bluuebunny/crossref_metadata_2025 huggingface dataset:
Proteomic and bioinformatic pipeline to screen the ligands of S. pneumoniae interacting with human brain microvascular endothelial cells
Authors: Jiménez-Munguía Irene , Pulzova Lucia , Kanova Evelina , Tomeckova Zuzana , Majerova Petra , Bhide Katarina , Comor Lubos , Sirochmanova Ivana , Kovac Andrej , Bhide Mangesh
Published: March 2018

The mechanisms by which Streptococcus pneumoniae penetrates the blood-brain barrier (BBB), reach the CNS and causes meningitis are not fully understood. Adhesion of bacterial cells on the brain microvascular endothelial cells (BMECs), mediated through protein-protein interactions, is one of the crucial steps in translocation of bacteria across BBB. In this work, we proposed a systematic workflow for identification of cell wall associated ligands of pneumococcus that might adhere to the human BMECs. The proteome of S. pneumoniae was biotinylated and incubated with BMECs. Interacting proteins were recovered by affinity purification and identified by data independent acquisition (DIA). A total of 44 proteins were identified from which 22 were found to be surface-exposed. Based on the subcellular location, ontology, protein interactive analysis and literature review, five ligands (adhesion lipoprotein, endo-β-N-acetylglucosaminidase, PhtA and two hypothetical proteins, Spr0777 and Spr1730) were selected to validate experimentally (ELISA and immunocytochemistry) the ligand-BMECs interaction. In this study, we proposed a high-throughput approach to generate a dataset of plausible bacterial ligands followed by systematic bioinformatics pipeline to categorize the protein candidates for experimental validation. The approach proposed here could contribute in the fast and reliable screening of ligands that interact with host cells.
Non-invasive quantification of human swallowing using a simple motion tracking system
Authors: Hashimoto Hiroaki , Hirata Masayuki , Takahashi Kazutaka , Kameda Seiji , Katsuta Yuri , Yoshida Fumiaki , Hattori Noriaki , Yanagisawa Takufumi , Palmer Jason , Oshino Satoru , Yoshimine Toshiki , Kishima Haruhiko
Published: March 2018

The number of patients with dysphagia is rapidly increasing due to the ageing of the population. Therefore, the importance of objectively assessing swallowing function has received increasing attention. Videofluoroscopy and videoendoscopy are the standard clinical examinations for dysphagia, but these techniques are not suitable for daily use because of their invasiveness. Here, we aimed to develop a novel, non-invasive method for measuring swallowing function using a motion tracking system, the Kinect v2 sensor. Five males and five females with normal swallowing function participated in this study. We defined three mouth-related parameters and two larynx-related parameters and recorded data from 2.5 seconds before to 2.5 seconds after swallowing onset. Changes in mouth-related parameters were observed before swallowing and reached peak values at the time of swallowing. In contrast, larynx-related parameters showed little change before swallowing and reached peak values immediately after swallowing. This simple swallow tracking system (SSTS) successfully quantified the swallowing process from the oral phase to the laryngeal phase. This SSTS is non-invasive, wireless, easy to set up, and simultaneously measures the dynamics of swallowing from the mouth to the larynx. We propose the SSTS for use as a novel and non-invasive swallowing assessment tool in the clinic.
Structure and Dynamics of Polymeric Canopies in Nanoscale Ionic Materials: An Electrical Double Layer Perspective
Authors: Yu Zhou , Yang Fengchang , Dai Sheng , Qiao Rui
Published: March 2018

Nanoscale ionic materials (NIMs) are an emerging class of materials consisting of charged nanoparticles and polymeric canopies attaching to them dynamically by electrostatic interactions. Using molecular simulations, we examine the structure and dynamics of the polymeric canopies in model NIMs in which the canopy thickness is much smaller than the nanoparticle diameter. Without added electrolyte ions, the charged terminal groups of polymers adsorb strongly on charged walls, thereby electrostatically “grafting” polymers to the wall. These polymers are highly stretched. They rarely desorb from the wall, but maintain modest in-plane mobility. When electrolyte ion pairs are introduced, the counterions adsorb on the wall, causing some electrostatically “grafted” polymers to desorb. The desorbed polymers, however, are less than the adsorbed counter-ions, which leads to an overscreening of wall charges. The desorbed polymers’ charged terminal groups do not distribute uniformly across the canopy but are depleted in some regions; they adopt conformation similar to those in bulk and exchange with the “grafted” polymers rapidly, hence dilating the canopy and accelerating its dynamics. We understand these results by taking the canopy as an electrical double layer, and highlight the importance of the interplay of electrostatic and entropic effects in determining its structure and dynamics.
Methylation-to-Expression Feature Models of Breast Cancer Accurately Predict Overall Survival, Distant-Recurrence Free Survival, and Pathologic Complete Response in Multiple Cohorts
Authors: Thompson Jeffrey A. , Christensen Brock C. , Marsit Carmen J.
Published: March 2018

