bluuebunny/crossref_metadata_2025 huggingface dataset:
Blocking distinct interactions between Glioblastoma cells and their tissue microenvironment: A novel multi-targeted therapeutic approach
Authors: Mettang Melanie , Meyer-Pannwitt Viola , Karpel-Massler Georg , Zhou Shaoxia , Carragher Neil O. , Föhr Karl Josef , Baumann Bernd , Nonnenmacher Lisa , Enzenmüller Stefanie , Dahlhaus Meike , Siegelin Markus D. , Stroh Sebastien , Mertens Daniel , Fischer-Posovszky Pamela , Schneider E. Marion , Halatsch Marc-Eric , Debatin Klaus-Michael , Westhoff Mike-Andrew
Published: March 2018

Due to the highly invasive nature of Glioblastoma (GB), complete surgical resection is not feasible, while motile tumour cells are often associated with several specific brain structures that enhance treatment-resistance. Here, we investigate the therapeutic potential of Disulfiram and Carbenoxolone, that inhibit two distinct interactions between GB and the brain tissue microenvironment: stress-induced cell-matrix adhesion and gap junction mediated cell-cell communication, respectively. Increase in cell numbers of tumour-initiating cells, which are cultured in suspension as cell clusters, and adherent differentiated cells can be blocked to a similar extent by Carbenoxolone, as both cell populations form gap junctions, but the adherent differentiated cells are much more sensitive to Disulfiram treatment, which – via modulation of NF-κB signalling – interferes with cell-substrate adhesion. Interestingly, inducing adhesion in tumour-initiating cells without differentiating them does not sensitize for Disulfiram. Importantly, combining Disulfiram, Carbenoxolone and the standard chemotherapeutic drug Temozolomide reduces tumour size in an orthotopic mouse model. Isolating GB cells from their direct environment within the brain represents an important addition to current therapeutic approaches. The blockage of cellular interactions via the clinically relevant substances Disulfiram and Carbenoxolone, has distinct effects on different cell populations within a tumour, potentially reducing motility and/or resistance to apoptosis.
SIRT6 facilitates directional telomere movement upon oxidative damage
Authors: Gao Ying , Tan Jun , Jin Jingyi , Ma Hongqiang , Chen Xiukai , Leger Brittany , Xu Jianquan , Spagnol Stephen T. , Dahl Kris Noel , Levine Arthur S. , Liu Yang , Lan Li
Published: March 2018

Oxidative damage to telomeres leads to telomere attrition and genomic instability, resulting in poor cell viability. Telomere dynamics contribute to the maintenance of telomere integrity; however, whether oxidative damage induces telomere movement and how telomere mobility is regulated remain poorly understood. Here, we show that oxidative damage at telomeres triggers directional telomere movement. The presence of the human Sir2 homolog, Sirtuin 6 (SIRT6) is required for oxidative damage-induced telomeric movement. SIRT6 knock out (KO) cells show neither damage-induced telomere movement nor chromatin decondensation at damaged telomeres; both are observed in wild type (WT) cells. A deacetylation mutant of SIRT6 increases damage-induced telomeric movement in SIRT6 KO cells as well as WT SIRT6. SIRT6 recruits the chromatin-remodeling protein SNF2H to damaged telomeres, which appears to promote chromatin decondensation independent of its deacetylase activity. Together, our results suggest that SIRT6 plays a role in the regulation of telomere movement upon oxidative damage, shedding new light onto the function of SIRT6 in telomere maintenance.
High-resolution GPS tracking reveals sex differences in migratory behaviour and stopover habitat use in the Lesser Black-backed Gull Larus fuscus
Authors: Baert Jan M. , Stienen Eric W. M. , Heylen Brigitte C. , Kavelaars Marwa M. , Buijs Roland-Jan , Shamoun-Baranes Judy , Lens Luc , Müller Wendt
Published: March 2018

Sex-, size- or age-dependent variation in migration strategies in birds is generally expected to reflect differences in competitive abilities. Theoretical and empirical studies thereby focus on differences in wintering areas, by which individuals may benefit from avoiding food competition during winter or ensuring an early return and access to prime nesting sites in spring. Here, we use GPS tracking to assess sex- and size-related variation in the spatial behaviour of adult Lesser Black-backed Gulls (Larus fuscus) throughout their annual cycle. We did not find sex- or size-dependent differences in wintering area or the timing of spring migration. Instead, sexual differences occurred prior to, and during, autumn migration, when females strongly focussed on agricultural areas. Females exhibited a more protracted autumn migration strategy, hence spent more time on stopover sites and arrived 15 days later at their wintering areas, than males. This shift in habitat use and protracted autumn migration coincided with the timing of moult, which overlaps with chick rearing and migration. Our results suggest that this overlap between energy-demanding activities may lead females to perform a more prolonged autumn migration, which results in spatiotemporal differences in foraging habitat use between the sexes.
Systemic IGF-1 gene delivery by rAAV9 improves spontaneous autoimmune peripheral polyneuropathy (SAPP)
Authors: Gao Tong , Bogdanova Nataliia , Ghauri Sameera , Zhang Gang , Lin Jianxin , Sheikh Kazim
Published: March 2018

