bluuebunny/crossref_metadata_2025 huggingface dataset:
Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology
Authors: Hirsch Alec J. , Roberts Victoria H. J. , Grigsby Peta L. , Haese Nicole , Schabel Matthias C. , Wang Xiaojie , Lo Jamie O. , Liu Zheng , Kroenke Christopher D. , Smith Jessica L. , Kelleher Meredith , Broeckel Rebecca , Kreklywich Craig N. , Parkins Christopher J. , Denton Michael , Smith Patricia , DeFilippis Victor , Messer William , Nelson Jay A. , Hennebold Jon D. , Grafe Marjorie , Colgin Lois , Lewis Anne , Ducore Rebecca , Swanson Tonya , Legasse Alfred W. , Axthelm Michael K. , MacAllister Rhonda , Moses Ashlee V. , Morgan Terry K. , Frias Antonio E. , Streblow Daniel N.
Published: January 2018

Zika virus (ZIKV) infection during pregnancy leads to an increased risk of fetal growth restriction and fetal central nervous system malformations, which are outcomes broadly referred to as the Congenital Zika Syndrome (CZS). Here we infect pregnant rhesus macaques and investigate the impact of persistent ZIKV infection on uteroplacental pathology, blood flow, and fetal growth and development. Despite seemingly normal fetal growth and persistent fetal-placenta-maternal infection, advanced non-invasive in vivo imaging studies reveal dramatic effects on placental oxygen reserve accompanied by significantly decreased oxygen permeability of the placental villi. The observation of abnormal oxygen transport within the placenta appears to be a consequence of uterine vasculitis and placental villous damage in ZIKV cases. In addition, we demonstrate a robust maternal-placental-fetal inflammatory response following ZIKV infection. This animal model reveals a potential relationship between ZIKV infection and uteroplacental pathology that appears to affect oxygen delivery to the fetus during development.
Oxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis
Authors: Carroll Bernadette , Otten Elsje G. , Manni Diego , Stefanatos Rhoda , Menzies Fiona M. , Smith Graham R. , Jurk Diana , Kenneth Niall , Wilkinson Simon , Passos Joao F. , Attems Johannes , Veal Elizabeth A. , Teyssou Elisa , Seilhean Danielle , Millecamps Stéphanie , Eskelinen Eeva-Liisa , Bronowska Agnieszka K. , Rubinsztein David C. , Sanz Alberto , Korolchuk Viktor I.
Published: January 2018

Cellular homoeostatic pathways such as macroautophagy (hereinafter autophagy) are regulated by basic mechanisms that are conserved throughout the eukaryotic kingdom. However, it remains poorly understood how these mechanisms further evolved in higher organisms. Here we describe a modification in the autophagy pathway in vertebrates, which promotes its activity in response to oxidative stress. We have identified two oxidation-sensitive cysteine residues in a prototypic autophagy receptor SQSTM1/p62, which allow activation of pro-survival autophagy in stress conditions. The Drosophila p62 homologue, Ref(2)P, lacks these oxidation-sensitive cysteine residues and their introduction into the protein increases protein turnover and stress resistance of flies, whereas perturbation of p62 oxidation in humans may result in age-related pathology. We propose that the redox-sensitivity of p62 may have evolved in vertebrates as a mechanism that allows activation of autophagy in response to oxidative stress to maintain cellular homoeostasis and increase cell survival.
Theoretical potential for low energy consumption phase change memory utilizing electrostatically-induced structural phase transitions in 2D materials
Authors: Rehn Daniel A. , Li Yao , Pop Eric , Reed Evan J.
Published: January 2018

Structural phase-change materials are of great importance for applications in information storage devices. Thermally driven structural phase transitions are employed in phase-change memory to achieve lower programming voltages and potentially lower energy consumption than mainstream nonvolatile memory technologies. However, the waste heat generated by such thermal mechanisms is often not optimized, and could present a limiting factor to widespread use. The potential for electrostatically driven structural phase transitions has recently been predicted and subsequently reported in some two-dimensional materials, providing an athermal mechanism to dynamically control properties of these materials in a nonvolatile fashion while achieving potentially lower energy consumption. In this work, we employ DFT-based calculations to make theoretical comparisons of the energy required to drive electrostatically-induced and thermally-induced phase transitions. Determining theoretical limits in monolayer MoTe2 and thin films of Ge2Sb2Te5, we find that the energy consumption per unit volume of the electrostatically driven phase transition in monolayer MoTe2 at room temperature is 9% of the adiabatic lower limit of the thermally driven phase transition in Ge2Sb2Te5. Furthermore, experimentally reported phase change energy consumption of Ge2Sb2Te5 is 100–10,000 times larger than the adiabatic lower limit due to waste heat flow out of the material, leaving the possibility for energy consumption in monolayer MoTe2-based devices to be orders of magnitude smaller than Ge2Sb2Te5-based devices.
Modifiable lifestyle behaviors, but not a genetic risk score, associate with metabolic syndrome in evening chronotypes
Authors: Vera Beatriz , Dashti Hassan S. , Gómez-Abellán Purificación , Hernández-Martínez Antonio M. , Esteban Alberto , Scheer Frank A. J. L. , Saxena Richa , Garaulet Marta
Published: January 2018

