bluuebunny/crossref_metadata_2025 huggingface dataset:
Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas
Authors: Geyer Felipe C. , Li Anqi , Papanastasiou Anastasios D. , Smith Alison , Selenica Pier , Burke Kathleen A. , Edelweiss Marcia , Wen Huei-Chi , Piscuoglio Salvatore , Schultheis Anne M. , Martelotto Luciano G. , Pareja Fresia , Kumar Rahul , Brandes Alissa , Fan Dan , Basili Thais , Da Cruz Paula Arnaud , Lozada John R. , Blecua Pedro , Muenst Simone , Jungbluth Achim A. , Foschini Maria P. , Wen Hannah Y. , Brogi Edi , Palazzo Juan , Rubin Brian P. , Ng Charlotte K. Y. , Norton Larry , Varga Zsuzsanna , Ellis Ian O. , Rakha Emad A. , Chandarlapaty Sarat , Weigelt Britta , Reis-Filho Jorge S.
Published: May 2018

Adenomyoepithelioma of the breast is a rare tumor characterized by epithelial−myoepithelial differentiation, whose genetic underpinning is largely unknown. Here we show through whole-exome and targeted massively parallel sequencing analysis that whilst estrogen receptor (ER)-positive adenomyoepitheliomas display PIK3CA or AKT1 activating mutations, ER-negative adenomyoepitheliomas harbor highly recurrent codon Q61 HRAS hotspot mutations, which co-occur with PIK3CA or PIK3R1 mutations. In two- and three-dimensional cell culture models, forced expression of HRASQ61R in non-malignant ER-negative breast epithelial cells with or without a PIK3CAH1047R somatic knock-in results in transformation and the acquisition of the cardinal features of adenomyoepitheliomas, including the expression of myoepithelial markers, a reduction in E-cadherin expression, and an increase in AKT signaling. Our results demonstrate that adenomyoepitheliomas are genetically heterogeneous, and qualify mutations in HRAS, a gene whose mutations are vanishingly rare in common-type breast cancers, as likely drivers of ER-negative adenomyoepitheliomas.
Networks of genetic similarity reveal non-neutral processes shape strain structure in Plasmodium falciparum
Authors: He Qixin , Pilosof Shai , Tiedje Kathryn E. , Ruybal-Pesántez Shazia , Artzy-Randrup Yael , Baskerville Edward B. , Day Karen P. , Pascual Mercedes
Published: May 2018

Pathogens compete for hosts through patterns of cross-protection conferred by immune responses to antigens. In Plasmodium falciparum malaria, the var multigene family encoding for the major blood-stage antigen PfEMP1 has evolved enormous genetic diversity through ectopic recombination and mutation. With 50–60 var genes per genome, it is unclear whether immune selection can act as a dominant force in structuring var repertoires of local populations. The combinatorial complexity of the var system remains beyond the reach of existing strain theory and previous evidence for non-random structure cannot demonstrate immune selection without comparison with neutral models. We develop two neutral models that encompass malaria epidemiology but exclude competitive interactions between parasites. These models, combined with networks of genetic similarity, reveal non-neutral strain structure in both simulated systems and an extensively sampled population in Ghana. The unique population structure we identify underlies the large transmission reservoir characteristic of highly endemic regions in Africa.
Proteomic analysis reveals that auxin homeostasis influences the eighth internode length heterosis in maize (Zea mays)
Authors: Chen Yongqiang , Zhou Qingqian , Tian Runmiao , Ma Zhihui , Zhao Xiaofeng , Tang Jihua , Fu Zhiyuan
Published: May 2018

Ear height is an important maize morphological trait that influences plant lodging resistance in the field, and is based on the number and length of internodes under the ear. To explore the effect of internodes on ear height, the internodes under the ear were analysed in four commercial hybrids (Jinsai6850, Zhengdan958, Xundan20, and Yuyu22) from different heterotic groups in China. The eighth internode, which is the third aboveground extended internode, exhibited high-parent or over high-parent heterosis and contributed considerably to ear height. Thus, the proteome of the eighth internode was examined. Sixty-six protein spots with >1.5-fold differences in accumulation (P < 0.05) among the four hybrids were identified by mass spectrometry and data analyses. Most of the differentially accumulated proteins exhibited additive accumulation patterns, but with epistatic effects on heterosis performance. Proteins involved in phenylpropanoid and benzoxazinoid metabolic pathways were observed to influence indole-3-acetic acid biosynthesis and polar auxin transport during internode development. Moreover, indole-3-acetic acid content was positively correlated with the eighth internode length, but negatively correlated with the extent of the heterosis of the eighth internode length.
TRPV1 and the MCP-1/CCR2 Axis Modulate Post-UTI Chronic Pain
Authors: Rosen John M. , Yaggie Ryan E. , Woida Patrick J. , Miller Richard. J. , Schaeffer Anthony J. , Klumpp David J.
Published: May 2018