Spontaneous autoimmune peripheral polyneuropathy (SAPP) is a mouse model of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in non-obese diabetic (NOD) mice null for costimulatory molecule, B7-2 gene (B7-2−/−). SAPP is a chronic progressive and multifocal inflammatory and demyelinating polyneuropathy of spontaneous onset with secondary axonal degeneration. Insulin-like growth factor 1(IGF-1) is a pleiotropic factor with neuroprotective, regenerative, and anti-inflammatory effects with extensive experience in its preclinical and clinical use. Systemic delivery of recombinant adeno-associated virus serotype 9 (rAAV9) provides robust and widespread gene transfer to central and peripheral nervous systems making it suitable for gene delivery in neurological diseases. A significant proportion of patients with inflammatory neuropathies like CIDP do not respond to current clinical therapies and there is a need for new treatments. In this study, we examined the efficacy IGF-1 gene therapy by systemic delivery with rAAV9 in SAPP model. The rAAV9 construct also contained a reporter gene to monitor the surrogate expression of IGF-1. We found significant improvement in neuropathic disease after systemic delivery of rAAV9/IGF-1 gene at presymptomatic and symptomatic stages of SAPP model. These findings support that IGF-1 treatment (including gene therapy) is a viable therapeutic option in immune neuropathies such as CIDP.
SFTS phlebovirus promotes LC3-II accumulation and nonstructural protein of SFTS phlebovirus co-localizes with autophagy proteins
Authors: Sun Yue , Liu Miao-miao , Lei Xiao-ying , Yu Xue-jie
Published: March 2018

Autophagy is essential for eukaryotic cell homeostasis and can perform both anti-viral and pro-viral roles depending on the kinds of viruses, cell types and cell environment. Severe fever with thrombocytopenia syndrome phlebovirus (SFTSV) is a newly discovered tick-borne virus in the Phenuiviridae family that causes a severe hemorrhagic fever disease in East Asia. In this study we determined interactions between SFTSV and autophagy. Our results showed that LC3-II (microtubule associated protein 1 light chain 3-II) protein accumulated from 4 h to 24 h after SFTSV infection compared to mock-infected Vero cells, and the use of E64d and pepstatin A did not affect the expression of LC3-II protein, which indicated that the increased LC3-II may be the result of inhibition of autophagic degradation caused by SFTSV infection. However, knockdown of LC3B promotes SFTSV replication, which indicated a negative role of LC3B protein in SFTSV replication. We also detected co-localization of SFTSV non-structure (NSs) protein with LC3B, p62 and Lamp2b respectively in SFTSV infected Vero cells, which indicated the possibility of selective autophagy or chaperone-mediated autophagy involving in SFTSV infection. Our results indicated that SFTSV infection promotes LC3 accumulation and several proteins of the autophagy pathway co-localize with NSs protein during SFTSV infection.
Comparative genome-wide analysis of extracellular small RNAs from the mucormycosis pathogen Rhizopus delemar
Authors: Liu Muxing , Bruni Gillian O. , Taylor Christopher M. , Zhang Zhengguang , Wang Ping
Published: March 2018

Rhizopus delemar is an emerging fungal pathogen causing devastating mucormycosis in immunocompromised individuals. The organism remains understudied and there are urgent needs for new methods of rapid disease diagnosis for timely therapy. Extracellular vesicles with encapsulated RNAs have recently been discovered to have great potential applications for disease diagnoses and treatments. To explore the utilization of ex-RNA in studies of mucormycosis, we have performed RNA-Seq of ex-sRNAs from two clinical strains of R. delemar. Approximately 3.3 and 3.2 million clean reads were obtained from FGSC-9543 and CDC-8219 strains, respectively. The median sequence length of the sRNAs was 22 nts, with a minimum of 18 and a maximum of 30 nts. Further annotation identified 560 and 526 miRNAs from FGSC-9543 and CDC-8219 strains, respectively. miRNA target prediction and analysis of GO and KEGG pathways have revealed that the regulation of metabolism, secondary metabolite biosynthesis, and two-component system signaling are important during growth. We have also validated RNA-Seq by qRT-PCR and Northern blotting analysis of randomly selected miRNAs. Our results show that R. delemar has a rich reservoir of secreted ex-sRNAs and our studies could facilitate the development of improved diagnostic methods as well as elucidating virulence mechanisms for R. delemar infection.
Epigenetic Transgenerational Inheritance of Altered Sperm Histone Retention Sites
Authors: Ben Maamar Millissia , Sadler-Riggleman Ingrid , Beck Daniel , Skinner Michael K.
Published: March 2018

A variety of environmental toxicants and factors have been shown to induce the epigenetic transgenerational inheritance of disease and phenotypic variation. Epigenetic alterations in the germline (sperm or egg) are required to transmit transgenerational phenotypes. The current study was designed to investigate the potential role of histones in sperm to help mediate the epigenetic transgenerational inheritance. The agricultural fungicide vinclozolin and the pesticide DDT (dichlorodiphenyltrichloroethane) were independently used to promote the epigenetic transgenerational inheritance of disease. Purified cauda epididymal sperm were collected from the transgenerational F3 generation control and exposure lineage male rats for histone analysis. A reproducible core of histone H3 retention sites was observed using an H3 chromatin immunoprecipitation (ChIP-Seq) analysis in control lineage sperm. Interestingly, the same core group of H3 retention sites plus additional differential histone retention sites (DHRs) were observed in the F3 generation exposure lineage sperm. Although new histone H3 retention sites were observed, negligible change in histone modification (methylation of H3K27me3) was observed between the control and exposure lineages. Observations demonstrate that in addition to alterations in sperm DNA methylation and ncRNA previously identified, the induction of differential histone retention sites (DHRs) also appear to be involved in environmentally induced epigenetic transgenerational inheritance.
Using human brain activity to guide machine learning
Authors: Fong Ruth C. , Scheirer Walter J. , Cox David D.
Published: March 2018