Prognostic biomarkers serve a variety of purposes in cancer treatment and research, such as prediction of cancer progression, and treatment eligibility. Despite growing interest in multi-omic data integration for defining prognostic biomarkers, validated methods have been slow to emerge. Given that breast cancer has been the focus of intense research, it is amenable to studying the benefits of multi-omic prognostic models due to the availability of datasets. Thus, we examined the efficacy of our methylation-to-expression feature model (M2EFM) approach to combining molecular and clinical predictors to create risk scores for overall survival, distant metastasis, and chemosensitivity in breast cancer. Gene expression, DNA methylation, and clinical variables were integrated via M2EFM to build models of overall survival using 1028 breast tumor samples and applied to validation cohorts of 61 and 327 samples. Models of distant recurrence-free survival and pathologic complete response were built using 306 samples and validated on 182 samples. Despite different populations and assays, M2EFM models validated with good accuracy (C-index or AUC ≥ 0.7) for all outcomes and had the most consistent performance compared to other methods. Finally, we demonstrated that M2EFM identifies functionally relevant genes, which could be useful in translating an M2EFM biomarker to the clinic.
Lower serum calcium is independently associated with CKD progression
Authors: Janmaat Cynthia J. , van Diepen Merel , Gasparini Alessandro , Evans Marie , Qureshi Abdul Rashid , Ärnlöv Johan , Barany Peter , Elinder Carl-Gustaf , Rotmans Joris I. , Vervloet Marc , Dekker Friedo W. , Carrero Juan Jesus
Published: March 2018

Disturbances in calcium metabolism are common in individuals with chronic kidney disease (CKD), but whether they are associated with subsequent kidney function decline is less clear. In a CKD 3–5 cohort of 15,755 adult citizens of Stockholm with creatinine tests taken during 2006–2011 and concurrent calcium testing at cohort entry, we investigated the association between baseline serum calcium and the subsequent change in estimated glomerular filtration rate (eGFR, by CKD-EPI) decline using linear mixed models. Mean (SD) baseline corrected serum calcium was 9.6 (0.5) mg/dL. Mean (95%-confidence interval [CI]) eGFR decline was −0.82 (−0.90; −0.74) mL/min/1.73 m2/year. In advanced CKD stages, higher baseline serum calcium was associated with less rapid kidney function decline. The adjusted change (95%-CI) in eGFR decline associated with each mg/dL increase in baseline serum calcium was −0.10 (−0.28; 0.26), 0.39 (0.07; 0.71), 0.34 (−0.02; 0.70) and 0.68 (0.36; 1.00) mL/min/1.73 m2/year for individuals in CKD stage 3a, 3b, 4, and 5, respectively. In a subgroup of patients using vitamin D supplements, the association between baseline serum calcium and CKD progression was eliminated, especially in CKD stage 3b and 4. To conclude, in individuals with CKD stage 3b to 5, lower baseline corrected serum calcium, rather than higher baseline serum calcium, associated with a more rapid CKD progression. Lower serum corrected calcium seems to be indicative for vitamin D deficiency.
Whole-exome Sequencing Helps the Diagnosis and Treatment in Children with Neurodevelopmental Delay Accompanied Unexplained Dyspnea
Authors: Tong Wenjia , Wang Yajian , Lu Yun , Ye Tongsheng , Song Conglei , Xu Yuanyuan , Li Min , Ding Jie , Duan Yuanyuan , Zhang Le , Gu Weiyue , Zhao Xiaoling , Yang Xiu-An , Jin Danqun
Published: March 2018

Neurodevelopmental delay accompanied unexplained dyspnea is a highly lethal disease in clinic. This study is to investigate the performance characteristics of trio whole exome sequencing (Trio-WES) in a pediatric setting by presenting our patient cohort and displaying the diagnostic yield. A total of 31 pediatric patients showing neurodevelopmental delay accompanied unexplained dyspnea were admitted to our hospital and referred for molecular genetic testing using Trio-WES. Eight genes namely MMACHC, G6PC, G6PT, ETFDH, OTC, NDUFAF5, SLC22A5, and MAGEL2 were suspected to be responsible for the onset of the clinical symptoms and 6 variants were novel. Standard interpretation according to ACMG guideline showed that the variants were pathogenic. Finally, diagnosis of methylmalonic aciduria and homocystinuria, glycogen storage disease, ornithine transcarbamylase deficiency, glutaric acidemia II, mitochondrial complex 1 deficiency, carnitine deficiency, and Schaaf-Yang syndrome was made in 12 out of the 31 patients. Trio-WES is an effective means for molecular diagnosis of infantile neurodevelopmental delay accompanied unexplained dyspnea. As for molecular etiology identification, when routine potential monogenetic inheritance patterns including de novo, autosomal recessive, autosomal dominant, and X-linked recessive inheritance analysis is negative, physicians should take into account imprinted genes.
Proteomic analysis of plasma extracellular vesicles reveals mitochondrial stress upon HTLV-1 infection
Authors: Jeannin Patricia , Chaze Thibault , Giai Gianetto Quentin , Matondo Mariette , Gout Olivier , Gessain Antoine , Afonso Philippe V.
Published: March 2018

Extracellular vesicles (EVs) can participate in intercellular communication and pathogenesis. EVs contain many cargos, including proteins, and the composition of EVs differs between cell-types and activation levels. Thus, plasma EVs can be used as a biomarker of systemic response to infection and/or disease progression. In this study, we aimed at describing alterations in the protein content of plasma EVs upon infection with the human T-lymphotropic retrovirus type 1 (HTLV-1). HTLV-1 is the etiological agent of a lymphoproliferative disease (ATL) and a series of inflammatory diseases, including a neurodegenerative inflammatory disease (HAM/TSP). We found that plasma EVs are more abundant and smaller in HTLV-1 asymptomatic carriers or HAM/TSP patients when compared to uninfected healthy donors. Moreover, EVs from HTLV-1 infected donors contain markers of metabolic and mitochondrial stress.
Saturation-Recovery Myocardial T1-Mapping during Systole: Accurate and Robust Quantification in the Presence of Arrhythmia
Authors: Meßner Nadja M. , Budjan Johannes , Loßnitzer Dirk , Papavassiliu Theano , Schad Lothar R. , Weingärtner Sebastian , Zöllner Frank G.
Published: March 2018