The etiology of chronic pelvic pain syndromes remains unknown. In a murine urinary tract infection (UTI) model, lipopolysaccharide of uropathogenic E. coli and its receptor TLR4 are required for post-UTI chronic pain development. However, downstream mechanisms of post-UTI chronic pelvic pain remain unclear. Because the TRPV1 and MCP-1/CCR2 pathways are implicated in chronic neuropathic pain, we explored their role in post-UTI chronic pain. Mice were infected with the E. coli strain SΦ874, known to produce chronic allodynia, and treated with the TRPV1 antagonist capsazepine. Mice treated with capsazepine at the time of SΦ874 infection failed to develop chronic allodynia, whereas capsazepine treatment of mice at two weeks following SΦ874 infection did not reduce chronic allodynia. TRPV1-deficient mice did not develop chronic allodynia either. Similar results were found using novelty-suppressed feeding (NSF) to assess depressive behavior associated with neuropathic pain. Imaging of reporter mice also revealed induction of MCP-1 and CCR2 expression in sacral dorsal root ganglia following SΦ874 infection. Treatment with a CCR2 receptor antagonist at two weeks post-infection reduced chronic allodynia. Taken together, these results suggest that TRPV1 has a role in the establishment of post-UTI chronic pain, and CCR2 has a role in maintenance of post-UTI chronic pain.
Hemoglobin Levels Modulate Nitrite Toxicity to Daphnia magna
Authors: Eytcheson Stephanie A. , LeBlanc Gerald A.
Published: May 2018

Nitrogenous compounds enter the environment through various anthropogenic sources. Among these are nitrate (NO3−) and nitrite (NO2−) which can oxidize the heme moiety of hemoglobin and reduce the oxygen-carrying capacity of the molecule resulting in toxicity. Of the two anions, nitrite is more toxic. Hemoglobin levels are influenced by environmental conditions; thus, we hypothesized that hemoglobin levels would influence the toxicity of nitrite with low hemoglobin levels resulting in enhanced toxicity and high hemoglobin levels resulting in reduced toxicity. We tested this hypothesis by elevating hemoglobin levels with pyriproxyfen treatment and lowering hemoglobin levels using siRNA in Daphnia magna. Exposure to pyriproxyfen significantly elevated hemoglobin mRNA levels and induced copper coloration of the organisms, indicative of increased hemoglobin protein accumulation. siRNA treatment significantly reduced hemoglobin mRNA levels in both untreated and pyriproxyfen-treated organisms and attenuated copper coloration. Pyriproxyfen treatment increased the tolerance of daphnids to the acute toxicity of nitrite approximately 2-fold while siRNA treatment significantly decreased the tolerance of daphnids to nitrite toxicity. Results indicate that increased hemoglobin levels increase the tolerance of daphnids to nitrite toxicity which may serve to protect daphnids in environments subject to hemoglobin-elevating hypoxia or elevated temperatures.
Maximally nonlocal Clauser-Horne-Shimony-Holt scenarios
Authors: Urías Jesús , Méndez Martínez José Manuel
Published: May 2018

The key feature in correlations established by multi-party quantum entangled states is nonlocality. A quantity to measure the average nonlocality, distinguishing it from shared randomness and in a direct relation with no-signaling stochastic processes (which provide an operational interpretation of quantum correlations, without involving information transmission between the parties as to sustain causality), is proposed and resolved exhaustively for the quantum correlations established by a Clauser-Horne-Shimony-Holt setup (or CHSH box). The amount of nonlocality that is available in a CHSH box is measured by its proximity to the nearest Popescu-Rohrlich set of causal stochastic processes (aka a PR box) in the no-signaling polytope, related by polyhedral duality to Bell’s correlation function. The proposed amount of average nonlocality is an entanglement monotone with a simple relation to concurrence. We provide the optimal setup vectors of a maximally nonlocal CHSH box for any entangled pair. The strongest nonlocality is the fraction $$\sqrt{2}-\,1\approx 0.414$$

2

−

1
≈
0.414
of a PR box, attained by maximally entangled qubit pairs. The most economical causal stochastic process reproducing any maximally nonlocal CHSH box is developed. Data produced by a computer implementation of the simulator agrees with the quantum mechanical formulas.
Author Correction: Cancer cell responses to Hsp70 inhibitor JG-98: Comparison with Hsp90 inhibitors and finding synergistic drug combinations
Authors: Yaglom Julia A. , Wang Yongmei , Li Amy , Li Zhenghu , Monti Stephano , Alexandrov Ilya , Lu Xiongbin , Sherman Michael Y.
Published: May 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
PrismPlus: a mouse line expressing distinct fluorophores in four different brain cell types
Authors: Gaire Janak , Lee Heui Chang , Ward Ray , Currlin Seth , Woolley Andrew J. , Coleman Jason E. , Williams Justin C. , Otto Kevin J.
Published: May 2018

To screen the complex central nervous system (CNS) injury responses, we created a quadruple-labelled ‘PrismPlus’ mouse line with a genetically encoded distinct fluorescent tag in oligodendrocytes, microglia, neurons, and astrocytes. Cx3cr1-gfp and Prism mice originally developed by Jung et al., 2000 and Dougherty et al., 2012, respectively, were cross-bred. First, we confirmed the presence of fluorophores in appropriate cell types in PrismPlus mice. PrismPlus mice were then used to examine the cellular responses to brain implanted micro-devices. We observed an increase in microglial response at earlier time points as compared to 4 weeks, a progressive astrocytic response, and fewer neurons at the vicinity of an implanted device. These results are similar to what has been described in literature using other rodent strains, previously attainable only through time-consuming and variable immunohistochemistry methods. Finally, we demonstrate the compatibility of PrismPlus brain tissue with CLARITY, an advanced tissue clearing technique, opening the door to future thick tissue imaging studies. This report confirms PrismPlus transgenic fluorescence and highlights the utility of these mice to study CNS injuries. The work herein seeks to establish a novel transgenic mouse line to improve experimental scope, consistency, and efficiency for CNS researchers.
Systematic analysis of DEMETER-like DNA glycosylase genes shows lineage-specific Smi-miR7972 involved in SmDML1 regulation in Salvia miltiorrhiza
Authors: Li Jiang , Li Caili , Lu Shanfa
Published: May 2018