Machine learning is a field of computer science that builds algorithms that learn. In many cases, machine learning algorithms are used to recreate a human ability like adding a caption to a photo, driving a car, or playing a game. While the human brain has long served as a source ofinspirationfor machine learning, little effort has been made to directly use data collected from working brains as aguidefor machine learning algorithms. Here we demonstrate a new paradigm of “neurally-weighted” machine learning, which takes fMRI measurements of human brain activity from subjects viewing images, and infuses these data into the training process of an object recognition learning algorithm to make it more consistent with the human brain. After training, these neurally-weighted classifiers are able to classify images without requiring any additional neural data. We show that our neural-weighting approach can lead to large performance gains when used with traditional machine vision features, as well as to significant improvements with already high-performing convolutional neural network features. The effectiveness of this approach points to a path forward for a new class of hybrid machine learning algorithms which take both inspiration and direct constraints from neuronal data.
Activation of Eosinophils and Mast Cells in Functional Dyspepsia: an Ultrastructural Evaluation
Authors: Vanheel Hanne , Vicario Maria , Boesmans Werend , Vanuytsel Tim , Salvo-Romero Eloisa , Tack Jan , Farré Ricard
Published: March 2018

We recently identified mucosal mast cell and eosinophil hyperplasia in association with a duodenal impaired barrier function in functional dyspepsia (FD). We aimed to further describe the implication of these immune cells by assessing their activation state at the ultrastructural level and by evaluating the association between impaired epithelial integrity and immune activation. Duodenal biopsies were obtained from 24 FD patients and 37 healthy controls. The ultrastructure of mast cells and eosinophils was analyzed by transmission electron microscopy. Transepithelial electrical resistance and paracellular permeability were measured to evaluate epithelial barrier function. The type of degranulation in eosinophils and mast cells was piecemeal. Eosinophils displayed higher degree of degranulation in FD patients than in controls (p < 0.0001). Quantification revealed a decreased granular density in eosinophils of FD patients (p < 0.0001). The degree of degranulation in mast cells was similar in both groups. However, a more heterogeneous profile was found in the FD group (p < 0.0001). No association between epithelial integrity and the number and activation state of mucosal eosinophils and mast cells was found. We demonstrated ultrastructural changes in degranulation state of eosinophils and mast cells, suggesting that eosinophil and mast cell activation play a role in the pathophysiology of FD.
Characterization of Split Fluorescent Protein Variants and Quantitative Analyses of Their Self-Assembly Process
Authors: Köker Tuğba , Fernandez Anthony , Pinaud Fabien
Published: March 2018

Many biotechniques use complementary split-fluorescent protein (sFPs) fragments to visualize protein-protein interactions, image cells by ensemble or single molecule fluorescence microscopy, or assemble nanomaterials and protein superstructures. Yet, the reassembly mechanisms of sFPs, including fragment binding rates, folding, chromophore maturation and overall photophysics remain poorly characterized. Here, we evolved asymmetric and self-complementing green, yellow and cyan sFPs together with their full-length equivalents (flFPs) and described their biochemical and photophysical propertiesin vitroand in cells. While re-assembled sFPs have spectral properties similar to flFPs, they display slightly reduced quantum yields and fluorescence lifetimes due to a less sturdy β-barrel structure. The complementation of recombinant sFPs expressedin vitrofollows a conformational selection mechanism whereby the larger sFP fragments exist in a monomer-dimer equilibrium and only monomers are competent for fluorescence complementation. This bimolecular fragment interaction involves a slow and irreversible binding step, followed by chromophore maturation at a rate similar to that of flFPs. When expressed as fusion tags in cells, sFPs behave as monomers directly activated with synthetic complementary fragments. This study resulted in the development of sFP color variants having improved maturation kinetics, brightness, and photophysics for fluorescence microscopy imaging of cellular processes, including single molecule detection.
Evaluation of Screened Lignin-degrading Fungi for the Biological Pretreatment of Corn Stover
Authors: Su Yingjie , Yu Xiaoxiao , Sun Yang , Wang Gang , Chen Huan , Chen Guang
Published: March 2018

The biological pretreatment of lignocellulosic biomass is a low-cost and eco-friendly method for facilitating enzymatic hydrolysis. In this study, strains with lignin depletion capability were screened using a high-throughput screening method. Sixty-three strains were screened out and Myrothecium verrucaria secreted three lignin-degrading enzymes simultaneously during the bio-pretreatment process. The activity levels of laccase, lignin peroxidase and manganese peroxidase were 6.61, 0.78 and 1.31 U g−1 dry biomass. The content of lignin in corn stover decreased by 42.30% after bio-pretreatment, and the conversion rate increased by 123.84% during the subsequent saccharification process in comparison with the untreated corn stover. Furthermore, the effects of bio-pretreatment on the structure of corn stover were presented using a scanning electron microscope (SEM), Brunauer-Emmet-Teller (BET), X-ray diffractometer (XRD) and Fourier transform infrared spectroscopy (FTIR). The results showed that M.V. is a promising lignin-degrading fungus. This research demonstrated an efficient pretreatment approach for enhancing the enzymatic saccharification of corn stover.
Low testosterone in ApoE/LDL receptor double-knockout mice is associated with rarefied testicular capillaries together with fewer and smaller Leydig cells
Authors: Steinfeld Kai , Beyer Daniela , Mühlfeld Christian , Mietens Andrea , Eichner Gerrit , Altinkilic Bora , Kampschulte Marian , Jiang Qingkui , Krombach Gabriele A. , Linn Thomas , Weidner Wolfgang , Middendorff Ralf
Published: March 2018