Evening chronotype associates with health complications possibly via lifestyle factors, while the contribution of genetics is unknown. The aim was to study the relative contributions of genetics, lifestyle, and circadian-related physiological characteristics in metabolic risk of evening chronotype. In order to capture a biological contribution to chronotype, a genetic-risk-score (GRS), comprised of 15 chronotype-related variants, was tested. Moreover, a wide range of behavioral and emotional eating factors was studied within the same population. Chronotype, lifestyle, and metabolic syndrome (MetS) outcomes were assessed (n = 2,126), in addition to genetics (n = 1,693) and rest-activity/wrist-temperature rhythms (n = 100). Evening chronotype associated with MetS and insulin resistance (P < 0.05), and several lifestyle factors including poorer eating behaviors, lower physical activity and later sleep and wake times. We observed an association between higher evening GRS and evening chronotype (P < 0.05), but not with MetS. We propose a GRS as a tool to capture the biological component of the inter-individual differences in chronotype. Our data show that several modifiable factors such as sedentary lifestyle, difficulties in controlling the amount of food eaten, alcohol intake and later wake and bed times that characterized evening-types, may underlie chronotype-MetS relationship. Our findings provide insights into the development of strategies, particularly for evening chronotype.
The role of NFκB in spheroid formation of human breast cancer cells cultured on the Random Positioning Machine
Authors: Kopp Sascha , Sahana Jayashree , Islam Tawhidul , Petersen Asbjørn Graver , Bauer Johann , Corydon Thomas J. , Schulz Herbert , Saar Kathrin , Huebner Norbert , Slumstrup Lasse , Riwaldt Stefan , Wehland Markus , Infanger Manfred , Luetzenberg Ronald , Grimm Daniela
Published: January 2018

Human MCF-7 breast cancer cells were exposed to a Random Positioning Machine (RPM). After 24 hours (h) the cells grew either adherently within a monolayer (AD) or within multicellular spheroids (MCS). AD and MCS populations were separately harvested, their cellular differences were determined performing qPCR on genes, which were differently expressed in AD and MCS cells. Gene array technology was applied to detect RPM-sensitive genes in MCF-7 cells after 24 h. Furthermore, the capability to form multicellular spheroids in vitro was compared with the intracellular distribution of NF-kappaB (NFκB) p65. NFκB was equally distributed in static control cells, but predominantly localized in the cytoplasm in AD cells and nucleus in MCS cells exposed to the RPM. Gene array analyses revealed a more than 2-fold change of only 23 genes including some whose products are affected by oxygen levels or regulate glycolysis. Significant upregulations of the mRNAs of enzymes degrading heme, of ANXA1, ANXA2, CTGF, CAV2 and ICAM1, as well as of FAS, Casp8, BAX, p53, CYC1 and PARP1 were observed in MCS cells as compared with 1g-control and AD cells. An interaction analysis of 47 investigated genes suggested that HMOX-1 and NFκB variants are activated, when multicellular spheroids are formed.
RETRACTED ARTICLE: Associations between VDR Gene Polymorphisms and Osteoporosis Risk and Bone Mineral Density in Postmenopausal Women: A systematic review and Meta-Analysis
Authors: Zhang Liang , Yin Xin , Wang Jingcheng , Xu Daolinag , Wang Yongxiang , Yang Jiandong , Tao Yuping , Zhang Shengfei , Feng Xinmin , Yan Caifeng
Published: January 2018

Results on the relationships between vitamin D receptor (VDR) gene polymorphisms and postmenopausal osteoporosis (PMOP) susceptibility and bone mineral density (BMD) are conflicting. The aim of the study is to identify more eligible studies that calculated pooled OR and WMD with 95% CI to assess their associations. Overall, there were significant correlations between VDRApaI, VDRFokI and PMOP susceptibility. Subgroup analysis showed that VDRApaI polymorphism significantly decreased the osteoporosis risk in Caucasian postmenopausal women. In Asian populations, VDRBsmI and VDRFokI were associated with an increased risk of PMOP. As to the associations between VDR polymorphisms and BMD, Caucasian PMOP women carrying theApaI aa genotype were at risk of high BMD in femoral neck, and low femoral neck BMD was observed in Caucasian PMOP women withFokI Ff genotype. PMOP women with theCdx2 GA genotype had a lower lumbar spine BMD in overall and Caucasian populations compared with PMOP women with GG genotype. Different VDR gene polymorphisms have different impacts on PMOP risk and BMD.
The bacterial Type III toxin-antitoxin system, ToxIN, is a dynamic protein-RNA complex with stability-dependent antiviral abortive infection activity
Authors: Short Francesca L. , Akusobi Chidiebere , Broadhurst William R. , Salmond George P. C.
Published: January 2018

Bacteria have evolved numerous defense systems to protect themselves from viral (bacteriophage) infection. The ToxIN system of Pectobacterium atrosepticum is a Type III toxin-antitoxin complex and “altruistic suicide” anti-phage system, which kills phage-infected cells through the release of a ribonuclease toxin, ToxN. ToxN is counteracted by a co-transcribed antitoxic RNA pseudoknot, ToxI, which self-assembles with ToxN into an inactive 3 ToxI:3 ToxN complex in vitro. However it is not known whether this complex is predominant in vivo, or how the complex is disassembled following infection to trigger a lethal, “altruistic” response. In this study, we characterise ToxI turnover and folding, and explore the link between complex stability and anti-phage activity, with a view to understanding events that lead to ToxN-mediated suicide following phage infection. We present evidence that ToxN constantly cleaves fresh ToxI in vivo rather than staying associated with pre-processed antitoxin, and that the ToxI antitoxin can partially fold spontaneously using conserved nucleotides. We also show that reducing the stability of the ToxIN complex can increase the strength of the antiviral response in a phage-dependent manner. Based on this information, we propose a revised model for ToxN inhibition, complex assembly and activation by infecting bacteriophage.
Critical conditions for escape of a high-speed fullerene from a BNC nanobeam after collision
Authors: Cai Kun , Yang Li-Kui , Shi Jiao , Qin Qing-Hua
Published: January 2018