DEMETER-like DNA glycosylases (DMLs) initiate the base excision repair-dependent DNA demethylation to regulate a wide range of biological processes in plants. Six putative SmDML genes, termed SmDML1–SmDML6, were identified from the genome of S. miltiorrhiza, an emerging model plant for Traditional Chinese Medicine (TCM) studies. Integrated analysis of gene structures, sequence features, conserved domains and motifs, phylogenetic analysis and differential expression showed the conservation and divergence of SmDMLs. SmDML1, SmDML2 and SmDML4 were significantly down-regulated by the treatment of 5Aza-dC, a general DNA methylation inhibitor, suggesting involvement of SmDMLs in genome DNA methylation change. SmDML1 was predicted and experimentally validated to be target of Smi-miR7972. Computational analysis of forty whole genome sequences and almost all of RNA-seq data from Lamiids revealed that MIR7972s were only distributed in some plants of the three orders, including Lamiales, Solanales and Boraginales, and the number of MIR7972 genes varied among species. It suggests that MIR7972 genes underwent expansion and loss during the evolution of some Lamiids species. Phylogenetic analysis of MIR7972s showed closer evolutionary relationships between MIR7972s in Boraginales and Solanales in comparison with Lamiales. These results provide a valuable resource for elucidating DNA demethylation mechanism in S. miltiorrhiza.
Significantly increased low shear rate viscosity, blood elastic modulus, and RBC aggregation in adults following cardiac surgery
Authors: Wu Yi-Fan , Hsu Po-Shun , Tsai Chien-Sung , Pan Pin-Cheng , Chen Yeng-Long
Published: May 2018

Open heart surgeries are common for treating ischemic and heart valve disease. During cardiac surgery, cardiopulmonary bypass (CPB) can temporarily take over the function of heart and lungs. However, elevated red blood cell (RBC) aggregation may lead to the common side-effects such as microinfarction. We investigated blood physical properties changes and the correlation between blood microstructure, viscoelastic response and biochemical changes following surgery with CPB. We examined shear-rate dependent blood viscosity, elasticity and RBC aggregate size in the pre-surgery disease state, post-surgery state and long-term recovery state of cardiac surgical patients. Within a week following surgery, the patient hematocrit was significantly lower due to CPB. Despite lower RBC concentration, the RBC aggregate shape became larger and more rounded, which is correlated to the elevated plasma fibrinogen related to systemic inflammatory response. During the same period, the hematocrit-adjusted low shear rate viscosity increased significantly, as did the yield stress, indicating more solid-like behavior for blood. Six months to one year later, all the physical and biochemical properties measured returned to baseline.
Cell-type specific expression of oncogenic and tumor suppressive microRNAs in the human prostate and prostate cancer
Authors: Kumar Binod , Rosenberg Avi Z. , Choi Su Mi , Fox-Talbot Karen , De Marzo Angelo M. , Nonn Larisa , Brennen W. Nathaniel , Marchionni Luigi , Halushka Marc K. , Lupold Shawn E.
Published: May 2018

MiR-1 and miR-143 are frequently reduced in human prostate cancer (PCa), while miR-141 and miR-21 are frequently elevated. Consequently, these miRNAs have been studied as cell-autonomous tumor suppressors and oncogenes. However, the cell-type specificity of these miRNAs is not well defined in prostate tissue. Through two different microdissection techniques, and droplet digital RT-PCR, we quantified these miRNAs in the stroma and epithelium of radical prostatectomy specimens. In contrast to their purported roles as cell-autonomous tumor suppressors, we found miR-1 and miR-143 expression to be predominantly stromal. Conversely, miR-141 was predominantly epithelial. miR-21 was detected in both stroma and epithelium. Strikingly, the levels of miR-1 and miR-143 were significantly reduced in tumor-associated stroma, but not tumor epithelium. Gene expression analyses in human cell lines, tissues, and prostate-derived stromal cultures support the cell-type selective expression of miR-1, miR-141, and miR-143. Analyses of the PCa Genome Atlas (TCGA-PRAD) showed a strong positive correlation between stromal markers and miR-1 and miR-143, and a strong negative correlation between stromal markers and miR-141. In these tumors, loss of miR-1 and gain of miR-21 was highly associated with biochemical recurrence. These data shed new light on stromal and epithelial miRNA expression in the PCa tumor microenvironment.
NADH/NADPH bi-cofactor-utilizing and thermoactive ketol-acid reductoisomerase from Sulfolobus acidocaldarius
Authors: Chen Chin-Yu , Ko Tzu-Ping , Lin Kuan-Fu , Lin Bo-Lin , Huang Chun-Hsiang , Chiang Cheng-Hung , Horng Jia-Cherng
Published: May 2018

Ketol-acid reductoisomerase (KARI) is a bifunctional enzyme in the second step of branched-chain amino acids biosynthetic pathway. Most KARIs prefer NADPH as a cofactor. However, KARI with a preference for NADH is desirable in industrial applications including anaerobic fermentation for the production of branched-chain amino acids or biofuels. Here, we characterize a thermoacidophilic archaeal Sac-KARI from Sulfolobus acidocaldarius and present its crystal structure at a 1.75-Å resolution. By comparison with other holo-KARI structures, one sulphate ion is observed in each binding site for the 2′-phosphate of NADPH, implicating its NADPH preference. Sac-KARI has very high affinity for NADPH and NADH, with K
M
values of 0.4 μM for NADPH and 6.0 μM for NADH, suggesting that both are good cofactors at low concentrations although NADPH is favoured over NADH. Furthermore, Sac-KARI can catalyze 2(S)-acetolactate (2S-AL) with either cofactor from 25 to 60 °C, but the enzyme has higher activity by using NADPH. In addition, the catalytic activity of Sac-KARI increases significantly with elevated temperatures and reaches an optimum at 60 °C. Bi-cofactor utilization and the thermoactivity of Sac-KARI make it a potential candidate for use in metabolic engineering or industrial applications under anaerobic or harsh conditions.
Haplotypic polymorphisms and mutation rate estimates of 22 Y-chromosome STRs in the Northern Chinese Han father–son pairs
Authors: Yang Yaran , Wang Weini , Cheng Feng , Chen Man , Chen Tong , Zhao Jing , Chen Chong , Shi Yan , Li Chen , Chen Chuguang , Liu Yacheng , Yan Jiangwei
Published: May 2018