The testis as a site for atherosclerotic changes has so far attracted little attention. We used the apolipoprotein E (ApoE)/low density lipoprotein (LDL) receptor deficient mouse model (KO) for atherosclerosis (20, 40, 60 and 87-week-old) to investigate whether Leydig cells or the capillary network are responsible for reduced serum testosterone levels previously observed in extreme ages of this model. In KO mice, overall testosterone levels were reduced whereas the adrenal gland-specific corticosterone was increased excluding a general defect of steroid hormone production. In addition to micro-CT investigations for bigger vessels, stereology revealed a reduction of capillary length, volume and surface area suggesting capillary rarefaction as a factor for diminished testosterone. Stereological analyses of interstitial cells demonstrated significantly reduced Leydig cell numbers and size. These structural changes in the testis occurred on an inflammatory background revealed by qPCR. Reduced litter size of the KO mice suggests hypo- or infertility as a consequence of the testicular defects. Our data suggest reduced testosterone levels in this atherosclerosis model might be explained by both, rarefication of the capillary network and reduced Leydig cell number and size. Thus, this study calls for specific treatment of male infertility induced by microvascular damage through hypercholesterolemia and atherosclerosis.
Multistep transition of diamond to warm dense matter state revealed by femtosecond X-ray diffraction
Authors: Medvedev Nikita , Ziaja Beata
Published: March 2018

Diamond bulk irradiated with a free-electron laser pulse of 6100 eV photon energy, 5 fs duration, at the ~19–25 eV/atom absorbed doses, is studied theoretically on its way to warm dense matter state. Simulations with our hybrid code XTANT show disordering on sub-100 fs timescale, with the diffraction peak (220) vanishing faster than the peak (111). The warm dense matter formation proceeds as a nonthermal damage of diamond with the band gap collapse triggering atomic disordering. Short-living graphite-like state is identified during a few femtoseconds between the disappearance of (220) peak and the disappearance of (111) peak. The results obtained are compared with the data from the recent experiment at SACLA, showing qualitative agreement. Challenges remaining for the accurate modeling of the transition of solids to warm dense matter state and proposals for supplementary measurements are discussed in detail.
RETRACTED ARTICLE: Differences in cognitive functions between cytomegalovirus-infected and cytomegalovirus-free university students: a case control study
Authors: Chvátalová Veronika , Šebánková Blanka , Hrbáčková Hana , Tureček Petr , Flegr Jaroslav
Published: March 2018

Cytomegalovirus (CMV) is the herpetic virus, which infects 45–100% people worldwide. Many reports suggest that CMV could impair cognitive functions of infected subjects. Here we searched for indices of effects of CMV on infected subjects’ intelligence and knowledge. The Intelligence Structure Test I-S-T 2000 R was used to compare IQ of 148 CMV-infected and 135 CMV-free university students. Infected students expressed higher intelligence. Paradoxically, their IQ decreased with decreasing concentration of anti-CMV antibodies, which can be used, statistically, as a proxy of the time passed from the moment of infection in young subjects when the age of subjects is statistically controlled. The paradox of seemingly higher intelligence of CMV infected subjects could be explained by the presence of the subpopulation of about 5–10% CMV-positive individuals in the population of “CMV-negative students”. These false negative subjects had probably not only the oldest infections and therefore the lowest concentration of anamnestic antibodies, but also the lowest intelligence among the infected students. Prevalence of CMV infection in all countries is very high, approaching sometimes 90%. Therefore, the total impact of CMV on human intelligence may be large.
Renal Prognosis and Related Risk Factors for Henoch-Schönlein Purpura Nephritis: A Chinese Adult Patient Cohort
Authors: Huang Xiao , Wu Xiaomei , Le Weibo , Hao Yaxin , Wu Jing , Zeng Caihong , Liu Zhihong , Tang Zheng
Published: March 2018

This study investigated the clinicopathological characteristics of Henoch-Schönlein purpura nephritis (HSPN) in Chinese adult patients and analyzed the renal outcomes and prognostic risk factors for progression to end-stage renal disease (ESRD). Adult patients who had biopsy-proven HSPN were studied. Their clinicopathological data, renal prognoses and related risk factors were assessed. A total of 698 patients were studied, including 363 men (52.0%) and 335 women (48.0%). Most of the patients had hematuria (85.8%) and/or proteinuria (82.1%). During a median follow-up of 54.0 months, 32 patients (4.6%) progressed to ESRD. The 5- and 10-year cumulative renal survival rates from ESRD were 96.4% and 88.6%, respectively. Baseline urinary protein, renal insufficiency, glomerular sclerosis and tubular atrophy/interstitial fibrosis were independent predictors of renal outcomes. Both the time-average mean arterial pressure and proteinuria during follow-up also influenced the renal prognosis. The patients with a time-average proteinuria <0.4 g/day had the lowest rates of ESRD or a 50% decline in renal function. In conclusion, identifying of clinical and histological prognostic factors may permit the prediction of renal outcomes. The optimal goal of therapy for HSPN patients may be to lower proteinuria to <0.4 g/day and control hypertension to achieve an ideal renal outcome.
Diagnostic accuracy of liver stiffness measurement in chronic hepatitis B patients with normal or mildly elevated alanine transaminase levels
Authors: Li Qiang , Chen Liang , Zhou Yu
Published: March 2018