For a resonator-based nano-balance, the capability of capturing a nanoparticle is essential for it to measure the mass of the particle. In the present study, a clamped-clamped nanobeam from a Boron-Nitride and Carbon (BNC) nanotube acts as the nano-balance, and a fullerene, e.g., C60, is chosen as the particle, and the capturing capability is quantitatively estimated by the minimal escape velocity (MEV) of the fullerene from the nanobeam after collision. When centrally colliding with the nanobeam, the escape of fullerene depends on both incidence of fullerene and temperature of the system. When the colliding in the Boron-Nitride (BN) area of the beam surface, the nanoball escapes easier than that at the carbon area. The MEV of the nanoball is lower at higher temperature. As the nanoball sometimes slides for a few pica-seconds on the beam surface before being bounced out, the nanoball can escape only when the beam surface can provide the nanoball enough kinetic energy to overcome the van der Waals interaction between them. The capturing capability of the nano-balance can, thus, be improved by reducing the initial kinetic energy of the system.
The phosphatase PPM1A controls monocyte-to-macrophage differentiation
Authors: Smith Samuel R. , Schaaf Kaitlyn , Rajabalee Nusrah , Wagner Frederic , Duverger Alexandra , Kutsch Olaf , Sun Jim
Published: January 2018

Differentiation of circulating monocytes into tissue-bound or tissue-resident macrophages is a critical regulatory process affecting host defense and inflammation. However, the regulatory signaling pathways that control the differentiation of monocytes into specific and distinct functional macrophage subsets are poorly understood. Herein, we demonstrate that monocyte-to-macrophage differentiation is controlled by the Protein Phosphatase, Mg2+/Mn2+-dependent 1A (PPM1A). Genetic manipulation experiments demonstrated that overexpression of PPM1A attenuated the macrophage differentiation program, while knockdown of PPM1A expression accelerated the ability of monocytes to differentiate into macrophages. We identify imiquimod and Pam3CSK4 as two Toll-like receptor agonists that induce PPM1A expression, and show that increased expression of PPM1A at the onset of differentiation impairs cellular adherence, reduces expression of inflammatory (M1) macrophage-specific markers, and inhibits the production of inflammatory cytokines. Our findings reveal PPM1A as a negative threshold regulator of M1-type monocyte-to-macrophage differentiation, establishing it as a key phosphatase that orchestrates this program.
Endothelial nitric oxide synthase overexpressing human early outgrowth cells inhibit coronary artery smooth muscle cell migration through paracrine functions
Authors: Guber Sergio , Ebrahimian Talin , Heidari Maryam , Eliopoulos Nicoletta , Lehoux Stephanie
Published: January 2018

Cells mobilized from the bone marrow can contribute to endothelial regeneration and repair. Nevertheless, cardiovascular diseases are associated with diminished numbers and function of these cells, attenuating their healing potential. Gene transfer of endothelial nitric oxide synthase (eNOS) can restore the activity of circulating cells. Furthermore, estrogen accelerates the reendothelialization capacity of early outgrowth cells (EOCs). We hypothesized that overexpressing eNOS alone or in combination with estrogen stimulation in EOCs would potentiate the beneficial effects of these cells in regulating smooth muscle cell (SMC) function. Native human EOCs did not have any effect on human coronary artery SMC (hCASMC) proliferation or migration. Transfecting EOCs with a human eNOS plasmid and/or stimulating with 17β-estradiol (E2) increased NO production 3-fold and enhanced EOC survival. Moreover, in co-culture studies, eNOS overexpressing or E2-stimulated EOCs reduced hCASMC migration (by 23% and 56% respectively), vs. control EOCs. These effects do not implicate ERK1/2 or focal adhesion kinases. Nevertheless, NOS-EOCs had no effect on hCASMC proliferation. These results suggest that overexpressing or activating eNOS in EOCs increases their survival and enhances their capacity to regulate SMC migration through paracrine effects. These data elucidate how eNOS overexpression or activation in EOCs can prevent vascular remodeling.
Dictionary learning-based reverberation removal enables depth-resolved photoacoustic microscopy of cortical microvasculature in the mouse brain
Authors: Govinahallisathyanarayana Sushanth , Ning Bo , Cao Rui , Hu Song , Hossack John A.
Published: January 2018

Photoacoustic microscopy (PAM) capitalizes on the optical absorption of blood hemoglobin to enable label-free high-contrast imaging of the cerebral microvasculature in vivo. Although time-resolved ultrasonic detection equips PAM with depth-sectioning capability, most of the data at depths are often obscured by acoustic reverberant artifacts from superficial cortical layers and thus unusable. In this paper, we present a first-of-a-kind dictionary learning algorithm to remove the reverberant signal while preserving underlying microvascular anatomy. This algorithm was validated in vitro, using dyed beads embedded in an optically transparent polydimethylsiloxane phantom. Subsequently, we demonstrated in the live mouse brain that the algorithm can suppress reverberant artifacts by 21.0 ± 5.4 dB, enabling depth-resolved PAM up to 500 µm from the brain surface.
Impact of tissue kinetic heterogeneity on PET quantification: case study with the L-[1-11C]leucine PET method for cerebral protein synthesis rates
Authors: Veronese Mattia , Bertoldo Alessandra , Tomasi Giampaolo , Smith Carolyn Beebe , Schmidt Kathleen C.
Published: January 2018