Y chromosome Short tandem repeats (Y-STRs) analysis has been widely used in forensic identification, kinship testing, and population evolution. An accurate understanding of haplotype and mutation rate will benefit these applications. In this work, we analyzed 1123 male samples from Northern Chinese Han population which including 578 DNA-confirmed father-son pairs at 22 Y-STRs loci. A total of 537 haplotypes were observed and the overall haplotype diversity was calculated as 1.0000 ± 0.0001. Except that only two haplotypes were observed twice, all the rest of the 535 were unique. Furthermore, totally 47 mutations were observed during 13,872 paternal meiosis. The mutation rate for each locus estimates ranged from 0.0 to 15.6 × 10−3 with an average mutation rate 3.4 × 10−3 (95% CI 2.5–4.5 × 10−3). Among the 22 loci, DYS449, DYS389 II and DYS458 are the most prone to mutations. This study adds to the growing data on Y-STR haplotype diversity and mutation rates and could be very useful for population and forensic genetics.
Infants’ dietary arsenic exposure during transition to solid food
Authors: Signes-Pastor Antonio J. , Cottingham Kathryn L. , Carey Manus , Sayarath Vicki , Palys Thomas , Meharg Andrew A. , Folt Carol L. , Karagas Margaret R.
Published: May 2018

Early-life exposure to inorganic arsenic (i-As) may cause long-lasting health effects, but as yet, little is known about exposure among weaning infants. We assessed exposure before and during weaning and investigated the association between solid food intake and infants’ urinary arsenic species concentrations. Following the recording of a comprehensive 3 day food diary, paired urine samples (pre- and post-weaning) were collected and analyzed for arsenic speciation from 15 infants participating in the New Hampshire Birth Cohort Study. Infants had higher urinary i-As (p-value = 0.04), monomethylarsonic acid (MMA) (p-value = 0.002), dimethylarsinic acid (DMA) (p-value = 0.01), and sum of arsenic species (i-As + MMA + DMA, p-value = 0.01) during weaning than while exclusively fed on a liquid diet (i.e., breast milk, formula, or a mixture of both). Among weaning infants, increased sum of urinary arsenic species was pairwise-associated with intake of rice cereal (Spearman’s ρ = 0.90, p-value = 0.03), fruit (ρ = 0.70, p-value = 0.03), and vegetables (ρ = 0.86, p-value = 0.01). Our observed increases in urinary arsenic concentrations likely indicate increased exposure to i-As during the transition to solid foods, suggests the need to minimize exposure during this critical period of development.
Different patterns of epileptiform-like activity are generated in the sclerotic hippocampus from patients with drug-resistant temporal lobe epilepsy
Authors: Reyes-Garcia Selvin Z. , Scorza Carla A. , Araújo Noemi S. , Ortiz-Villatoro Nancy N. , Jardim Anaclara Prada , Centeno Ricardo , Yacubian Elza Márcia Targas , Faber Jean , Cavalheiro Esper A.
Published: May 2018

Human hippocampal slice preparations from patients with temporal lobe epilepsy (TLE) associated with hippocampal sclerosis (HS) are excellent material for the characterization of epileptiform-like activity. However, it is still unknown if hippocampal regions ascornu Ammonis(CA) 1, CA3 and CA4, generate population epileptiform-like activity. Here, we investigated epileptiform activities of the subiculum, CA1, CA2, CA3, CA4 (induced by elevation of extracellular potassium concentration) and the dentate gyrus (induced with hilar stimulation and elevation of potassium concentration) from sclerotic hippocampi of patients with drug-resistant TLE. Five types of epileptiform-like activity were observed: interictal-like events; periodic ictal spiking; seizure-like events; spreading depression-like events; tonic seizure-like events and no activity. Different susceptibilities to generate epileptiform activity among hippocampal regions were observed; the dentate gyrus was the most susceptible region followed by the subiculum, CA4, CA1, CA2 and CA3. The incidence of epileptiform activity pattern was associated with specific regions of the hippocampal formation. Moreover, it was observed that each region of the hippocampal formation exhibits frequency-specific ranges in each subfield of the sclerotic human tissue. In conclusion, this study demonstrates that epileptiform-like activity may be induced in different regions of the hippocampal formation, including regions that are severely affected by neuronal loss.
Ameliorative potential of desalted Salicornia europaea L. extract in multifaceted Alzheimer’s-like scopolamine-induced amnesic mice model
Authors: Karthivashan Govindarajan , Park Shin-Young , Kweon Mee-Hyang , Kim Joonsoo , Haque Md. Ezazul , Cho Duk-Yeon , Kim In-Su , Cho Eun-Ah , Ganesan Palanivel , Choi Dong-Kug
Published: May 2018