We aimed to evaluate the diagnostic accuracy of liver stiffness measurement (LSM) in 188 chronic hepatitis B (CHB) patients with alanine transaminase (ALT) ≤ twice the upper limit of normal (ULN). Liver fibrosis was staged using METAVIR scoring system. Define significant fibrosis as F2-F4, severe fibrosis as F3-F4, and cirrhosis as F4. To predict F2-F4, the AUROC of LSM was higher than that of APRI (0.86 vs 0.73, p = 0.001) and FIB-4 (0.86 vs 0.61, p < 0.001). To predict F4, the AUROC of LSM was also higher than that of APRI (0.93 vs 0.77, p = 0.012) and FIB-4 (0.93 vs 0.64, p < 0.001). Patients with ALT levels 1–2 ULN had higher cut-off values than patients with normal ALT levels for the diagnosis of F2-F4 (6.5 vs 6 kPa) and F4 (10.2 vs 7.8 kPa). Using cut-off values regardless of ALT levels, the diagnostic accuracy of LSM was 81% for F2-F4, and 89% for F4. Applying ALT-stratified cut-off values, the diagnostic accuracy of LSM was 82% for F2-F4, and 86% for F4. In conclusion, LSM is a reliable noninvasive test for the diagnosis of liver fibrosis. Applying ALT-stratified cut-off values did not enhance diagnostic accuracy of LSM in CHB patients with ALT ≤ 2 ULN.
Spatiotemporal deformation patterns of the Lake Urmia Causeway as characterized by multisensor InSAR analysis
Authors: Karimzadeh Sadra , Matsuoka Masashi , Ogushi Fumitaka
Published: March 2018

We present deformation patterns in the Lake Urmia Causeway (LUC) in NW Iran based on data collected from four SAR sensors in the form of interferometric synthetic aperture radar (InSAR) time series. Sixty-eight images from Envisat (2004–2008), ALOS-1 (2006–2010), TerraSAR-X (2012–2013) and Sentinel-1 (2015–2017) were acquired, and 227 filtered interferograms were generated using the small baseline subset (SBAS) technique. The rate of line-of-sight (LOS) subsidence of the LUC peaked at 90 mm/year between 2012 and 2013, mainly due to the loss of most of the water in Lake Urmia. Principal component analysis (PCA) was conducted on 200 randomly selected time series of the LUC, and the results are presented in the form of the three major components. The InSAR scores obtained from the PCA were used in a hydro-thermal model to investigate the dynamics of consolidation settlement along the LUC based on detrended water level and temperature data. The results can be used to establish a geodetic network around the LUC to identify more detailed deformation patterns and to help plan future efforts to reduce the possible costs of damage.
Mesenchymal Stromal Cells-Derived β2-Microglobulin Promotes Epithelial–Mesenchymal Transition of Esophageal Squamous Cell Carcinoma Cells
Authors: Wang Junjie , Yang Weilin , Wang Tao , Chen Xiaoyong , Wang Jiancheng , Zhang Xiaoran , Cai Chuang , Zhong Beilong , Wu Jiabin , Chen Zhenguang , Xiang Andy Peng , Huang Weijun
Published: March 2018

Mesenchymal stromal cells (MSCs) have been considered as one of the pivotal type of cells composing the tumor microenvironment. Although contact-dependent mechanisms and paracrine factors are thought to collaborate in governing the MSCs-based effects on tumors progression, the underlying mechanisms remain largely unknown. In particular, the involvement of MSCs-derived cytokines in the epithelial–mesenchymal transition (EMT) of esophageal squamous cell carcinoma (ESCC) has not been clarified. In this study, we observed that β2-Microglobulin (B2M) is highly expressed in MSCs but scarcely in ESCC cells. Based on the previously described EMT promoting effect of B2M, we investigated the in vitro effect of MSCs-derived B2M on the EMT of ESCC cells, and discovered its subsequent enhancing effects on cell mobility and tumor-initiation. Further xenograft transplantation experiments confirmed the in vivo induction of tumor-initiation by MSCs-derived B2M. Noteworthy, we showed that the B2M expression positively correlated with poor prognosis. The fact that B2M is primarily expressed by the stroma of the ESCC tissue strengthens our hypothesis that in ESCC, MSCs-derived B2M promotes tumor-initiation and invasion via enhancing EMT, resulting in an adverse prognosis for the patients. Our results will be valuable for the prediction of the development and treatment of ESCC.
Long-term effects of low calcium dialysates on the serum calcium levels during maintenance hemodialysis treatments: A systematic review and meta-analysis
Authors: Yoshikawa Masahiro , Takase Osamu , Tsujimura Taro , Sano Etsuko , Hayashi Matsuhiko , Takato Tsuyoshi , Hishikawa Keiichi
Published: March 2018