Myocardial T1-mapping, a cardiac magnetic resonance imaging technique, facilitates a quantitative measure of fibrosis which is linked to numerous cardiovascular symptoms. To overcome the problems of common techniques, including lack of accuracy and robustness against partial-voluming and heart-rate variability, we introduce a systolic saturation-recovery T1-mapping method. The Saturation-Pulse Prepared Heart-rate independent Inversion-Recovery (SAPPHIRE) T1-mapping method was modified to enable imaging during systole. Phantom measurements were used to evaluate the insensitivity of systolic T1-mapping towards heart-rate variability. In-vivo feasibility and accuracy were demonstrated in ten healthy volunteers with native and post-contrast T1-mappping during systole and diastole. To show benefits in the presence of RR-variability, six arrhythmic patients underwent native T1-mapping. Resulting systolic SAPPHIRE T1-values showed no dependence on arrhythmia in phantom (CoV < 1%). In-vivo, significantly lower T1 (1563 ± 56 ms, precision: 84.8 ms) and ECV-values (0.20 ± 0.03) than during diastole (T1 = 1580 ± 62 ms, p = 0.0124; precision: 60.2 ms, p = 0.03; ECV = 0.21 ± 0.03, p = 0.0098) were measured, with a strong correlation of systolic and diastolic T1 (r = 0.89). In patients, mis-triggering-induced motion caused significant imaging artifacts in diastolic T1-maps, whereas systolic T1-maps displayed resilience to arrythmia. In conclusion, the proposed method enables saturation-recovery T1-mapping during systole, providing increased robustness against partial-voluming compared to diastolic imaging, for the benefit of T1-measurements in arrhythmic patients.
Engineered 3D vascular and neuronal networks in a microfluidic platform
Authors: Osaki Tatsuya , Sivathanu Vivek , Kamm Roger D.
Published: March 2018

Neurovascular coupling plays a key role in the pathogenesis of neurodegenerative disorders including motor neuron disease (MND). In vitro models provide an opportunity to understand the pathogenesis of MND, and offer the potential for drug screening. Here, we describe a new 3D microvascular and neuronal network model in a microfluidic platform to investigate interactions between these two systems. Both 3D networks were established by co-culturing human embryonic stem (ES)-derived MN spheroids and endothelial cells (ECs) in microfluidic devices. Co-culture with ECs improves neurite elongation and neuronal connectivity as measured by Ca2+ oscillation. This improvement was regulated not only by paracrine signals such as brain-derived neurotrophic factor secreted by ECs but also through direct cell-cell interactions via the delta-notch pathway, promoting neuron differentiation and neuroprotection. Bi-directional signaling was observed in that the neural networks also affected vascular network formation under perfusion culture. This in vitro model could enable investigations of neuro-vascular coupling, essential to understanding the pathogenesis of neurodegenerative diseases including MNDs such as amyotrophic lateral sclerosis.
MultiBacMam Bimolecular Fluorescence Complementation (BiFC) tool-kit identifies new small-molecule inhibitors of the CDK5-p25 protein-protein interaction (PPI)
Authors: Bellón-Echeverría Itxaso , Carralot Jean-Philippe , Del Rosario Andrea Araujo , Kueng Stephanie , Mauser Harald , Schmid Georg , Thoma Ralf , Berger Imre
Published: March 2018

Protein-protein interactions (PPIs) are at the core of virtually all biological processes in cells. Consequently, targeting PPIs is emerging at the forefront of drug discovery. Cellular assays which closely recapitulate native conditions in vivo are instrumental to understand how small molecule drugs can modulate such interactions. We have integrated MultiBacMam, a baculovirus-based mammalian gene delivery tool we developed, with bimolecular fluorescence complementation (BiFC), giving rise to a highly efficient system for assay development, identification and characterization of PPI modulators. We used our system to analyze compounds impacting on CDK5-p25 PPI, which is implicated in numerous diseases including Alzheimer’s. We evaluated our tool-kit with the known inhibitor p5T, and we established a mini-screen to identify compounds that modulate this PPI in dose-response experiments. Finally, we discovered several compounds disrupting CDK5-p25 PPI, which had not been identified by other screening or structure-based methods before.
Elevated tropospheric CO2 and O3 concentrations impair organic pollutant removal from grassland soil
Authors: Ai Fuxun , Eisenhauer Nico , Jousset Alexandre , Butenschoen Olaf , Ji Rong , Guo Hongyan
Published: March 2018

The concentrations of tropospheric CO2 and O3 have been rising due to human activities. These rising concentrations may have strong impacts on soil functions as changes in plant physiology may lead to altered plant-soil interactions. Here, the effects of eCO2 and eO3 on the removal of polycyclic aromatic hydrocarbon (PAH) pollutants in grassland soil were studied. Both elevated CO2 and O3 concentrations decreased PAH removal with lowest removal rates at elevated CO2 and elevated O3 concentrations. This effect was linked to a shift in soil microbial community structure by structural equation modeling. Elevated CO2 and O3 concentrations reduced the abundance of gram-positive bacteria, which were tightly linked to soil enzyme production and PAH degradation. Although plant diversity did not buffer CO2 and O3 effects, certain soil microbial communities and functions were affected by plant communities, indicating the potential for longer-term phytoremediation approaches. Results of this study show that elevated CO2 and O3 concentrations may compromise the ability of soils to degrade organic pollutants. On the other hand, the present study also indicates that the targeted assembly of plant communities may be a promising tool to shape soil microbial communities for the degradation of organic pollutants in a changing world.
Humans significantly metabolize and excrete the mycotoxin deoxynivalenol and its modified form deoxynivalenol-3-glucoside within 24 hours
Authors: Vidal Arnau , Claeys Liesel , Mengelers Marcel , Vanhoorne Valérie , Vervaet Chris , Huybrechts Bart , De Saeger Sarah , De Boevre Marthe
Published: March 2018