Functional quantification with PET is generally based on modeling that assumes tissue regions are kinetically homogeneous. Even in regions sufficiently small to approach homogeneity, spillover due to resolution limitations of PET scanners may introduce heterogeneous kinetics into measured data. Herein we consider effects of kinetic heterogeneity at the smallest volume accessible, the single image voxel. We used L-[1-11C]leucine PET and compared rates of cerebral protein synthesis (rCPS) estimated voxelwise with methods that do (Spectral Analysis Iterative Filter, SAIF) and do not (Basis Function Method, BFM) allow for kinetic heterogeneity. In high resolution PET data with good counting statistics BFM produced estimates of rCPS comparable to SAIF, but at lower computational cost; thus the simpler, less costly method can be applied. With poorer counting statistics (lower injected radiotracer doses), BFM estimates were more biased. In data smoothed to simulate lower resolution PET, BFM produced estimates of rCPS 9–14% higher than SAIF, overestimation consistent with applying a homogeneous tissue model to kinetically heterogeneous data. Hence with lower resolution data it is necessary to account for kinetic heterogeneity in the analysis. Kinetic heterogeneity may impact analyses of other tracers and scanning protocols differently; assessments should be made on a case by case basis.
Wee1 inhibitor MK1775 sensitizes KRAS mutated NSCLC cells to sorafenib
Authors: Caiola Elisa , Frapolli Roberta , Tomanelli Michele , Valerio Rossana , Iezzi Alice , Garassino Marina C. , Broggini Massimo , Marabese Mirko
Published: January 2018

Non-Small-Cell Lung Cancer (NSCLC) is a poorly chemosensitive tumor and targeted therapies are only used for about 15% of patients where a specific driving and druggable lesion is observed (EGFR, ALK, ROS). KRAS is one of the most frequently mutated genes in NSCLC and patients harboring these mutations do not benefit from specific treatments. Sorafenib, a multi-target tyrosine kinase inhibitor, was proposed as a potentially active drug in KRAS-mutated NSCLC patients, but clinical trials results were not conclusive. Here we show that the NSCLC cells’ response to sorafenib depends on the type of KRAS mutation. KRAS G12V cells respond less to sorafenib than the wild-type counterpart, in vitro and in vivo. To overcome this resistance, we used high-throughput screening with a siRNA library directed against 719 human kinases, and Wee1 was selected as a sorafenib response modulator. Inhibition of Wee1 by its specific inhibitor MK1775 in combination with sorafenib restored the KRAS mutated cells’ response to the multi-target tyrosine kinase inhibitor. This combination of the Wee1 inhibitor with sorafenib, if confirmed in models with different genetic backgrounds, might be worth investigating further as a new strategy for KRAS mutated NSCLC.
nNOS-positive minor-branches of the dorsal penile nerves is associated with erectile function in the bilateral cavernous injury model of rats
Authors: Chen Yen-Lin , Chao Ting-Ting , Wu Yi-No , Chen Meng-Chuan , Lin Ying-Hung , Liao Chun-Hou , Wu Chien-Chih , Chen Kuo-Chiang , Chou Shang-Shing P. , Chiang Han-Sun
Published: January 2018

The changes in neuronal nitric oxide synthases (nNOS) in the dorsal penile nerves (DPNs) are consistent with cavernous nerve (CN) injury in rat models. However, the anatomical relationship and morphological changes between the minor branches of the DPNs and the CNs after injury have never been clearly explored. There were forty 12 week old male Sprague-Dawley rats receiving bilateral cavernous nerve injury (BCNI). Erectile function of intracavernous pressure and mean arterial pressure were measured. The histology and ultrastructure with H&E stain, Masson’s trichrome stain and immunohistochemical stains were applied on the examination of CNs and DPNs. We demonstrated communicating nerve branches between the DPNs and the CNs in rats. The greatest damage and lowest erectile function were seen in the 14thday and partially recovered in the 28thday after BCNI. The nNOS positive DPN minor branches’ number was significantly correlated with erectile function. The sub-analysis of the number of nNOS positive DPN minor branches also matched with the time course of the erectile function after BCNI. We suggest the regeneration of the DPNs minor branches would ameliorate the erectile function in BCNI rats.
Radiological and clinical differences among three assisted technologies in pedicle screw fixation of adult degenerative scoliosis
Authors: Fan Yong , Peng Du Jin , Liu Ji Jun , Zhang Jia Nan , Liu Shi Chang , Hao Ding Jun
Published: January 2018

The purpose of this study was to compare the clinical and radiological differences among three advanced guided technologies in adult degenerative scoliosis. A total of 1012 pedicle screws were inserted in 83 patients using a spine robot (group A), 886 screws were implanted in 75 patients using a drill guide template (group B), and 1276 screws were inserted in 109 patients using CT-based navigation (group C). Screw positions were evaluated using postoperative CT scans according to the Gertzbein and Robbins classification. Other relevant data were also collected. Perfect pedicle screw insertion (Grade A) accuracy in groups A, B, and C was 91.3%, 81.3%, and 84.1%, respectively. Clinically acceptable accuracy of screw implantation (Grades A + B) respectively was 96.0%, 90.6%, and 93.0%. Statistical analysis showed the perfect and clinically acceptable accuracy in group A was significant different compared with groups B and C. Group A exhibited the lowest intra-op radiation dose and group B showed the shortest surgical time compared with the other two groups. Robotic-assisted technology demonstrated significantly higher accuracy than the drill guide template or CT-based navigation systems for difficult screw implantations in adult degenerative scoliosis and reduced the intra-op radiation dose, although it failed to reduce surgery time.
The Drosophila Gr28bD product is a non-specific cation channel that can be used as a novel thermogenetic tool
Authors: Mishra Aditi , Salari Autoosa , Berigan Benton R. , Miguel Kayla C. , Amirshenava Marzie , Robinson Abbey , Zars Benjamin C. , Lin Jenna L. , Milescu Lorin S. , Milescu Mirela , Zars Troy
Published: January 2018