The Salicornia europaea L. (SE) plant is a halophyte that has been widely consumed as a seasoned vegetable, and it has been recently reported to counteract chronic diseases related to oxidative and inflammatory stress. In this study, we performed an initial phytochemical analysis with in vitro biochemical tests and chromatographic profiling of desalted and enzyme-digested SE ethanol extract (SE-EE). Subsequently, we evaluated the anti-neuroinflammatory and ameliorative potential of SE-EE in LPS-inflicted BV-2 microglial cells and scopolamine-induced amnesic C57/BL6N mice, respectively. SE-EE possess considerable polyphenols and flavonoids that are supposedly responsible to improve its bio-efficacy. SE-EE dose-dependently attenuated LPS-induced inflammation in BV-2 cells, significantly repressed behavioural/cognitive impairment, dose-dependently regulated the cholinergic function, suppressed oxidative stress markers, regulated inflammatory cytokines/associated proteins expression and effectively ameliorated p-CREB/BDNF levels, neurogenesis (DCX stain), neuron proliferation (Ki67 stain) in scopolamine-administered mice. Thus, SE-EE extract shows promising multifactorial disease modifying activities and can be further developed as an effective functional food, drug candidate, or supplemental therapy to treat neuroinflammatory mediated disorders.
Observation of Magnetic Radial Vortex Nucleation in a Multilayer Stack with Tunable Anisotropy
Authors: Karakas Vedat , Gokce Aisha , Habiboglu Ali Taha , Arpaci Sevdenur , Ozbozduman Kaan , Cinar Ibrahim , Yanik Cenk , Tomasello Riccardo , Tacchi Silvia , Siracusano Giulio , Carpentieri Mario , Finocchio Giovanni , Hauet Thomas , Ozatay Ozhan
Published: May 2018

Recently discovered exotic magnetic configurations, namely magnetic solitons appearing in the presence of bulk or interfacial Dzyaloshinskii-Moriya Interaction (i-DMI), have excited scientists to explore their potential applications in emerging spintronic technologies such as race-track magnetic memory, spin logic, radio frequency nano-oscillators and sensors. Such studies are motivated by their foreseeable advantages over conventional micro-magnetic structures due to their small size, topological stability and easy spin-torque driven manipulation with much lower threshold current densities giving way to improved storage capacity, and faster operation with efficient use of energy. In this work, we show that in the presence of i-DMI in Pt/CoFeB/Ti multilayers by tuning the magnetic anisotropy (both in-plane and perpendicular-to-plane) via interface engineering and postproduction treatments, we can stabilize a variety of magnetic configurations such as Néel skyrmions, horseshoes and most importantly, the recently predicted isolated radial vortices at room temperature and under zero bias field. Especially, the radial vortex state with its absolute convergence to or divergence from a single point can potentially offer exciting new applications such as particle trapping/detrapping in addition to magnetoresistive memories with efficient switching, where the radial vortex state can act as a source of spin-polarized current with radial polarization.
Impact of technological innovation and regulation development on e-waste toxicity: a case study of waste mobile phones
Authors: Chen Yu , Chen Mengjun , Li Yungui , Wang Bin , Chen Shu , Xu Zhonghui
Published: May 2018

Technology innovation has accelerated progress in Information and Communications Technology (ICT), especially in the mobile phones sector. Concurrently, local, national, and international governments are enforcing stricter regulations to protect natural resources and human health. The paper attempts to address the question: Have technological innovations and regulation development had a positive impact on ecosystems and public health? We identified 36 waste mobile phones (WMPs) manufactured between 2002 and 2013, assessed their metals concentration, leachability, and potential impact on environment and human health using digestion, Toxicity Characteristic Leaching Procedure (TCLP), and USEtox model, respectively. The results highlight that regulations did not have significant impact on total metal content, except some heavy metals, while technology innovation recorded stronger impact. WMPs should be classified as hazardous due to excessive lead content. Copper posed the most significant ecotoxicity risk, and chromium showed the most significant risk for both cancerous and non-cancerous diseases. Additionally, we demonstrated that WMPs toxicity increased with technology innovation.
Fishing and temperature effects on the size structure of exploited fish stocks
Authors: Tu Chen-Yi , Chen Kuan-Ting , Hsieh Chih-hao
Published: May 2018

Size structure of fish stock plays an important role in maintaining sustainability of the population. Size distribution of an exploited stock is predicted to shift toward small individuals caused by size-selective fishing and/or warming; however, their relative contribution remains relatively unexplored. In addition, existing analyses on size structure have focused on univariate size-based indicators (SBIs), such as mean length, evenness of size classes, or the upper 95-percentile of the length frequency distribution; these approaches may not capture full information of size structure. To bridge the gap, we used the variation partitioning approach to examine how the size structure (composition of size classes) responded to fishing, warming and the interaction. We analyzed 28 exploited stocks in the West US, Alaska and North Sea. Our result shows fishing has the most prominent effect on the size structure of the exploited stocks. In addition, the fish stocks experienced higher variability in fishing is more responsive to the temperature effect in their size structure, suggesting that fishing may elevate the sensitivity of exploited stocks in responding to environmental effects. The variation partitioning approach provides complementary information to univariate SBIs in analyzing size structure.
Lack of genetic support for shared aetiology of Coronary Artery Disease and Late-onset Alzheimer’s disease
Authors: Grace Christopher , Clarke Robert , Goel Anuj , Farrall Martin , Watkins Hugh , Hopewell Jemma C.
Published: May 2018