For the first time, a comprehensive human intervention study was conducted to unravel the urinary excretion profile and metabolism of the fungal metabolite deoxynivalenol (DON) and its modified form deoxynivalenol-3-glucoside (DON-3-glucoside). Twenty volunteers were restricted in consuming cereals and cereal-based foods for 4 days. At day 3, a single bolus of 1 µg/kg body weight of DON and a single bolus of 1 µg/kg body weight of DON-3-glucoside after a washing-out period of two months was administered, and a 24-h urine collection was performed. The urine was analysed for DON, DON-3-glucoside, 3-ADON, 15-ADON, deepoxy-deoxynivalenol (DOM-1), deoxynivalenol-3-glucuronide (DON-3-glucuronide) and deoxynivalenol-15-glucuronide (DON-15-glucuronide). The urinary biomarker-analysis revealed that DON and DON-3-glucoside were rapidly absorbed, distributed, metabolized and excreted. Sixty-four % of the administered DON and 58% of DON-3-glucoside was recovered in the urine collected within 24 h. DON-15-glucuronide was the most prominent urinary biomarker followed by free DON and DON-3-glucuronide. Moreover, correlations among the presence of DON-15-glucuronide and DON-3-glucuronide were observed (within 24 hours (r = 0.61)). The DOM-1 detected in the urine was higher after the DON-3-glucoside administration. The obtained results are imperative to construct a standardized method to estimate DON-intake by means of urinary biomarkers.
Application of Quantitative Microstructural MR Imaging with Atlas-based Analysis for the Spinal Cord in Cervical Spondylotic Myelopathy
Authors: Hori Masaaki , Hagiwara Akifumi , Fukunaga Issei , Ueda Ryo , Kamiya Kouhei , Suzuki Yuichi , Liu Wei , Murata Katsutoshi , Takamura Tomohiro , Hamasaki Nozomi , Irie Ryusuke , Kamagata Koji , Kumamaru Kanako Kunishima , Suzuki Michimasa , Aoki Shigeki
Published: March 2018

Mapping of MR fiber g-ratio, which is the ratio of the diameter of the axon to the diameter of the neuronal fiber, is introduced in this article. We investigated the MR fiber g-ratio, the axon volume fraction (AVF) and the myelin volume fraction (MVF) to evaluate microstructural changes in the spinal cord in patients with cervical spondylotic myelopathy (CSM) in vivo, using atlas-based analysis. We used diffusion MRI data acquired with a new simultaneous multi-slice accelerated readout-segmented echo planar imaging sequence for diffusion analysis for AVF calculation and magnetization transfer saturation imaging for MVF calculation. The AVFs of fasciculus gracilis in the affected side spinal cord, fasciculus cuneatus and lateral corticospinal tracts (LSCT) in the affected and unaffected side spinal cord were significantly lower (P = 0.019, 0.001, 0019, 0.000, and 0.002, respectively) than those of normal controls. No difference was found in the MVFs. The fiber g-ratio of LSCT was significantly lower (P = 0.040) in the affected side spinal cords than in the normal controls. The pathological microstructural changes in the spinal cord in patients with CSM, presumably partial axonal degenerations with preserved myelin. This technique has the potential to be a clinical biomarker in patients with CSM in vivo.
Low affinity uniporter carrier proteins can increase net substrate uptake rate by reducing efflux
Authors: Bosdriesz Evert , Wortel Meike T. , Haanstra Jurgen R. , Wagner Marijke J. , de la Torre Cortés Pilar , Teusink Bas
Published: March 2018

Many organisms have several similar transporters with different affinities for the same substrate. Typically, high-affinity transporters are expressed when substrate is scarce and low-affinity ones when it is abundant. The benefit of using low instead of high-affinity transporters remains unclear, especially when additional nutrient sensors are present. Here, we investigate two hypotheses. It was previously hypothesized that there is a trade-off between the affinity and the catalytic efficiency of transporters, and we find some but no definitive support for it. Additionally, we propose that for uptake by facilitated diffusion, at saturating substrate concentrations, lowering the affinity enhances the net uptake rate by reducing substrate efflux. As a consequence, there exists an optimal, external-substrate-concentration dependent transporter affinity. A computational model of Saccharomyces cerevisiae glycolysis shows that using the low affinity HXT3 transporter instead of the high affinity HXT6 enhances the steady-state flux by 36%. We tried to test this hypothesis with yeast strains expressing a single glucose transporter modified to have either a high or a low affinity. However, due to the intimate link between glucose perception and metabolism, direct experimental proof for this hypothesis remained inconclusive. Still, our theoretical results provide a novel reason for the presence of low-affinity transport systems.
Dietary genistein supplementation for breeders and their offspring improves the growth performance and immune function of broilers
Authors: Lv Zengpeng , Fan Hao , Zhang Beibei , Xing Kun , Guo Yuming
Published: March 2018