Extrinsic control of single neurons and neuronal populations is a powerful approach for understanding how neural circuits function. Adding new thermogenetic tools to existing optogenetic and other forms of intervention will increase the complexity of questions that can be addressed. A good candidate for developing new thermogenetic tools is the Drosophila gustatory receptor family, which has been implicated in high-temperature avoidance behavior. We examined the five members of the Gr28b gene cluster for temperature-dependent properties via three approaches: biophysical characterization in Xenopus oocytes, functional calcium imaging in Drosophila motor neurons, and behavioral assays in adult Drosophila. Our results show that Gr28bD expression in Xenopus oocytes produces a non-specific cationic current that is activated by elevated temperatures. This current is non-inactivating and non-voltage dependent. When expressed in Drosophila motor neurons, Gr28bD can be used to change the firing pattern of individual cells in a temperature-dependent fashion. Finally, we show that pan-neuronal or motor neuron expression of Gr28bD can be used to alter fruit fly behavior with elevated temperatures. Together, these results validate the potential of the Gr28bD gene as a founding member of a new class of thermogenetic tools.
Integrated climate-chemical indicators of diffuse pollution from land to water
Authors: Mellander Per-Erik , Jordan Phil , Bechmann Marianne , Fovet Ophélie , Shore Mairead M. , McDonald Noeleen T. , Gascuel-Odoux Chantal
Published: January 2018

Management of agricultural diffuse pollution to water remains a challenge and is influenced by the complex interactions of rainfall-runoff pathways, soil and nutrient management, agricultural landscape heterogeneity and biogeochemical cycling in receiving water bodies. Amplified cycles of weather can also influence nutrient loss to water although they are less considered in policy reviews. Here, we present the development of climate-chemical indicators of diffuse pollution in highly monitored catchments in Western Europe. Specifically, we investigated the influences and relationships between weather processes amplified by the North Atlantic Oscillation during a sharp upward trend (2010–2016) and the patterns of diffuse nitrate and phosphorus pollution in rivers. On an annual scale, we found correlations between local catchment-scale nutrient concentrations in rivers and the influence of larger, oceanic-scale climate patterns defined by the intensity of the North Atlantic Oscillation. These influences were catchment-specific showing positive, negative or no correlation according to a typology. Upward trends in these decadal oscillations may override positive benefits of local management in some years or indicate greater benefits in other years. Developing integrated climate-chemical indicators into catchment monitoring indicators will provide a new and important contribution to water quality management objectives.
A surfactant polymer dressing potentiates antimicrobial efficacy in biofilm disruption
Authors: Das Ghatak Piya , Mathew-Steiner Shomita S. , Pandey Priyanka , Roy Sashwati , Sen Chandan K.
Published: January 2018

A 100% water-soluble surfactant polymer dressing (SPD) that is bio-compatible and non-ionic has been reported to improve wound closure in preliminary clinical studies. The mechanism of action of SPD in wound healing remains unclear. Biofilm infection is a significant problem that hinders proper wound closure. The objective of this study was to characterize the mechanism of action of SPD inhibition of bacterial biofilm development. Static biofilms (48 h) of the primary wound pathogens Pseudomonas aeruginosa (PA01), Staphylococcus aureus (USA300) were grown on polycarbonate membranes and treated with SPD with and without antibiotics for an additional 24 h. The standard antibiotics – tobramycin (10 μg/ml) for PA01 and rifampicin (10 μg/ml) for USA300, were used in these studies. Following 24 h treatment with and without antibiotics, the biofilms were characterized using scanning electron microscopy (SEM) structural imaging, in vitro imaging system (IVIS) proliferation imaging, colony forming units (CFU), viability assay, quantitative PCR (qPCR) for virulence gene expression. Because SPD is a surfactant based dressing, it potentially has a direct effect on Gram negative bacteria such as Pseudomonas primarily due to the lipid-based outer membrane of the bacteria. SPD is a surfactant based dressing that has potent anti-biofilm properties directly or in synergy with antibiotics.
Correlations between mitochondrial DNA haplogroup D5 and chronic hepatitis B virus infection in Yunnan, China
Authors: Li Xiao , Zhou Tai-Cheng , Wu Chang-Hui , Tao Li-Lin , Bi Rui , Chen Li-Jun , Deng De-Yao , Liu Chang , Otecko Newton O. , Tang Yang , Lai Xin , Zhang Liang , Wei Jia
Published: January 2018

Mitochondrial abnormality is frequently reported in individuals with hepatitis B virus (HBV) infection, but the associated hosts’ mitochondrial genetic factors remain obscure. We hypothesized that mitochondria may affect host susceptibility to HBV infection. In this study, we aimed to detect the association between chronic HBV infection and mitochondrial DNA in Chinese from Yunnan, Southwest China. A total of 272 individuals with chronic HBV infection (CHB), 310 who had never been infected by HBV (healthy controls, HC) and 278 with a trace of HBV infection (spontaneously recovered, SR) were analysed for mtDNA sequence variations and classified into respective haplogroups. Haplogroup frequencies were compared between HBV infected patients, HCs and SRs. Haplogroup D5 presented a higher frequency in CHBs than in HCs (P = 0.017, OR = 2.87, 95% confidence interval [CI] = (1.21–6.81)) and SRs (P = 0.049, OR = 2.90, 95% CI = 1.01–8.35). The network of haplogroup D5 revealed a distinct distribution pattern between CHBs and non-CHBs. A trend of higher viral load among CHBs with haplogroup D5 was observed. Our results indicate the risk potential of mtDNA haplogroup D5 in chronic HBV infection in Yunnan, China.
The ferroptosis inducer erastin irreversibly inhibits system xc− and synergizes with cisplatin to increase cisplatin’s cytotoxicity in cancer cells
Authors: Sato Mami , Kusumi Ryosuke , Hamashima Shinji , Kobayashi Sho , Sasaki Satoru , Komiyama Yuhei , Izumikawa Takuji , Conrad Marcus , Bannai Shiro , Sato Hideyo
Published: January 2018

