrid Au-ZnO Heterostructures with Different Hierarchical Structures: Towards Highly Efficient Photocatalysts
Authors: Yang Shuo , Wang Lijing , Yan Yongsheng , Yang Lili , Li Xin , Lu Ziyang , Zhai Hongju , Han Donglai , Huo Pengwei
Published: November 2019

A new paradigm for photocatalysts based on two different hierarchically structured honeycomb and porous cylindrical Au-ZnO heterostructures was successfully developed via a straightforward and cost-effective hydrothermal method under different preparation conditions, which can be promising for industrial applications. The photocatalytic performance of all as-prepared samples under the illumination of sunlight was evaluated by the photocatalytic degradation of rhodamine B (RhB) and malachite green (MG) aqueous solutions. The results show that the photocatalytic degradation efficiency of RhB and MG was 55.3% and 40.7% for ZnO, 95.3% and 93.4% for the porous cylindrical Au-ZnO heterostructure, and 98.6% and 99.5% for the honeycomb Au-ZnO heterostructure, respectively. Compared with those from the ZnO, the results herein demonstrate an excellent reduction in the photoluminescence and improvement in the photocatalysis for the Au-ZnO hybrids with different morphologies. These results were attributed not only to the greatly improved sunlight utilization efficiency due to the surface plasmon resonance (SPR) absorption of Au nanoparticles in the visible region coupled with the UV light utilization by the ZnO nanostructures and multi-reflections of the incident light in the pore structures of their interior cavities but also to the high charge separation efficiency and low Schottky barrier generated by the combination of Au nanoparticles and ZnO micromaterials. Moreover, the honeycomb Au-ZnO heterostructure had a high Au content, surface area and surface oxygen vacancy (OV), which enabled photocatalytic properties that were higher than those of the porous cylindrical Au-ZnO heterostructures. In addition, two different formation mechanisms for the morphology and possible photocatalytic mechanisms are proposed in this paper.
High arrhythmic risk in antero-septal acute myocardial ischemia is explained by increased transmural reentry occurrence
Authors: Martinez-Navarro Hector , Mincholé Ana , Bueno-Orovio Alfonso , Rodriguez Blanca
Published: November 2019

Acute myocardial ischemia is a precursor of sudden arrhythmic death. Variability in its manifestation hampers understanding of arrhythmia mechanisms and challenges risk stratification. Our aim is to unravel the mechanisms underlying how size, transmural extent and location of ischemia determine arrhythmia vulnerability and ECG alterations. High performance computing simulations using a human torso/biventricular biophysically-detailed model were conducted to quantify the impact of varying ischemic region properties, including location (LAD/LCX occlusion), transmural/subendocardial ischemia, size, and normal/slow myocardial propagation. ECG biomarkers and vulnerability window for reentry were computed in over 400 simulations for 18 cases evaluated. Two distinct mechanisms explained larger vulnerability to reentry in transmural versus subendocardial ischemia. Macro-reentry around the ischemic region was the primary mechanism increasing arrhythmic risk in transmural versus subendocardial ischemia, for both LAD and LCX occlusion. Transmural micro-reentry at the ischemic border zone explained arrhythmic vulnerability in subendocardial ischemia, especially in LAD occlusion, as reentries were favoured by the ischemic region intersecting the septo-apical region. ST elevation reflected ischemic extent in transmural ischemia for LCX and LAD occlusion but not in subendocardial ischemia (associated with mild ST depression). The technology and results presented can inform safety and efficacy evaluation of anti-arrhythmic therapy in acute myocardial ischemia.
Nitrogen enrichment leads to changing fatty acid composition of phytoplankton and negatively affects zooplankton in a natural lake community
Authors: Trommer Gabriele , Lorenz Patrick , Lentz Ameli , Fink Patrick , Stibor Herwig
Published: November 2019

Secondary production in freshwater zooplankton is frequently limited by the food quality of phytoplankton. One important parameter of phytoplankton food quality are essential polyunsaturated fatty acids (PUFAs). Since the fatty acid composition of phytoplankton is variable and depends on the algae’s nutrient supply status, inorganic nutrient supply may affect the algal PUFA composition. Therefore, an indirect transfer of the effects of nutrient availability on zooplankton by changes in algal PUFA composition is conceivable. While the phosphorus (P) supply in lakes is largely decreasing, nitrogen (N) inputs continue to increase. This paper presents data from a mesocosm field experiment in which we exposed phytoplankton communities to increasing N enrichment. As a consequence, the PUFA composition of the phytoplankton community changed. With increasing nitrogen fertilisation, we observed lower quantities of essential PUFAs, together with a decrease in the abundances of the dominant herbivorous zooplanktonDaphnia sp. Their biomass was significantly correlated with phytoplankton PUFA content (C18:3 ω3, C20:5 ω3, C18:2 ω6). Our data therefore indicate that changes in nitrogen supply, together with the resultant changes in phytoplankton food quality, can negatively affect the secondary production of herbivorous zooplankton by reducing the availability of essential polyunsaturated fatty acids.
Musical imagery depends upon coordination of auditory and sensorimotor brain activity
Authors: Gelding Rebecca W. , Thompson William F. , Johnson Blake W.
Published: November 2019