Genistein (GEN) is mainly extracted from soy plants and has potential functions as an antioxidant and in promoting immune function and growth. This study evaluated the effects of feeding breeders and their offspring dietary GEN on the immune function and growth performance of broiler chicks. Breeders were assigned to a control diet or GEN diet (control diet +400 mg/kg GEN), and their offspring were fed a control diet or GEN diet (control diet +40 mg/kg GEN). GEN treatment increased the body weight gain, tibial length, tibial width and slaughter performance of broilers and decreased the feed conversion ratio. The treatment also affected skeletal muscle myosin assembly and growth and increased growth hormone levels and IGF-I and IGFBP1 expression. Following GEN treatment, antigen processing and presentation, macrophage activation, B lymphocyte, NK cell and helper T cell proliferation, and CD4+ T lymphocyte differentiation all increased significantly. Increases were also observed in IgM and IgG concentrations, antibody titers, and antioxidant capacity. In addition, GEN treatment activated the Toll-like receptor signaling pathway and MAPK cascade signaling pathway. In summary, dietary GEN supplementation for breeders and their offspring can improve the growth performance and immune function of broiler chicks.
Head tracking extends local active control of broadband sound to higher frequencies
Authors: Elliott Stephen J. , Jung Woomin , Cheer Jordan
Published: March 2018

Local active sound control systems provide useful reductions in noise within a zone of quiet which only extends to about one tenth of an acoustic wavelength. If active control is required above a few hundred hertz, this generally limits the movement of a listener to unrealistically small changes in head position. We describe a local active sound control system using a fixed array of monitoring microphones, in which the pressures at the ear positions are estimated from these microphone signals using head position information from an optical head tracker. These signals are then actively controlled to give robust attenuation at the ear positions, even as the listener moves their head. Feedforward control provides selective attenuation of noise and broadband attenuation of around 20 dB is measured up to excitation frequencies of 1 kHz under favourable conditions, with head tracking achieved in a few seconds. The active control performance is thus comparable with that achieved with active headphones, but without the listener having anything attached to their head.
Cross-talk between primary osteocytes and bone marrow macrophages for osteoclastogenesis upon collagen treatment
Authors: Elango Jeevithan , Sanchez Christelle , de Val José Eduardo Maté Sánchez , Henrotin Yves , Wang Shujun , Motaung Keolebogile Shirley Caroline Mamots , Guo Ruihua , Wang Chunxiao , Robinson Jeyashakila , Regenstein Joe M. , Bao Bin , Wu Wenhui
Published: March 2018

Homeostasis of osteoclast formation from bone marrow macrophages (BMM) is regulated by paracrine signals of the neighbourhood bone cells particularly mesenchymal stem cells (MSC), osteoblasts and osteocytes (OC). Besides paracrine cues, collagen and glycosaminoglycan are involved in controlling bone homeostasis. Towards this approach, different molecular weight collagens were reacted with MSC, OC and BMM to understand the bone homeostasis activity of collagen. The up-regulating effect of collagens on osteogenic cell growth was confirmed by the presence of mineralized nodules in the osteoblastogenic lineage cells and increased osteogenic stimulatory gene expression. The decreased BMM-derived TRAP+ osteoclasts number and osteoclastogenic regulatory gene expression of OC could demonstrate the exploitive osteoclastogenic activity of collagens. Osteoclastogenesis from BMM was triggered by paracrine cues of OC in some extend, but it was down-regulated by collagen. Overall, the effect of collagen on osteoclastogenesis and osteoblastogenesis may depend on the molecular weight of collagens, and collagen suppresses osteoclastogenesis, at least in part by downregulating the secretion of cytokines in OC.
Dnmt3a in the dorsal dentate gyrus is a key regulator of fear renewal
Authors: Gong Zhiting , Zhou Qiang
Published: March 2018

Renewal of extinguished fear memory in an altered context is widely believed to be a major limiting issue for exposure therapy in treating various psychiatric diseases. Effective prevention of fear renewal will significantly improve the efficacy of exposure therapy. DNA methyltransferase (DNMTs) mediated epigenetic processes play critical roles in long term memory, but little is known about their functions in fear memory extinction or renewal. Here we investigated whether DNMTs regulate fear renewal after extinction. We found that elevated Dnmt3a level in the dorsal dentate gyrus (dDG) of hippocampus was associated with the absence of fear renewal in an altered context after extinction training. Overexpression and knockdown of Dnmt3a in the dDG regulated the occurrence of fear renewal in a bi-directional manner. In addition, Dnmt3a overexpression was associated with elevated expression of c-Fos in the dDG during extinction training. Furthermore, we found that renewal of remote fear memory can be prevented, and the absence of renewal was concurrent with an elevated Dnmt3a level. Our results indicate that Dnmt3a in the dDG is a key regulator of fear renewal after extinction, and Dnmt3a may play a critical role in controlling fear memory return and thus has therapeutic values.
Extracting biological age from biomedical data via deep learning: too much of a good thing?
Authors: Pyrkov Timothy V. , Slipensky Konstantin , Barg Mikhail , Kondrashin Alexey , Zhurov Boris , Zenin Alexander , Pyatnitskiy Mikhail , Menshikov Leonid , Markov Sergei , Fedichev Peter O.
Published: March 2018