System xc− was recently described as the most upstream node in a novel form of regulated necrotic cell death, called ferroptosis. In this context, the small molecule erastin was reported to target and inhibit system xc−, leading to cysteine starvation, glutathione depletion and consequently ferroptotic cell death. Although the inhibitory effect of erastin towards system xc− is well-documented, nothing is known about its mechanism of action. Therefore, we sought to interrogate in more detail the underlying mechanism of erastin’s pro-ferroptotic effects. When comparing with some well-known inhibitors of system xc−, erastin was the most efficient inhibitor acting at low micromolar concentrations. Notably, only a very short exposure of cells with low erastin concentrations was sufficient to cause a strong and persistent inhibition of system xc−, causing glutathione depletion. These inhibitory effects towards system xc− did not involve cysteine modifications of the transporter. More importantly, short exposure of tumor cells with erastin strongly potentiated the cytotoxic effects of cisplatin to efficiently eradicate tumor cells. Hence, our data suggests that only a very short pre-treatment of erastin suffices to synergize with cisplatin to efficiently induce cancer cell death, findings that might guide us in the design of novel cancer treatment paradigms.
Characterization of signaling pathways regulating the expression of pro-inflammatory long form thymic stromal lymphopoietin upon human metapneumovirus infection
Authors: Li Youxian , Lund Cecilie , Nervik Ida , Loevenich Simon , Døllner Henrik , Anthonsen Marit W. , Johnsen Ingvild B.
Published: January 2018

Thymic stromal lymphopoietin (TSLP) is associated with several allergic diseases including asthma. Two isoforms of TSLP exist in humans, a long form (lfTSLP) and a short form (sfTSLP), displaying distinct immunological functions. Recently, TSLP was found to be upregulated in human airway cells upon human metapneumovirus (hMPV) infection, yet it remains unclear if the two isoforms are regulated differently during hMPV infection. Importantly, the molecular mechanisms underlying hMPV-mediated TSLP induction remain undescribed. In this study, we characterized the expression and regulation of TSLP in hMPV-infected human airway cells. We demonstrated that hMPV strongly induced the expression of pro-inflammatory lfTSLP in human airway epithelial cells and lung fibroblasts. Further, knockdown of pattern recognition receptors retinoic acid-inducible gene I (RIG-I) or Toll-like receptor 3 (TLR3), as well as downstream signal transducers, abrogated hMPV-mediated lfTSLP induction. Importantly, silencing of TANK-binding kinase 1 (TBK1) also impaired hMPV-mediated lfTSLP induction, which could be attributed to compromised NF-κB activation. Overall, these results suggest that TBK1 may be instrumental for hMPV-mediated activation of NF-κB downstream RIG-I and TLR3, leading to a specific induction of lfTSLP in hMPV-infected human airway cells.
Increased left ventricular mass index is present in patients with type 2 diabetes without ischemic heart disease
Authors: Seferovic Jelena P. , Tesic Milorad , Seferovic Petar M. , Lalic Katarina , Jotic Aleksandra , Biering-Sørensen Tor , Giga Vojislav , Stankovic Sanja , Milic Natasa , Lukic Ljiljana , Milicic Tanja , Macesic Marija , Gajovic Jelena Stanarcic , Lalic Nebojsa M.
Published: January 2018

Left ventricular mass index (LVMI) increase has been described in hypertension (HTN), but less is known about its association with type 2 diabetes (T2DM). As these conditions frequently co-exist, we investigated the association of T2DM, HTN and both with echocardiographic parameters, and hypothesized that patients with both had highest LVMI, followed by patients with only T2DM or HTN. Study population included 101 T2DM patients, 62 patients with HTN and no T2DM, and 76 patients with T2DM and HTN, excluded for ischemic heart disease. Demographic and clinical data, biochemical measurements, stress echocardiography, transthoracic 2D Doppler and tissue Doppler echocardiography were performed. Multivariable logistic regression was used to determine the independent association with T2DM. Linear regression models and Pearson’s correlation were used to assess the correlations between LVMI and other parameters. Patients with only T2DM had significantly greater LVMI (84.9 ± 20.3 g/m2) compared to patients with T2DM and HTN (77.9 ± 16 g/m2) and only HTN (69.8 ± 12.4 g/m2). In multivariate logistic regression analysis, T2DM was associated with LVMI (OR 1.033, 95%CI 1.003–1.065, p = 0.029). A positive correlation of LVMI was found with fasting glucose (p < 0.001) and HbA1c (p = 0.0003). Increased LVMI could be a potential, pre-symptomatic marker of myocardial structural change in T2DM.
Development and validation of a brief diabetic foot ulceration risk checklist among diabetic patients: a multicenter longitudinal study in China
Authors: Zhou Qiuhong , Peng Min , Zhou Lihuan , Bai Jiaojiao , Tong Ao , Liu Min , Ng In I , Cheng Yuxia , Cai Yunmin , Yang Yujin , Chen Yilian , Gao Suwen , Li Zhong , Fu Xiaoai , Shen Minxue , Zhang Jianglin , Chen Xiang
Published: January 2018