Epidemiological studies suggest a positive association between coronary artery disease (CAD) and late-onset Alzheimer’s disease (LOAD). This large-scale genetic study brings together ‘big data’ resources to examine the causal impact of genetic determinants of CAD on risk of LOAD. A two-sample Mendelian randomization approach was adopted to estimate the causal effect of CAD on risk of LOAD using summary data from 60,801 CAD cases from CARDIoGRAMplusC4D and 17,008 LOAD cases from the IGAP Consortium. Additional analyses assessed the independent relevance of genetic associations at the APOE locus for both CAD and LOAD. Higher genetically determined risk of CAD was associated with a slightly higher risk of LOAD (Odds Ratio (OR) per log-odds unit of CAD [95% CI]: 1.07 [1.01–1.15]; p = 0.027). However, after exclusion of the APOE locus, the estimate of the causal effect of CAD for LOAD was attenuated and no longer significant (OR 0.94 [0.88–1.01]; p = 0.072). This Mendelian randomization study indicates that the APOE locus is the chief determinant of shared genetic architecture between CAD and LOAD, and suggests a lack of causal relevance of CAD for risk of LOAD after exclusion of APOE.
Mammary fibroblasts reduce apoptosis and speed estrogen-induced hyperplasia in an organotypic MCF7-derived duct model
Authors: Morgan Molly M. , Livingston Megan K. , Warrick Jay W. , Stanek Eli M. , Alarid Elaine T. , Beebe David J. , Johnson Brian P.
Published: May 2018

The estrogen receptor (ER) regulates the survival and growth of breast cancer cells, but it is less clear how components of the tissue microenvironment affect ER-mediated responses. We set out to test how human mammary fibroblasts (HMFs) modulate ER signaling and downstream cellular responses. We exposed an organotypic mammary model consisting of a collagen-embedded duct structure lined with MCF7 cells to 17-β estradiol (E2), with and without HMFs in the surrounding matrix. MCF7 cells grown as ductal structures were polarized and proliferated at rates comparable to in vivo breast tissue. In both culture platforms, exposure to E2 increased ER transactivation, increased proliferation, and induced ductal hyperplasia. When the surrounding matrix contained HMFs, the onset and severity of E2-induced ductal hyperplasia was increased due to decreased apoptosis. The reduced apoptosis may be due to fibroblasts modulating ER signaling in MCF7 cells, as suggested by the increased ER transactivation and reduced ER protein in MCF7 cells grown in co-culture. These findings demonstrate the utility of organotypic platforms when studying stromal:epithelial interactions, and add to existing literature that implicate the mammary microenvironment in ER + breast cancer progression.
Patient-derived mutations within the N-terminal domains of p85α impact PTEN or Rab5 binding and regulation
Authors: Mellor Paul , Marshall Jeremy D. S. , Ruan Xuan , Whitecross Dielle E. , Ross Rebecca L. , Knowles Margaret A. , Moore Stanley A. , Anderson Deborah H.
Published: May 2018

The p85α protein regulates flux through the PI3K/PTEN signaling pathway, and also controls receptor trafficking via regulation of Rab-family GTPases. In this report, we determined the impact of several cancer patient-derived p85α mutations located within the N-terminal domains of p85α previously shown to bind PTEN and Rab5, and regulate their respective functions. One p85α mutation, L30F, significantly reduced the steady state binding to PTEN, yet enhanced the stimulation of PTEN lipid phosphatase activity. Three other p85α mutations (E137K, K288Q, E297K) also altered the regulation of PTEN catalytic activity. In contrast, many p85α mutations reduced the binding to Rab5 (L30F, I69L, I82F, I177N, E217K), and several impacted the GAP activity of p85α towards Rab5 (E137K, I177N, E217K, E297K). We determined the crystal structure of several of these p85α BH domain mutants (E137K, E217K, R262T E297K) for bovine p85α BH and found that the mutations did not alter the overall domain structure. Thus, several p85α mutations found in human cancers may deregulate PTEN and/or Rab5 regulated pathways to contribute to oncogenesis. We also engineered several experimental mutations within the p85α BH domain and identified L191 and V263 as important for both binding and regulation of Rab5 activity.
On the design of random metasurface based devices
Authors: Dupré Matthieu , Hsu Liyi , Kanté Boubacar
Published: May 2018

Metasurfaces are generally designed by placing scatterers in periodic or pseudo-periodic grids. We propose and discuss design rules for functional metasurfaces with randomly placed anisotropic elements that randomly sample a well-defined phase function. By analyzing the focusing performance of random metasurface lenses as a function of their density and the density of the phase-maps used to design them, we find that the performance of 1D metasurfaces is mostly governed by their density while 2D metasurfaces strongly depend on both the density and the near-field coupling configuration of the surface. The proposed approach is used to design all-polarization random metalenses at near infrared frequencies. Challenges, as well as opportunities of random metasurfaces compared to periodic ones are discussed. Our results pave the way to new approaches in the design of nanophotonic structures and devices from lenses to solar energy concentrators.
Locus specific engineering of tandem DNA repeats in the genome of Saccharomyces cerevisiae using CRISPR/Cas9 and overlapping oligonucleotides
Authors: Lancrey Astrid , Joubert Alexandra , Boulé Jean-Baptiste
Published: May 2018