Age-related physiological changes in humans are linearly associated with age. Naturally, linear combinations of physiological measures trained to estimate chronological age have recently emerged as a practical way to quantify aging in the form of biological age. In this work, we used one-week long physical activity records from a 2003–2006 National Health and Nutrition Examination Survey (NHANES) to compare three increasingly accurate biological age models: the unsupervised Principal Components Analysis (PCA) score, a multivariate linear regression, and a state-of-the-art deep convolutional neural network (CNN). We found that the supervised approaches produce better chronological age estimations at the expense of a loss of the association between the aging acceleration and all-cause mortality. Consequently, we turned to the NHANES death register directly and introduced a novel way to train parametric proportional hazards models suitable for out-of-the-box implementation with any modern machine learning software. As a demonstration, we produced a separate deep CNN for mortality risks prediction that outperformed any of the biological age or a simple linear proportional hazards model. Altogether, our findings demonstrate the emerging potential of combined wearable sensors and deep learning technologies for applications involving continuous health risk monitoring and real-time feedback to patients and care providers.
Interleukin-23 as a therapeutic target for inflammatory myopathy
Authors: Umezawa Natsuka , Kawahata Kimito , Mizoguchi Fumitaka , Kimura Naoki , Yoshihashi-Nakazato Yoko , Miyasaka Nobuyuki , Kohsaka Hitoshi
Published: March 2018

Current treatments of polymyositis and dermatomyositis (PM/DM) depend on non-specific immunosuppressants. This study was performed to elucidate the role of interleukin (IL)-23, as their possible therapeutic target. As was reported earlier in PM/DM patients, serum IL-23 levels were elevated in mice with C protein induced-myositis (CIM), a murine model of PM. IL-23 was expressed by macrophages in the PM/DM and CIM muscles and by dendritic cells and macrophages in the lymph nodes from the CIM mice. It was also expressed by macrophages in the chemically injured muscles, but not those recruited into the muscles by footpad injection of Freund’s complete adjuvant, demonstrating that IL-23 production should be associated with muscle damage. Genetic deletion of IL-23 as well as preventive and therapeutic administration of blocking antibodies against IL-23p19 subunit suppressed CIM. When lymph node cells from the CIM mice were transferred adoptively into naive wild type or IL-23p19 deficient recipient mice, both recipients developed myositis equally. Thus, elevated IL-23 should promote dendritic cells and macrophages to activate the autoaggressive T cells. Our findings suggest that IL-23 should mediate positive feedback loop from the muscle damage to the T cell activation and be a promising therapeutic target for autoimmune myositis.
A prominent air pollutant, Indeno[1,2,3-cd]pyrene, enhances allergic lung inflammation via aryl hydrocarbon receptor
Authors: Wong Tzu-Hsuan , Lee Chon-Lin , Su Hsiang-Han , Lee Chin-Lai , Wu Chao-Chien , Wang Chin-Chou , Sheu Chau-Chyun , Lai Ruay-Sheng , Leung Sum-Yee , Lin Chi-Cheng , Wei Yu-Feng , Wang Chien-Jen , Lin Yu-Chun , Chen Hua-Ling , Huang Ming-Shyan , Yen Jeng-Hsien , Huang Shau-Ku , Suen Jau-Ling
Published: March 2018

Chronic exposure to ambient polycyclic aromatic hydrocarbons (PAHs) is associated with asthma, but its regulatory mechanisms remain incompletely defined. We report herein that elevated levels of urinary 1-hydroxypyrene, a biomarker of PAH exposure, were found in asthmatic subjects (n = 39) as compared to those in healthy subjects (n = 43) living in an industrial city of Taiwan, where indeno[1,2,3-cd]pyrene (IP) was found to be a prominent PAH associated with ambient PM2.5. In a mouse model, intranasal exposure of mice with varying doses of IP significantly enhanced antigen-induced allergic inflammation, including increased airway eosinophilia, Th2 cytokines, including IL-4 and IL-5, as well as antigen-specific IgE level, which was absent in dendritic cell (DC)-specific aryl hydrocarbon receptor (AhR)-null mice. Mechanistically, IP treatment significantly altered DC’s function, including increased level of pro-inflammatory IL-6 and decreased generation of anti-inflammatory IL-10. The IP’s effect was lost in DCs from mice carrying an AhR-mutant allele. Taken together, these results suggest that chronic exposure to environmental PAHs may pose a significant risk for asthma, in which IP, a prominent ambient PAH in Taiwan, was shown to enhance the severity of allergic lung inflammation in mice through, at least in part, its ability in modulating DC’s function in an AhR-dependent manner.
Latitudinal trends in human primary activities: characterizing the winter day as a synchronizer
Authors: Martín-Olalla José María
Published: March 2018

This work analyzes time use surveys from 19 countries (17 European and 2 American) in the middle latitude (38–61 degree) accounting for 45% of world population in this range. Time marks for primary activities are contrasted against light/dark conditions. The analysis reveals winter sunrise synchronizes labor start time below 54 degree, occurring within winter civil twilight. Winter sunset is a source of synchronization for labor end times. Winter terminator punctuate meal times in Europe: dinner occurs 3 h after winter sunset time within 1 h; 40% narrower than variability of dinner local times. The sleep-wake cycle of laborers is shown to be related to winter sunrise whereas standard population’s appears to be irrespective of latitude. The significance of the winter terminator depends on two competing factors average labor time (~7 h30 m) and the shortest photoperiod. Winter terminator gains significance when both roughly matches. That is within a latitude range from 38 degree to 54 degree. The significance of winter terminator as a source of synchronization is also related to contemporary year round time schedules: the shortest photoperiod represents the worst case scenario the society faces.
The Cish SH2 domain is essential for PLC-γ1 regulation in TCR stimulated CD8+ T cells
Authors: Guittard Geoffrey , Dios-Esponera Ana , Palmer Douglas C. , Akpan Itoro , Barr Valarie A. , Manna Asit , Restifo Nicholas P. , Samelson Lawrence E.
Published: March 2018