The study aims to develop and assess and validate a brief diabetic foot ulceration risk checklist among diabetic patients through a longitudinal study. Patients who had diabetes mellitus and had no foot ulceration and severe systematic disorders were recruited from eleven tertiary hospitals in nine provinces or municipalities of China. Internal consistency reliability, construct validity, concurrent validity, item property, and measurement invariance of the tool were assessed. The predictive capability of the tool was validated by the follow-up data using the receiver operating characteristic curve. At baseline, 477 valid cases were collected. Twelve items were remained after initial selection. Cronbach’s alpha was 0.56. Confirmatory factor analysis showed that the model had acceptable goodness-of-fit yet local dependency between two items. Item response theory showed that most items had acceptable discrimination and difficulty parameters. Differential item functioning showed that tool had measurement invariance. 278 were followed up one year after the baseline. Follow-up showed that one-year incidence of ulceration among the patients was 3.6%, and the area under the receiver operating characteristic curve was 0.77 (95% confidence interval: 0.61–0.93). The cut-off point of the tool was 4, when sensitivity and specificity were 0.62 and 0.75 respectively. The checklist has good psychometric properties according to mixed evidences from classical and modern test theory, and has good predictive capability.
Critical Shear Stress is Associated with Diabetic Kidney Disease in Patients with Type 2 Diabetes
Authors: Chung Seung Min , Oh Jung Hyun , Moon Jun Sung , Kim Yu Kyung , Yoon Ji Sung , Won Kyu Chang , Lee Hyoung Woo
Published: January 2018

Critical shear stress (CSS, mPa) is an index of red blood cell (RBC) aggregability, defined as the minimal shear stress required to disperse RBC aggregates. This study aimed to investigate the association between CSS and the risk of diabetic kidney disease (DKD). A total of 421 (mean age, 58.1 ± 11.5 years; male, 250) individuals with T2DM were enrolled and divided into three groups according to CSS level. CSS was measured using a transient microfluidic technique. DKD was defined as a glomerular filtration rate (GFR) <60 ml/min/1.73 m2 or a urine albumin-to-creatinine ratio (uACR) ≥30 mg/g. CSS was significantly higher in patients with DKD than in those without (317.43 ± 125.11 vs 385.22 ± 182.89, p < 0.001). Compared to the lowest CSS tertile, the highest CSS tertile was independently associated with the risk of DKD after adjusting for age, sex, duration of diabetes, presence of hypertension and haemoglobin. The cut-off value of CSS for DKD was approximately 310 mPa. These results suggest that haemorheologic changes may contribute to DKD, and further prospective studies are warranted to determine the role of CSS as a DKD screening tool.
Computational trans-omics approach characterised methylomic and transcriptomic involvements and identified novel therapeutic targets for chemoresistance in gastrointestinal cancer stem cells
Authors: Konno Masamitsu , Matsui Hidetoshi , Koseki Jun , Asai Ayumu , Kano Yoshihiro , Kawamoto Koichi , Nishida Naohiro , Sakai Daisuke , Kudo Toshihiro , Satoh Taroh , Doki Yuichiro , Mori Masaki , Ishii Hideshi
Published: January 2018

We investigated the relationship between methylomic [5-methylation on deoxycytosine to form 5-methylcytosine (5mC)] and transcriptomic information in response to chemotherapeutic 5-fluorouracil (5-FU) exposure and cisplatin (CDDP) administration using the ornithine decarboxylase (ODC) degron-positive cancer stem cell model of gastrointestinal tumour. The quantification of 5mC methylation revealed various alterations in the size distribution and intensity of genomic loci for each patient. To summarise these alterations, we transformed all large volume data into a smooth function and treated the area as a representative value of 5mC methylation. The present computational approach made the methylomic data more accessible to each transcriptional unit and allowed to identify candidate genes, including the tumour necrosis factor receptor-associated factor 4 (TRAF4), as novel therapeutic targets with a strong response to anti-tumour agents, such as 5-FU and CDDP, and whose significance has been confirmed in a mouse model in vivo. The present study showed that 5mC methylation levels are inversely correlated with gene expression in a chemotherapy-resistant stem cell model of gastrointestinal cancer. This mathematical method can be used to simultaneously quantify and identify chemoresistant potential targets in gastrointestinal cancer stem cells.
Sensory neuronal P2RX4 receptors controls BDNF signaling in inflammatory pain
Authors: Lalisse Sarah , Hua Jennifer , Lenoir Manon , Linck Nathalie , Rassendren François , Ulmann Lauriane
Published: January 2018

Chronic inflammatory and neuropathic pains are major public health concerns. Potential therapeutic targets include the ATP-gated purinergic receptors (P2RX) that contribute to these pathological types of pain in several different cell types. The purinergic receptors P2RX2 and P2RX3 are expressed by a specific subset of dorsal root ganglion neurons and directly shape pain processing by primary afferents. In contrast the P2RX4 and P2RX7 are mostly expressed in myeloid cells, where activation of these receptors triggers the release of various pro-inflammatory molecules. Here, we demonstrate that P2RX4 also controls calcium influx in mouse dorsal root ganglion neurons. P2RX4 is up-regulated in pain-processing neurons during long lasting peripheral inflammation and it co-localizes with Brain-Derived Neurotrophic Factor (BDNF). In the dorsal horn of the spinal cord, BDNF-dependent signaling pathways, phosphorylation of Erk1/2 and of the GluN1 subunit as well as the down regulation of the co-transporter KCC2, which are triggered by peripheral inflammation are impaired in P2RX4-deficient mice. Our results suggest that P2RX4, expressed by sensory neurons, controls neuronal BDNF release that contributes to hyper-excitability during chronic inflammatory pain and establish P2RX4 in sensory neurons as a new potential therapeutic target to treat hyperexcitability during chronic inflammatory pain.
Vision Status in Older Adults: The Brazilian Amazon Region Eye Survey
Authors: Salomão Solange R. , Berezovsky Adriana , Furtado João M. , Fernandes Arthur G. , Muñoz Sergio , Cavascan Nívea N. , Cypel Marcela C. , Cunha Cristina C. , Vasconcelos Galton C. , Mitsuhiro Márcia R. K. H. , Sacai Paula Y. , Campos Mauro , Morales Paulo H. A. , Cohen Marcos J. , Cohen Jacob M. , Watanabe Sung E. S. , Belfort Rubens
Published: January 2018