Recent magnetoencephalography (MEG) studies have established that sensorimotor brain rhythms are strongly modulated during mental imagery of musical beat and rhythm, suggesting that motor regions of the brain are important for temporal aspects of musical imagery. The present study examined whether these rhythms also play a role in non-temporal aspects of musical imagery including musical pitch. Brain function was measured with MEG from 19 healthy adults while they performed a validated musical pitch imagery task and two non-imagery control tasks with identical temporal characteristics. A 4-dipole source model probed activity in bilateral auditory and sensorimotor cortices. Significantly greater β-band modulation was found during imagery compared to control tasks of auditory perception and mental arithmetic. Imagery-induced β-modulation showed no significant differences between auditory and sensorimotor regions, which may reflect a tightly coordinated mode of communication between these areas. Directed connectivity analysis in the θ-band revealed that the left sensorimotor region drove left auditory region during imagery onset. These results add to the growing evidence that motor regions of the brain are involved in the top-down generation of musical imagery, and that imagery-like processes may be involved in musical perception.
Functional and topographic effects on DNA methylation in IDH1/2 mutant cancers
Authors: Bledea Ramona , Vasudevaraja Varshini , Patel Seema , Stafford James , Serrano Jonathan , Esposito Gianna , Tredwin Lilian M. , Goodman Nina , Kloetgen Andreas , Golfinos John G. , Zagzag David , Weigelt Britta , Iafrate A. John , Sulman Erik P. , Chi Andrew S. , Dogan Snjezana , Reis-Filho Jorge S. , Chiang Sarah , Placantonakis Dimitris , Tsirigos Aristotelis , Snuderl Matija
Published: November 2019

IDH1/2 mutations are early drivers present in diverse human cancer types arising in various tissue sites. IDH1/2 mutation is known to induce a global hypermethylator phenotype. However, the effects on DNA methylation across IDH mutant cancers and functionally different genome regions, remain unknown. We analyzed DNA methylation data from IDH1/2 mutant acute myeloid leukemia, oligodendroglioma, astrocytoma, solid papillary breast carcinoma with reverse polarity, sinonasal undifferentiated carcinoma and cholangiocarcinoma, which clustered by their embryonal origin. Hypermethylated common probes affect predominantly gene bodies while promoters in IDH1/2 mutant cancers remain unmethylated. Enhancers showed global hypermethylation, however commonly hypomethylated enhancers were associated with tissue differentiation and cell fate determination. We demonstrate that some chromosomes, chromosomal arms and chromosomal regions are more affected by IDH1/2 mutations while others remain resistant to IDH1/2 mutation induced methylation changes. Therefore IDH1/2 mutations have different methylation effect on different parts of the genome, which may be regulated by different mechanisms.
Frequency and Clinical Associating Factors of Valvular Heart Disease in Asymptomatic Korean Adults
Authors: Kim Min Sun , Cho Soo Jin , Park Sung-Ji , Cho Sung Won , Choi Soo-Hee , Kim Hye Seung , Carriere Keumhee , Kim Eun Kyoung , Chang Sung-A , Lee Sang-Chol , Park Seung Woo
Published: November 2019

Limited information is available on the prevalence and clinical determinants of valvular heart disease (VHD) in apparently healthy people. This study sought to assess the frequency and clinical associating factors of aortic stenosis (AS), aortic regurgitation (AR), mitral stenosis (MS), mitral regurgitation (MR), tricuspid regurgitation (TR) in asymptomatic individuals with health check-up examination. We included 23,254 subjects ≥50 years of age who underwent a health check-up examination with transthoracic echocardiography (TTE) between 2012 and 2016 in a single tertiary-care hospital in Korea. Among a total of 23,254 subjects, 15,358 men (66.0%) and 7,896 women (34.0%) underwent TTE. Newly identified (predominantly mild) VHD was detected in 9.4% of subjects. The most common VHD were TR (4.6%), AR (3.0%) and MR (2.4%). Clinically significant (more than moderate) VHD was identified in 176 subjects (0.8%). Age ≥75 years was associated with all clinically significant VHD, and female gender was associated with AR, MS and TR. Korea has been very active in the health check-up examination including echocardiography. We find that VHD in apparently healthy people is not uncommon than believed; all VHD except MS were more frequent in elderly over 75 years of age in a large population-based study.
Taxane-based Chemotherapy Induced Androgen Receptor Splice Variant 7 in Patients with Castration-Resistant Prostate Cancer: A Tissue-based Analysis
Authors: Shim Myungsun , Kim Yunlim , Park Yangsoon , Ahn Hanjong
Published: November 2019