Cish, participates within a multi-molecular E3 ubiquitin ligase complex, which ubiquitinates target proteins. It has an inhibitory effect on T cell activation mediated by PLC-γ1 regulation, and it functions as a potent checkpoint in CD8+ T cell tumor immunotherapy. To study the structural and functional relationships between Cish and PLC-γ1 during CD8+ T cell activation, we tested mutants of the Cish-SH2 (R107K) and D/BC (L222Q, C226Q) domains. We confirmed that Cish-SH2-specific binding was essential for PLC-γ1 ubiquitination and degradation. This domain was essential for the Cish-mediated inhibition of Ca2+ release upon TCR stimulation. No effect on inhibition of cytokine release was observed with SH2 or D/BC mutants, although the absence of Cish led to an increased release of IFN-γ and TNF-α. Using imaging we showed that Cish was expressed mostly in the cytoplasm and we did not see any Cish clustering at the plasma membrane upon stimulation. We conclude that the Cish-SH2 domain is essential for PLC-γ1 regulation in TCR-stimulated CD8+ T cells.
Highly efficient Fenton and enzyme-mimetic activities of NH2-MIL-88B(Fe) metal organic framework for methylene blue degradation
Authors: He Jianchuan , Zhang Yao , Zhang Xiaodan , Huang Yuming
Published: March 2018

Here, we show that NH2-MIL-88B(Fe) can be used as a peroxidase-like catalyst for Fenton-like degradation of methylene blue (MB) in water. The iron-based NH2-MIL-88B(Fe) metal organic framework (MOF) was synthesized by a facile and rapid microwave heating method. It was characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, powder X-ray diffraction, and the Brunauer–Emmett–Teller method. The NH2-MIL-88B(Fe) MOF possesses intrinsic oxidase-like and peroxidase-like activities. The reaction parameters that affect MB degradation were investigated, including the solution pH, NH2-MIL-88B(Fe) MOF and H2O2 concentrations, and temperature. The results show that the NH2-MIL-88B(Fe) MOF exhibits a wide working pH range (pH 3.0–11.0), temperature tolerance, and good recyclability for MB removal. Under the optimal conditions, complete removal of MB was achieved within 45 min. In addition, removal of MB was above 80% after five cycles, showing the good recyclability of NH2-MIL-88B(Fe). The NH2-MIL-88B(Fe) MOF has the features of easy preparation, high efficiency, and good recyclability for MB removal in a wide pH range. Electron spin resonance and fluorescence probe results suggest the involvement of hydroxyl radicals in MB degradation. These findings provide new insight into the application of high-efficient MOF-based Fenton-like catalysts for water purification.
Rydberg interaction induced enhanced excitation in thermal atomic vapor
Authors: Kara Dushmanta , Bhowmick Arup , Mohapatra Ashok K.
Published: March 2018

We present the experimental demonstration of interaction induced enhancement in Rydberg excitation or Rydberg anti-blockade in thermal atomic vapor. We have used optical heterodyne detection technique to measure Rydberg population due to two-photon excitation to the Rydberg state. The anti-blockade peak which doesn’t satisfy the two-photon resonant condition is observed along with the usual two-photon resonant peak which can’t be explained using the model with non-interacting three-level atomic system. A model involving two interacting atoms is formulated for thermal atomic vapor using the dressed states of three-level atomic system to explain the experimental observations. A non-linear dependence of vapor density is observed for the anti-blockade peak which also increases with increase in principal quantum number of the Rydberg state. A good agreement is found between the experimental observations and the proposed interacting model. Our result implies possible applications towards quantum logic gates using Rydberg anti-blockade in thermal atomic vapor.
Metal behavior in the extremes of dynamics
Authors: Zubelewicz Aleksander
Published: March 2018

When the rate of loading is faster than the rate at which material absorbs and converts energy to plastic work and damages, then there is an excess of energy that is partly stored in the material’s microstructure and the rest of it triggers micro-dynamic excitations. The additional storage necessitates the development of plastic flow constraints and is directly responsible for the observed dynamic strengthening. At extreme conditions, we find that the micro-excitations contribute to the dynamic behavior. The phenomena are universally observed in metals, frictional materials and polymers. In essence, strong dynamics creates conditions at which materials are pushed from equilibrium and temporarily reside in an excited state of behavior. This study is focused on the behavior of metals. The concept is incorporated into a mechanisms-based constitutive model and is examined for annealed OFHC copper.
Supplementation of Pelleted Hazel (Corylus avellana) Leaves Decreases Methane and Urinary Nitrogen Emissions by Sheep at Unchanged Forage Intake
Authors: Wang Shaopu , Terranova Melissa , Kreuzer Michael , Marquardt Svenja , Eggerschwiler Lukas , Schwarm Angela
Published: March 2018