Hypercalcemia and hyperparathyroidism in patients receiving maintenance hemodialysis (MHD) can cause the progression of cardiovascular diseases (CVD) and mineral bone disorders (MBD). The KDIGO recommends the dialysates with a calcium (Ca) concentration of 1.25–1.5 mmol/L for MHD treatments, but the optimal concentration remains controversial. Here, we conducted a systematic review and a meta-analysis of seven randomized controlled trials examining a total of 622 patients to investigate the optimal concentration for MHD for 6 months or longer. The dialysates with a low Ca concentration (1.125 or 1.25 mmol/L) significantly lowered the serum Ca and raised the intact parathyroid hormone levels by 0.52 mg/dL (95% confidence interval, 0.20–0.85) and 39.59 pg/mL (14.80–64.38), respectively, compared with a high Ca concentration (1.50 or 1.75 mmol/L). Three studies showed that a low concentration was preferred for lowering arterial calcifications or atherosclerosis in different arteries, but one study showed that coronary arterial calcifications increased with a low concentration. Two studies showed contradictory outcomes in terms of MBD. Our meta-analysis showed that a dialysate with a low Ca concentration lowered the serum Ca levels in patients receiving long-term MHD, but further studies are needed to determine the optimal Ca concentration in terms of CVD and MBD.
Transcriptome-wide mapping of signaling pathways and early immune responses in lumpfish leukocytes upon in vitro bacterial exposure
Authors: Eggestøl Håvard Ø. , Lunde Harald S. , Rønneseth Anita , Fredman David , Petersen Kjell , Mishra Charitra K. , Furmanek Tomasz , Colquhoun Duncan J. , Wergeland Heidrun I. , Haugland Gyri T.
Published: March 2018

We performed RNA sequencing, identified components of the immune system and mapped early immune responses of lumpfish (Cyclopterus lumpus) leukocytes following in vitro exposure to the pathogenic bacterium Vibrio anguillarum O1. This is the first characterization of immune molecules in lumpfish at the gene level. In silico analyses revealed that genes encoding proteins involved in pathogen recognition, cell signaling and cytokines in mammals and teleosts are conserved in lumpfish. Unique molecules were also identified. Pathogen recognition components include 13 TLRs, several NLRs and complement factors. Transcriptome-wide analyses of immune responses 6 and 24 hours post bacterial exposure revealed differential expression of 9033 and 15225 genes, respectively. These included TLR5S, IL-1β, IL-8, IL-6, TNFα, IL-17A/F3, IL-17C and several components of the complement system. The data generated will be valuable for comparative studies and make an important basis for further functional analyses of immune and pathogenicity mechanisms. Such knowledge is also important for design of immunoprophylactic measures in lumpfish, a species of fish now farmed intensively for use as cleaner-fish in Atlantic salmon (Salmo salar) aquaculture.
Subcutaneous Ehrlich Ascites Carcinoma mice model for studying cancer-induced cardiomyopathy
Authors: Mishra Sneha , Tamta Ankit Kumar , Sarikhani Mohsen , Desingu Perumal Arumugam , Kizkekra Shruti M. , Pandit Anwit Shriniwas , Kumar Shweta , Khan Danish , Raghavan Sathees C. , Sundaresan Nagalingam R.
Published: March 2018

Cardiomyopathy is one of the characteristic features of cancer. In this study, we establish a suitable model to study breast cancer-induced cardiomyopathy in mice. We used Ehrlich Ascites Carcinoma cells to induce subcutaneous tumor in 129/SvJ mice and studied its effect on heart function. In Ehrlich Ascites Carcinoma bearing mice, we found significant reduction in left ventricle wall thickness, ejection fraction, and fractional shortening increase in left ventricle internal diameter. We found higher muscle atrophy, degeneration, fibrosis, expression of cell-adhesion molecules and cell death in tumor-bearing mice hearts. As observed in cancer patients, we found that mTOR, a key signalling molecule responsible for maintaining cell growth and autophagy was suppressed in this model. Tumor bearing mice hearts show increased expression and nuclear localization of TFEB and FoxO3a transcription factors, which are involved in the upregulation of muscle atrophy genes, lysosomal biogenesis genes and autophagy genes. We propose that Ehrlich Ascites Carcinoma induced tumor can be used as a model to identify potential therapeutic targets for the treatment of heart failure in patients suffering from cancer-induced cardiomyopathy. This model can also be used to test the adverse consequences of cancer chemotherapy in heart.
A Lethal Fungus Infects the Chinese White Wax Scale Insect and Causes Dramatic Changes in the Host Microbiota
Authors: Sun Tao , Wang Xue-Qing , Zhao Zun-Ling , Yu Shu-Hui , Yang Pu , Chen Xiao-Ming
Published: March 2018

The Chinese white wax scale insect (Ericerus pela) is an economically valuable species with an important role in wax production. Recently, in a greenhouse in Kunming, we identified a genus of fungus that infects and kills E. pela females. This study sought to perform the molecular detection of entomopathogens and analyze the changes in the host microbiota after entomopathogen infection. We used library construction, high-throughput sequencing and real-time quantitative polymerase chain reaction (RT-qPCR) to identify the fungi infecting adult E. pela, to understand the changes in the host organism, and to determine the distribution of the entomopathogens. Cladosporium langeronii and C. sphaerospermum were the main pathogenic species that infected the E. pela females, and they were most prevalent in the dorsal cuticle. In vivo, after infection, the proportion of Cladosporium clearly increased. The infection had little influence on the fungal community but had a strong influence on the bacterial community. After infection, Arsenophonus was dominant, and numerous bacterial genera disappeared. However, Rickettsia, instead of Arsenophonus, became dominant in the Cladosporium-infected individuals that had also been infected with Rickettsia. We identified the species that infected E. pela females and determined the influence of infection on the host microorganisms.
Diffusion-localization transition caused by nonlinear transport on complex networks
Authors: Tamura Koutarou , Takayasu Hideki , Takayasu Misako
Published: March 2018