DNA repeats constitute a large part of genomes of multicellular eucaryotes. For a longtime considered as junk DNA, their role in genome organization and tuning of gene expression is being increasingly documented. Synthetic biology has so far largely ignored DNA repeats as regulatory elements to manipulate functions in engineered genomes. The yeastSaccharomyces cerevisiaehas been a workhorse of synthetic biology, owing to its genetic tractability. Here we demonstrate the ability to synthetize, in a simple manner, tandem DNA repeats of various size by Cas9-assisted oligonucleotidein vivoassembly in this organism. We show that long tandem DNA repeats of several kilobases can be assembled in one step for different monomer size and G/C content. The combinatorial nature of the approach allows exploring a wide variety of design for building synthetic tandem repeated DNA directly at a given locus in theSaccharomyces cerevisiaegenome. This approach provides a simple way to incorporate tandem DNA repeat in synthetic genome designs to implement regulatory functions.
Higher risk of hepatocellular carcinoma in Hispanic patients with hepatitis C cirrhosis and metabolic risk factors
Authors: Wong Alina , Le An , Lee Mei-Hsuan , Lin Yu-Ju , Nguyen Pauline , Trinh Sam , Dang Hansen , Nguyen Mindie H.
Published: May 2018

The effect of metabolic syndrome on chronic liver diseases other than non-alcoholic fatty liver disease has not been fully elucidated. Our goal was to evaluate if metabolic syndrome increased the risk of liver-related complications, specifically hepatocellular carcinoma (HCC) and decompensation, in cirrhotic chronic hepatitis C (CHC) patients. We conducted a retrospective cohort study of 3503 consecutive cirrhotic CHC patients seen at Stanford University from 1997–2015. HCC developed in 238 patients (8-year incidence 21%) and hepatic decompensation in 448 patients (8-year incidence 61%). The incidence of HCC and decompensation increased with Hispanic ethnicity, diabetes, and number of metabolic risk factors. Multivariate Cox regression analysis demonstrated that, independent of HCV therapy and cure and other background risks, Hispanic ethnicity with ≥2 metabolic risk factors significantly increased the risk of HCC and hepatic decompensation. There was no interaction between Hispanic ethnicity and metabolic risk factors. All in all, metabolic risk factors significantly increase the risk of liver-related complications in cirrhotic CHC patients, especially HCC among Hispanics. As the prevalence of metabolic syndrome increases globally, targeted health interventions are needed to help curb the effects of metabolic syndrome in CHC patients.
Publisher Correction: First-principles design of nanostructured hybrid photovoltaics based on layered transition metal phosphates
Authors: Lentz Levi C. , Kolpak Alexie M.
Published: May 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
VIPER regulates naive T cell activation and effector responses: Implication in TLR4 associated acute stage T cell responses
Authors: Sahoo Subhransu Sekhar , Pratheek Belluru M. , Meena Vikram S. , Nayak Tapas Kumar , Kumar P. Sanjai , Bandyopadhyay Saumya , Maiti Prasanta Kumar , Chattopadhyay Subhasis
Published: May 2018

Naive T cells are known to express the modest level of TLR4 while it is known to go down during TCR activation. However, information towards the requirement of TLR4 signaling during TCR or mitogenic activation of naive wild-type T cells remains scanty. Here we have investigated the endogenous functional expression of TLR4 in naive mice T cells during TCR and mitogenic stimulation in presence of VIPER peptide (VP), an established inhibitor of TLR4 signaling. As expected we found that TLR4 expression goes down during TCR and mitogenic activation. Interestingly, we observed that VP treatment restores TLR4 expression on those activated T cells. Moreover, VP was found to regulate such activation of naive T cell as evident by reduction of CD25, CD69 expression, effector cytokines (IL-2, IFN-γ, TNF) production, T cell proliferation and down-regulation of T cell activation-dependent Fas (CD95), FasL (CD95L) expression. Together, our current observation highlights a possible requirement of TLR4 responses in T cells, which might have possible implication towards the pathogenic acute phase activation of naive T cells.
Simultaneous quantification of serum monounsaturated and polyunsaturated phosphatidylcholines as potential biomarkers for diagnosing non-small cell lung cancer
Authors: Chen Yingrong , Ma Zhihong , Zhong Jing , Li Liqin , Min Lishan , Xu Limin , Li Hongwei , Zhang Jianbin , Wu Wei , Dai Licheng
Published: May 2018

Non-small cell lung cancer (NSCLC) is one of the most common malignancies worldwide. In this study, we investigated Ultrahigh Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry and Gas Chromatography Time-of-Flight/Mass Spectrometry-based non-targeted metabolomic profiles of serum samples obtained from early-stage NSCLC patients and healthy controls (HC). Metabolic pathways and the biological relevance of potential biomarkers were extensively studied to gain insights into dysregulated metabolism in NSCLC. The identified biomarker candidates were further externally validated via a targeted metabolomics analysis. The global metabolomics profiles could clearly distinguish NSCLC patients from HC. Phosphatidylcholine (PC) levels were found to be dysregulated in glycerophospholipid (GPL) metabolism, which was the top altered pathway in early-stage NSCLC. Compared with those in HC, significant increases in the levels of saturated and monounsaturated PCs such as PC (15:0/18:1), PC (18:0/16:0) and PC (18:0/20:1) were observed in NSCLC. Additionally, relative to those in HC, the levels of 9 polyunsaturated PCs, namely, PC (17:2/2:0), PC (18:4/3:0), and PC (15:0/18:2), and so on were significantly decreased in NSCLC patients. A panel of 12 altered PCs had good diagnostic performance in differentiating early-stage NSCLC patients from HC, and these PCs may thus be used as serum biomarkers for the early diagnosis of NSCLC.
CTmax is repeatable and doesn’t reduce growth in zebrafish
Authors: Morgan Rachael , Finnøen Mette H. , Jutfelt Fredrik
Published: May 2018