In total, 95 prostate cancer (Pca) patients who underwent transurethral resection of the prostate from 2000 to 2013 were assigned to four groups: Group 1, hormone-naïve and T1a or T1b Pca (n = 17); Group 2, hormone-sensitive and metastatic Pca (n = 33); Group 3, chemo-naïve castration-resistant Pca (CRPC), (n = 18); and Group 4, CRPC with chemotherapy (n = 27). Full-length androgen receptor (ARfl) transcript levels significantly increased from Group 1 through to Group 3 (p = 0.045), but decreased from Group 3 through to Group 4. AR splice variant 7 (ARV7) and glucocorticoid receptor (GR) transcript levels significantly increased from Group 1 through to Group 4 (p = 0.002 and 0.049, respectively). Kaplan–Meier curve revealed that the high transcript level of these three receptors resulted in significantly poorer cancer-specific survival (CSS) than that by low transcript level, although Cox regression analysis revealed that the ARV7 level alone was an independent prognostic factor for CSS in CRPC patients (high vs. low: hazard ratio, 1.897; 95% confidence interval, 1.102–3.625; p = 0.042). In conclusion, ARV7 and GR transcript levels significantly increase as Pca progresses to CRPC.
Mebendazole for Differentiation Therapy of Acute Myeloid Leukemia Identified by a Lineage Maturation Index
Authors: Li Yulin , Thomas Daniel , Deutzmann Anja , Majeti Ravindra , Felsher Dean W. , Dill David L.
Published: November 2019

Accurate assessment of changes in cellular differentiation status in response to drug treatments or genetic perturbations is crucial for understanding tumorigenesis and developing novel therapeutics for human cancer. We have developed a novel computational approach, the Lineage Maturation Index (LMI), to define the changes in differentiation state of hematopoietic malignancies based on their gene expression profiles. We have confirmed that the LMI approach can detect known changes of differentiation state in both normal and malignant hematopoietic cells. To discover novel differentiation therapies, we applied this approach to analyze the gene expression profiles of HL-60 leukemia cells treated with a small molecule drug library. Among multiple drugs that significantly increased the LMIs, we identified mebendazole, an anti-helminthic clinically used for decades with no known significant toxicity. We tested the differentiation activity of mebendazole using primary leukemia blast cells isolated from human acute myeloid leukemia (AML) patients. We determined that treatment with mebendazole induces dramatic differentiation of leukemia blast cells as shown by cellular morphology and cell surface markers. Furthermore, mebendazole treatment significantly extended the survival of leukemia-bearing mice in a xenograft model. These findings suggest that mebendazole may be utilized as a low toxicity therapeutic for human acute myeloid leukemia and confirm the LMI approach as a robust tool for the discovery of novel differentiation therapies for cancer.
Genetic diversity of Nile tilapia (Oreochromis niloticus) throughout West Africa
Authors: Lind Curtis E. , Agyakwah Seth K. , Attipoe Felix Y. , Nugent Christopher , Crooijmans Richard P. M. A. , Toguyeni Aboubacar
Published: November 2019

Nile tilapia (Oreochromis niloticus) is a globally significant aquaculture species rapidly gaining status as a farmed commodity. In West Africa, wild Nile tilapia genetic resources are abundant yet knowledge of fine-scale population structure and patterns of natural genetic variation are limited. Coinciding with this is a burgeoning growth in tilapia aquaculture in Ghana and other countries within the region underpinned by locally available genetic resources. Using 192 single nucleotide polymorphism (SNP) markers this study conducted a genetic survey of Nile tilapia throughout West Africa, sampling 23 wild populations across eight countries (Benin, Burkina Faso, Côte d’Ivoire, Ghana, Togo, Mali, Gambia and Senegal), representing the major catchments of the Volta, Niger, Senegal and Gambia River basins. A pattern of isolation-by-distance and significant spatial genetic structure was identified throughout West Africa (GlobalFST = 0.144), which largely corresponds to major river basins and, to a lesser extent, sub-basins. Two populations from the Gambia River (Kudang and Walekounda), one from the western Niger River (Lake Sélingué) and one from the upper Red Volta River (Kongoussi) showed markedly lower levels of diversity and high genetic differentiation compared to all other populations, suggesting genetically isolated populations occurring across the region. Genetic structure within the Volta Basin did not always follow the pattern expected for sub-river basins. This study identifies clear genetic structuring and differentiation amongst West African Nile tilapia populations, which concur with broad patterns found in previous studies. In addition, we provide new evidence for fine-scale genetic structuring within the Volta Basin and previously unidentified genetic differences of populations in Gambia. The 192 SNP marker suite used in this study is a useful tool for differentiating tilapia populations and we recommend incorporating this marker suite into future population screening ofO. niloticus. Our results form the basis of a solid platform for future research on wild tilapia genetic resources in West Africa, and the identification of potentially valuable germplasm for use in ongoing breeding programs for aquaculture.