Older adults living in remote areas with limited access to health services are at higher risk to develop visual impairment and blindness. We conducted a population-based survey to determine the vision status in subjects 45 years of age and older from urban and rural areas of Parintins city, Brazilian Amazon Region. Participants underwent ophthalmic examination, including uncorrected (UCVA), presenting (PVA) and best-corrected visual acuity (BCVA). Vision status was described as lines of visual acuity (VA) impairment and lines of VA improvement from UCVA to BCVA and from PVA to BCVA in the better-seeing eye. A total of 2384 subjects were enumerated, 2041 (85.6%) were examined, with reliable VA measurements obtained from 2025 participants. Vision status in lines of VA impairment was (mean ± standard deviation): 3.44 ± 3.53 for UCVA, 2.85 ± 3.52 for PVA and 1.50 ± 3.51 for BCVA. Female gender, older age and lower education were associated with ≥6 lines of UCVA impairment. Lines of improvement ≥3 was found in 626 (30.9%) participants and associated with female gender and rural residency. In conclusion, a third of participants could have at least three lines of VA improvement with proper refraction. Strategies to improve access to eye care and affordable glasses are needed.
Phenotypic diversity identified by cardiac magnetic resonance in a large hypertrophic cardiomyopathy family with a single MYH7 mutation
Authors: Wang Jie , Wan Ke , Sun Jiayu , Li Weihao , Liu Hong , Han Yuchi , Chen Yucheng
Published: January 2018

Limited data is available on phenotypic variations with the same genotype in hypertrophic cardiomyopathy (HCM). The present study aims to explore the relationship between genotype and phenotype characterized by cardiovascular magnetic resonance (CMR) in a large Chinese family. A proband diagnosed with HCM from a multigenerational family underwent next-generation sequencing based on a custom sureSelect panel, including 117 candidate pathogenic genes associated with cardiomyopathies. All genetic results were confirmed by the Sanger sequencing method. All confirmed mutation carriers underwent CMR exam and myocardial tissue characterization using T1 mapping and late gadolinium enhancement (LGE) on a 3T scanner (Siemens Trio, Gemany). After clinical and genetic screening of 36 (including the proband) members of a large Chinese family, nineteen family members are determined to carry the single p.T1377M (c.4130C>T) mutation in the MYH7 gene. Of these 19 mutation carriers, eight are diagnosed with HCM, one was considered as borderline affected and ten are not clinically or phenotypically affected. Different HCM phenotypes are present in the nine affected individuals in this family. In addition, we have found different tissue characteristics assessed by T1 mapping and LGE in these individuals. We describe a family that demonstrates the diverse HCM phenotypes associated with a single MYH7 mutation.
The Hessian Blob Algorithm: Precise Particle Detection in Atomic Force Microscopy Imagery
Authors: Marsh Brendan P. , Chada Nagaraju , Sanganna Gari Raghavendar Reddy , Sigdel Krishna P. , King Gavin M.
Published: January 2018

Imaging by atomic force microscopy (AFM) offers high-resolution descriptions of many biological systems; however, regardless of resolution, conclusions drawn from AFM images are only as robust as the analysis leading to those conclusions. Vital to the analysis of biomolecules in AFM imagery is the initial detection of individual particles from large-scale images. Threshold and watershed algorithms are conventional for automatic particle detection but demand manual image preprocessing and produce particle boundaries which deform as a function of user-defined parameters, producing imprecise results subject to bias. Here, we introduce the Hessian blob to address these shortcomings. Combining a scale-space framework with measures of local image curvature, the Hessian blob formally defines particle centers and their boundaries, both to subpixel precision. Resulting particle boundaries are independent of user defined parameters, with no image preprocessing required. We demonstrate through direct comparison that the Hessian blob algorithm more accurately detects biomolecules than conventional AFM particle detection techniques. Furthermore, the algorithm proves largely insensitive to common imaging artifacts and noise, delivering a stable framework for particle analysis in AFM.
A non-zircon Hf isotope record in Archean black shales from the Pilbara craton confirms changing crustal dynamics ca. 3 Ga ago
Authors: Nebel-Jacobsen Yona , Nebel Oliver , Wille Martin , Cawood Peter A.
Published: January 2018

Plate tectonics and associated subduction are unique to the Earth. Studies of Archean rocks show significant changes in composition and structural style around 3.0 to 2.5 Ga that are related to changing tectonic regime, possibly associated with the onset of subduction. Whole rock Hf isotope systematics of black shales from the Australian Pilbara craton, selected to exclude detrital zircon components, are employed to evaluate the evolution of the Archean crust. This approach avoids limitations of Hf-in-zircon analyses, which only provide input from rocks of sufficient Zr-concentration, and therefore usually represent domains that already underwent a degree of differentiation. In this study, we demonstrate the applicability of this method through analysis of shales that range in age from 3.5 to 2.8 Ga, and serve as representatives of their crustal sources through time. Their Hf isotopic compositions show a trend from strongly positive εHfinitial values for the oldest samples, to strongly negative values for the younger samples, indicating a shift from juvenile to differentiated material. These results confirm a significant change in the character of the source region of the black shales by 3 Ga, consistent with models invoking a change in global dynamics from crustal growth towards crustal reworking around this time.