We analyzed nonlinear transport as defined for directed complex networks, where the flux from one node to a neighboring node is given preferentially according to the scalar quantities at the neighbor nodes. This is known as the generalized gravity interaction. In our research, we discovered a novel phase transition type. In the diffusion phase, the scalar quantity is scattered over the whole system, whereas in the localization phase, the flow tends to form localized confluence patterns owing to nonlinearity, resulting in the appearance of special nodes that irreversibly attract huge amounts of flow. We analytically considered the transition for selected network configurations, demonstrating that the transition point depends on the network topology. We also demonstrated that the diffusion phase of this transport model fits well with data from business firms, implying that the whole network structure can be used to model money flow in the real world.
Predicting individual responses to the electroconvulsive therapy with hippocampal subfield volumes in major depression disorder
Authors: Cao Bo , Luo Qinghua , Fu Yixiao , Du Lian , Qiu Tian , Yang Xiangying , Chen Xiaolu , Chen Qibin , Soares Jair C. , Cho Raymond Y. , Zhang Xiang Yang , Qiu Haitang
Published: March 2018

Electroconvulsive therapy (ECT) is one of the most effective treatments for major depression disorder (MDD). ECT can induce neurogenesis and synaptogenesis in hippocampus, which contains distinct subfields, e.g., the cornu ammonis (CA) subfields, a granule cell layer (GCL), a molecular layer (ML), and the subiculum. It is unclear which subfields are affected by ECT and whether we predict the future treatment response to ECT by using volumetric information of hippocampal subfields at baseline? In this study, 24 patients with severe MDD received the ECT and their structural brain images were acquired with magnetic resonance imaging before and after ECT. A state-of-the-art hippocampal segmentation algorithm from Freesurfer 6.0 was used. We found that ECT induced volume increases in CA subfields, GCL, ML and subiculum. We applied a machine learning algorithm to the hippocampal subfield volumes at baseline and were able to predict the change in depressive symptoms (r = 0.81; within remitters, r = 0.93). Receiver operating characteristic analysis also showed robust prediction of remission with an area under the curve of 0.90. Our findings provide evidence for particular hippocampal subfields having specific roles in the response to ECT. We also provide an analytic approach for generating predictions about clinical outcomes for ECT in MDD.
Mechanisms of tactile sensory deterioration amongst the elderly
Authors: Skedung Lisa , El Rawadi Charles , Arvidsson Martin , Farcet Céline , Luengo Gustavo S. , Breton Lionel , Rutland Mark W.
Published: March 2018

It is known that roughness-smoothness, hardness-softness, stickiness-slipperiness and warm-cold are predominant perceptual dimensions in macro-, micro- and nano- texture perception. However, it is not clear to what extent active tactile texture discrimination remains intact with age. The general decrease in tactile ability induces physical and emotional dysfunction in elderly, and has increasing significance for an aging population. We report a method to quantify tactile acuity based on blinded active exploration of systematically varying micro-textured surfaces and a same-different paradigm. It reveals that elderly participants show significantly reduced fine texture discrimination ability. The elderly group also displays statistically lower finger friction coefficient, moisture and elasticity, suggesting a link. However, a subpopulation of the elderly retains discrimination ability irrespective of cutaneous condition and this can be related to a higher density of somatosensory receptors on the finger pads. Skin tribology is thus not the primary reason for decline of tactile discrimination with age. The remediation of cutaneous properties through rehydration, however leads to a significantly improved tactile acuity. This indicates unambiguously that neurological tactile loss can be temporarily compensated by restoring the cutaneous contact mechanics. Such mechanical restoration of tactile ability has the potential to increase the quality of life in elderly.
Effects of Intestinal Microbiota on Brain Development in Humanized Gnotobiotic Mice
Authors: Lu Jing , Lu Lei , Yu Yueyue , Cluette-Brown Joanne , Martin Camilia R. , Claud Erika C.
Published: March 2018

Poor growth in the Neonatal Intensive Care Unit is associated with an increased risk for poor neurodevelopmental outcomes for preterm infants, however the mechanism is unclear. The microbiome has increasingly been recognized as a modifiable environmental factor to influence host development. Here we explore the hypothesis that the microbiome influences both growth phenotype and brain development. A germ free mouse transfaunation model was used to examine the effects of preterm infant microbiotas known to induce either high growth or low growth phenotypes on postnatal brain development. The microbiome which induced the low growth phenotype was associated with decreases in the neuronal markers NeuN and neurofilament-L as well as the myelination marker MBP when compared to the microbiome associated with the high growth phenotype. Additionally, poor growth phenotype-associated microbiota was associated with increased neuroinflammation marked by increased Nos1, as well as alteration in IGF-1 pathway including decreased circulating and brain IGF-1, decreased circulating IGFBP3, and increased Igfbp3 brain mRNA expression. This study suggests that growth-associated microbiota can influence early neuron and oligodendrocyte development and that this effect may be mediated by effects on neuroinflammation and circulating IGF-1.
The Notch inhibitor cowanin accelerates nicastrin degradation
Authors: Arai Midori A. , Akamine Ryuta , Tsuchiya Anna , Yoneyama Tatsuro , Koyano Takashi , Kowithayakorn Thaworn , Ishibashi Masami
Published: March 2018

Aberrant activation of Notch signaling contributes to the pathogenesis of several different types of cancer, and Notch pathway inhibitors may have significant therapeutic potential. Using a unique cell-based assay system, we isolated twelve compounds, including one new natural product from Garcinia speciosa, that inhibit the Notch signaling pathway. HES1 and HES5 are target genes of the Notch cascade, and compound 2, referred to as cowanin, decreased the protein levels of HES1 and HES5 in assay cells. Furthermore, cowanin (2) showed potent cytotoxicity against human leukemic HPB-ALL cells. The Notch signaling inhibitory activity of cowanin (2) is linked to the increased degradation of nicastrin, which is one of the components of the γ-secretase complex. To the best of our knowledge, this is the first example of a compound with Notch pathway inhibitory activity mediated by nicastrin degradation.
Metabolomic approach for a rapid identification of natural products with cytotoxic activity against human colorectal cancer cells
Authors: Graziani Vittoria , Scognamiglio Monica , Belli Valentina , Esposito Assunta , D’Abrosca Brigida , Chambery Angela , Russo Rosita , Panella Marta , Russo Aniello , Ciardiello Fortunato , Troiani Teresa , Potenza Nicoletta , Fiorentino Antonio
Published: March 2018