This study is the first to quantify the effects of hazel (Corylus avellana) leaves on methane and urinary nitrogen emissions, digestibility, nitrogen and the energy balance of ruminants. Four experimental pellets were produced with 0, 30% and 60% hazel leaves, the latter also with 4% polyethylene glycol. Hazel leaves gradually replaced lucerne. The diet was composed of the pellets and grass hay (80%: 20%). Six adult sheep were allocated to all four treatments in a 6 × 4 crossover design. Including hazel leaves did not affect the feed intake, but it decreased the apparent digestibility of organic matter and fibre, especially at the high level. Methane emission was reduced by up to 25 to 33% per day, per unit of intake and per unit of organic matter digested. Urinary nitrogen excretion decreased by 33 to 72% with increasing levels of hazel leaves. The treatment with polyethylene glycol demonstrated that tannins in hazel leaves caused significant shares of the effects. In conclusion, the current results indicated a significant potential of hazel leaves as forage for ruminants to mitigate methane and urinary nitrogen emissions. Even high dietary hazel leaf proportions were palatable. The lower digestibility needs to be compensated with easily digestible diet ingredients.
Osteoarthritis-patterns, cardio-metabolic risk factors and risk of all-cause mortality: 20 years follow-up in patients after hip or knee replacement
Authors: Büchele G. , Günther K. P. , Brenner H. , Puhl W. , Stürmer T. , Rothenbacher D. , Brenner R. E.
Published: March 2018

Osteoarthritis (OA) is a common musculoskeletal disorder and occur in different patterns. However, its impact on long-term all-cause-mortality is inconclusive. Study aims: Investigate 20-year all-cause-mortality in patients with hip/knee arthroplasty (recruited 1995/1996, N = 809) from the Ulm Osteoarthritis Study-cohort, in comparison to general population. Furthermore, to enlighten the triangle between baseline life-style and cardio-metabolic risk factors, phenotypic OA-patterns (laterality, generalization, cause) and all-cause-mortality. Mortality was assessed during 20 years follow-up. Standardized mortality ratios (SMR), adjusted odds ratios and hazard ratios (aHR) were calculated. After five years cohort-mortality was reduced compared to the general population, however 20 years later assimilated (SMR = 1.11; 95%-CI 0.73-1.49). OA-patterns were associated with age, cholesterol, and overweight/obesity. In comparison to primary OA decreased mortality was observed for patients with secondary OA (aHR = 0.76; 95%-CI 0.61-0.95) adjusted for age, smoking, overweight/obesity, diabetes, hypertension, cardiac insufficiency, uric acid, and lower cholesterol. There was no increased mortality in patients after 20 years follow-up compared to general population. Significantly decreased mortality in secondary compared to primary OA suggests a subtype-specific involvement of systemic co-factors in determination of all-cause-mortality. Because cardio-metabolic risk factors were associated with increased risk of bilateral OA and lower long-term survival, those risk factors should be consequently targeted in OA-patients.
Population genetic analysis of the recently rediscovered Hula painted frog (Latonia nigriventer) reveals high genetic diversity and low inbreeding
Authors: Perl R. G. Bina , Geffen Eli , Malka Yoram , Barocas Adi , Renan Sharon , Vences Miguel , Gafny Sarig
Published: March 2018

After its recent rediscovery, the Hula painted frog (Latonia nigriventer) has remained one of the world’s rarest and least understood amphibian species. Together with its apparently low dispersal capability and highly disturbed niche, the low abundance of this living fossil calls for urgent conservation measures. We used 18 newly developed microsatellite loci and four different models to calculate the effective population size (Ne) of a total of 125 Hula painted frog individuals sampled at a single location. We compare the Ne estimates to the estimates of potentially reproducing adults in this population (Nad) determined through a capture-recapture study on 118 adult Hula painted frogs captured at the same site. Surprisingly, our data suggests that, despite Nad estimates of only ~234–244 and Ne estimates of ~16.6–35.8, the species appears to maintain a very high genetic diversity (HO = 0.771) and low inbreeding coefficient (FIS = −0.018). This puzzling outcome could perhaps be explained by the hypotheses of either genetic rescue from one or more unknown Hula painted frog populations nearby or by recent admixture of genetically divergent subpopulations. Independent of which scenario is correct, the original locations of these populations still remain to be determined.
NIPTmer: rapid k-mer-based software package for detection of fetal aneuploidies
Authors: Sauk Martin , Žilina Olga , Kurg Ants , Ustav Eva-Liina , Peters Maire , Paluoja Priit , Roost Anne Mari , Teder Hindrek , Palta Priit , Brison Nathalie , Vermeesch Joris R. , Krjutškov Kaarel , Salumets Andres , Kaplinski Lauris
Published: March 2018

Non-invasive prenatal testing (NIPT) is a recent and rapidly evolving method for detecting genetic lesions, such as aneuploidies, of a fetus. However, there is a need for faster and cheaper laboratory and analysis methods to make NIPT more widely accessible. We have developed a novel software package for detection of fetal aneuploidies from next-generation low-coverage whole genome sequencing data. Our tool – NIPTmer – is based on counting pre-defined per-chromosome sets of unique k-mers from raw sequencing data, and applying linear regression model on the counts. Additionally, the filtering process used for k-mer list creation allows one to take into account the genetic variance in a specific sample, thus reducing the source of uncertainty. The processing time of one sample is less than 10 CPU-minutes on a high-end workstation. NIPTmer was validated on a cohort of 583 NIPT samples and it correctly predicted 37 non-mosaic fetal aneuploidies. NIPTmer has the potential to reduce significantly the time and complexity of NIPT post-sequencing analysis compared to mapping-based methods. For non-commercial users the software package is freely available at http://bioinfo.ut.ee/NIPTMer/.