Critical thermal maximum (CTmax) is a commonly and increasingly used measure of an animal’s upper thermal tolerance limit. However, it is unknown how consistent CTmax is within an individual, and how physiologically taxing such experiments are. We addressed this by estimating the repeatability of CTmax in zebrafish, and measured how growth and survival were affected by multiple trials. The repeatability of CTmax over four trials was 0.22 (0.07–0.43). However, CTmax increased from the first to the second trial, likely because of thermal acclimation triggered by the heat shock. After this initial acclimation response individuals became more consistent in their CTmax, reflected in a higher repeatability measure of 0.45 (0.28–0.65) for trials 2–4. We found a high innate thermal tolerance led to a lower acclimation response, whereas a high acclimation response was present in individuals that displayed a low initial CTmax. This could indicate that different strategies for thermal tolerance (i.e. plasticity vs. high innate tolerance) can co-exist in a population. Additionally, repeated CTmax trials had no effect on growth, and survival was high (99%). This validates the method and, combined with the relatively high repeatability, highlights the relevance of CTmax for continued use as a metric for acute thermal tolerance.
Author Correction: MiRNA-29c regulates the expression of inflammatory cytokines in diabetic nephropathy by targeting tristetraprolin
Authors: Guo Jia , Li Jing , Zhao Jing , Yang Shuguang , Wang Luyao , Cheng Genyang , Liu Dong , Xiao Jing , Liu Zhangsuo , Zhao Zhanzheng
Published: May 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Author Correction: Mental workload and neural efficiency quantified in the prefrontal cortex using fNIRS
Authors: Causse Mickaël , Chua Zarrin , Peysakhovich Vsevolod , Del Campo Natalia , Matton Nadine
Published: May 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Author Correction: Genome-Guided Phylo-Transcriptomic Methods and the Nuclear Phylogenetic Tree of the Paniceae Grasses
Authors: Washburn Jacob D. , Schnable James C. , Conant Gavin C. , Brutnell Thomas P. , Shao Ying , Zhang Yang , Ludwig Martha , Davidse Gerrit , Pires J. Chris
Published: May 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Early events during human coronavirus OC43 entry to the cell
Authors: Owczarek Katarzyna , Szczepanski Artur , Milewska Aleksandra , Baster Zbigniew , Rajfur Zenon , Sarna Michal , Pyrc Krzysztof
Published: May 2018

The Coronaviridae family clusters a number of large RNA viruses, which share several structural and functional features. However, members of this family recognize different cellular receptors and exploit different entry routes, what affects their species specificity and virulence. The aim of this study was to determine how human coronavirus OC43 enters the susceptible cell. Using confocal microscopy and molecular biology tools we visualized early events during infection. We found that the virus employs caveolin-1 dependent endocytosis for the entry and the scission of virus-containing vesicles from the cell surface is dynamin-dependent. Furthermore, the vesicle internalization process requires actin cytoskeleton rearrangements. With our research we strove to broaden the understanding of the infection process, which in future may be beneficial for the development of a potential therapeutics.
Genetic alterations analysis in prognostic stratified groups identified TP53 and ARID1A as poor clinical performance markers in intrahepatic cholangiocarcinoma
Authors: Simbolo Michele , Vicentini Caterina , Ruzzenente Andrea , Brunelli Matteo , Conci Simone , Fassan Matteo , Mafficini Andrea , Rusev Borislav , Corbo Vincenzo , Capelli Paola , Bria Emilio , Pedron Serena , Turri Giona , Lawlor Rita T. , Tortora Giampaolo , Bassi Claudio , Guglielmi Alfredo , Scarpa Aldo
Published: May 2018

The incidence and mortality rates of intrahepatic cholangiocarcinoma have been rising worldwide. Few patients present an early-stage disease that is amenable to curative surgery and after resection, high recurrence rates persist. To identify new independent marker related to aggressive behaviour, two prognostic groups of patient were selected and divided according to prognostic performance. All patients alive at 36 months were included in good prognostic performers, while all patients died due to disease within 36 months in poor prognostic performers. Using high-coverage target sequencing we analysed principal genetic alterations in two groups and compared results to clinical data. In the 33 cases included in poor prognosis group, TP53 was most mutated gene (p = 0.011) and exclusively present in these cases. Similarly, ARID1A was exclusive of this group (p = 0.024). TP53 and ARID1A are mutually exclusive in this study. Statistical analysis showed mutations in TP53 and ARID1A genes and amplification of MET gene as independent predictors of poor prognosis (TP53, p = 0.0031, ARID1A, p = 0.0007, MET, p = 0.0003 in Cox analysis). LOH in PTEN was also identified as marker of disease recurrence (p = 0.04) in univariate analysis. This work improves our understanding of aggressiveness related to this tumour type and has identified novel prognostic markers of clinical outcome.
Online videos indicate human and dog behaviour preceding dog bites and the context in which bites occur
Authors: Owczarczak-Garstecka Sara C. , Watkins Francine , Christley Rob , Westgarth Carri
Published: May 2018

YouTube videos of dog bites present an unexplored opportunity to observe dog bites directly. We recorded the context of bites, bite severity, victim and dog characteristics for 143 videos and for 56 videos we coded human and dog behaviour before the bite. Perceived bite severity was derived from visual aspects of the bite. Associations between bite severity and victim, dog and context characteristics were analysed using a Bayesian hierarchical regression model. Human and dog behaviour before the bite were summarised with descriptive statistics. No significant differences in bite severity were observed between contexts. Only age of the victim was predictive of bite severity: adults were bitten more severely than infants and infants more severely than children. Non-neutral codes describing dog body posture and some displacement and appeasement behaviours increased approximately 20 seconds before the bite and humans made more tactile contacts with dogs 21 seconds before the bite. This analysis can help to improve understanding of context in which bites occur and improve bite prevention by highlighting observable human and dog behaviours occurring before the bite.