The discovery of bioactive compounds from natural sources entails an extremely lengthy process due to the timescale and complexity of traditional methodologies. In our study, we used a rapid NMR based metabolomic approach as tool to identify secondary metabolites with anti-proliferative activity against a panel of human colorectal cancer cell lines with different mutation profiles. For this purpose, fourteen Fabaceae species of Mediterranean vegetation were investigated using a double screening method: 1H NMR profiling enabled the identification of the main compounds present in the mixtures, whilst parallel biological assays allowed the selection of two plant extracts based on their strong anti-proliferative properties. Using high-resolution 2D NMR spectroscopy, putative active constituents were identified in the mixture and isolated by performing a bio-guided fractionation of the selected plant extracts. As a result, we found two active principles: a cycloartane glycoside and protodioscin derivative. Interestingly, these metabolites displayed a preferential anti-proliferative effect on colon cancer cell lines with an intrinsic resistance to anti-EGFR therapies. Our work provides an NMR-based metabolomic approach as a powerful and efficient tool to discover natural products with anticancer activities circumventing time-consuming procedures.
Increasing prosthetic foot energy return affects whole-body mechanics during walking on level ground and slopes
Authors: Childers W. Lee , Takahashi Kota Z.
Published: March 2018

Prosthetic feet are designed to store energy during early stance and then release a portion of that energy during late stance. The usefulness of providing more energy return depends on whether or not that energy transfers up the lower limb to aid in whole body propulsion. This research examined how increasing prosthetic foot energy return affected walking mechanics across various slopes. Five people with a uni-lateral transtibial amputation walked on an instrumented treadmill at 1.1 m/s for three conditions (level ground, +7.5°, −7.5°) while wearing a prosthetic foot with a novel linkage system and a traditional energy storage and return foot. The novel foot demonstrated greater range of motion (p = 0.0012), and returned more energy (p = 0.023) compared to the traditional foot. The increased energy correlated with an increase in center of mass (CoM) energy change during propulsion from the prosthetic limb (p = 0.012), and the increased prosthetic limb propulsion correlated to a decrease in CoM energy change (i.e., collision) on the sound limb (p < 0.001). These data indicate that this novel foot was able to return more energy than a traditional prosthetic foot and that this additional energy was used to increase whole body propulsion.
Case-control analysis of LRRK2 protective variants in Essential Tremor
Authors: Ng Adeline S. L. , Ng Ebonne Y. L. , Tan Yi Jayne , Prakash Kumar M. , Au Wing Lok , Tan Louis C. S. , Tan Eng-King
Published: March 2018

Co-existence of Parkinson’s disease (PD) and essential tremor (ET) may reflect overlapping pathophysiology underlying both conditions. Furthermore, PD patients with leucine-rich repeat kinase-2 (LRRK2) mutations may present with ET-like features, suggesting the possibility of common genetic underpinnings. Two common LRRK2 variants, R1398H and N551K, have been shown to be protective in multiple PD cohorts. We hypothesized that R1398H and N551K may show a similar effect in ET. In a case-control study involving 3198 subjects (2680 controls and 518 ET cases), R1398H was detected in 16.6% of ET cases compared to 18.0% in controls (OR = 0.91, 95% CI = 0.71–1.17, p = 0.46); while N551K was detected in 16.5% of ET cases compared to 18.0% of controls (OR = 0.89, 95% CI = 0.69–1.15, p = 0.37). While these results suggest that LRRK2 R1398H or N551K do not appear to modulate the risk of ET, it remains possible that a protective trend for both variants may be present in ET and a much larger sample size is required to identify this.
Examination of Csr regulatory circuitry using epistasis analysis with RNA-seq (Epi-seq) confirms that CsrD affects gene expression via CsrA, CsrB and CsrC
Authors: Potts Anastasia H. , Leng Yuanyuan , Babitzke Paul , Romeo Tony
Published: March 2018

The Csr global regulatory system coordinates gene expression in response to metabolic status. This system utilizes the RNA binding protein CsrA to regulate gene expression by binding to transcripts of structural and regulatory genes, thus affecting their structure, stability, translation, and/or transcription elongation. CsrA activity is controlled by sRNAs, CsrB and CsrC, which sequester CsrA away from other transcripts. CsrB/C levels are partly determined by their rates of turnover, which requires CsrD to render them susceptible to RNase E cleavage. Previous epistasis analysis suggested that CsrD affects gene expression through the other Csr components, CsrB/C and CsrA. However, those conclusions were based on a limited analysis of reporters. Here, we reassessed the global behavior of the Csr circuitry using epistasis analysis with RNA seq (Epi-seq). Because CsrD effects on mRNA levels were entirely lost in the csrA mutant and largely eliminated in a csrB/C mutant under our experimental conditions, while the majority of CsrA effects persisted in the absence of csrD, the original model accounts for the global behavior of the Csr system. Our present results also reflect a more nuanced role of CsrA as terminal regulator of the Csr system than has been recognized.