bluuebunny/crossref_metadata_2025 huggingface dataset:
Fucosylation of LAMP-1 and LAMP-2 by FUT1 correlates with lysosomal positioning and autophagic flux of breast cancer cells
Authors: Tan Keng-Poo , Ho Ming-Yi , Cho Huan-Chieh , Yu John , Hung Jung-Tung , Yu Alice Lin-Tsing
Published: August 2016

Alpha1,2-fucosyltransferases, FUT1 and FUT2, which transfer fucoses onto the terminal galactose of N-acetyl-lactosamine via α1,2-linkage have been shown to be highly expressed in various types of cancers. A few studies have shown the involvement of FUT1 substrates in tumor cell proliferation and migration. Lysosome-associated membrane protein 1, LAMP-1, has been reported to carry alpha1,2-fucosylated Lewis Y (LeY) antigens in breast cancer cells, however, the biological functions of LeY on LAMP-1 remain largely unknown. Whether or not its family member, LAMP-2, displays similar modifications and functions as LAMP-1 has not yet been addressed. In this study, we have presented evidence supporting that both LAMP-1 and 2 are substrates for FUT1, but not FUT2. We have also demonstrated the presence of H2 and LeY antigens on LAMP-1 by a targeted nanoLC-MS3 and the decreased levels of fucosylation on LAMP-2 by MALDI-TOF analysis upon FUT1 knockdown. In addition, we found that the expression of LeY was substantial in less invasive ER+/PR+/HER− breast cancer cells (MCF-7 and T47D) but negligible in highly invasive triple-negative MDA-MB-231 cells, of which LeY levels were correlated with the levels of LeY carried by LAMP-1 and 2. Intriguingly, we also observed a striking change in the subcellular localization of lysosomes upon FUT1 knockdown from peripheral distribution of LAMP-1 and 2 to a preferential perinuclear accumulation. Besides that, knockdown of FUT1 led to an increased rate of autophagic flux along with diminished activity of mammalian target of rapamycin complex 1 (mTORC1) and enhanced autophagosome–lysosome fusion. This may be associated with the predominantly perinuclear distribution of lysosomes mediated by FUT1 knockdown as lysosomal positioning has been reported to regulate mTOR activity and autophagy. Taken together, our results suggest that downregulation of FUT1, which leads to the perinuclear localization of LAMP-1 and 2, is correlated with increased rate of autophagic flux by decreasing mTOR signaling and increasing autolysosome formation.
NEMO regulates a cell death switch in TNF signaling by inhibiting recruitment of RIPK3 to the cell death-inducing complex II
Authors: Pescatore Alessandra , Esposito Elio , Draber Peter , Walczak Henning , Ursini Matilde Valeria
Published: August 2016

Incontinentia Pigmenti (IP) is a rare X-linked disease characterized by early male lethality and multiple abnormalities in heterozygous females. IP is caused by NF-κB essential modulator (NEMO) mutations. The current mechanistic model suggests that NEMO functions as a crucial component mediating the recruitment of the IκB-kinase (IKK) complex to tumor necrosis factor receptor 1 (TNF-R1), thus allowing activation of the pro-survival NF-κB response. However, recent studies have suggested that gene activation and cell death inhibition are two independent activities of NEMO. Here we describe that cells expressing the IP-associated NEMO-A323P mutant had completely abrogated TNF-induced NF-κB activation, but retained partial antiapoptotic activity and exhibited high sensitivity to death by necroptosis. We found that robust caspase activation in NEMO-deficient cells is concomitant with RIPK3 recruitment to the apoptosis-mediating complex. In contrast, cells expressing the ubiquitin-binding mutant NEMO-A323P did not recruit RIPK3 to complex II, an event that prevented caspase activation. Hence NEMO, independently from NF-κB activation, represents per se a key component in the structural and functional dynamics of the different TNF-R1-induced complexes. Alteration of this process may result in differing cellular outcomes and, consequently, also pathological effects in IP patients with different NEMO mutations.
A centrosome interactome provides insight into organelle assembly and reveals a non-duplication role for Plk4
Authors: Galletta Brian J. , Fagerstrom Carey J. , Schoborg Todd A. , McLamarrah Tiffany A. , Ryniawec John M. , Buster Daniel W. , Slep Kevin C. , Rogers Gregory C. , Rusan Nasser M.
Published: August 2016

The centrosome is the major microtubule-organizing centre of many cells, best known for its role in mitotic spindle organization. How the proteins of the centrosome are accurately assembled to carry out its many functions remains poorly understood. The non-membrane-bound nature of the centrosome dictates that protein–protein interactions drive its assembly and functions. To investigate this massive macromolecular organelle, we generated a ‘domain-level’ centrosome interactome using direct protein–protein interaction data from a focused yeast two-hybrid screen. We then used biochemistry, cell biology and the model organism Drosophila to provide insight into the protein organization and kinase regulatory machinery required for centrosome assembly. Finally, we identified a novel role for Plk4, the master regulator of centriole duplication. We show that Plk4 phosphorylates Cep135 to properly position the essential centriole component Asterless. This interaction landscape affords a critical framework for research of normal and aberrant centrosomes.
Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma
Authors: Cammareri Patrizia , Rose Aidan M. , Vincent David F. , Wang Jun , Nagano Ai , Libertini Silvana , Ridgway Rachel A. , Athineos Dimitris , Coates Philip J. , McHugh Angela , Pourreyron Celine , Dayal Jasbani H. S. , Larsson Jonas , Weidlich Simone , Spender Lindsay C. , Sapkota Gopal P. , Purdie Karin J. , Proby Charlotte M. , Harwood Catherine A. , Leigh Irene M. , Clevers Hans , Barker Nick , Karlsson Stefan , Pritchard Catrin , Marais Richard , Chelala Claude , South Andrew P. , Sansom Owen J. , Inman Gareth J.
Published: August 2016

Melanoma patients treated with oncogenic BRAF inhibitors can develop cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, driven by paradoxical RAS/RAF/MAPK pathway activation. Here we identify frequent TGFBR1 and TGFBR2 mutations in human vemurafenib-induced skin lesions and in sporadic cSCC. Functional analysis reveals these mutations ablate canonical TGFβ Smad signalling, which is localized to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through BrafV600E or KrasG12D knockin) and TGFβ signalling ablation (through Tgfbr1 deletion) in LGR5+ve stem cells enables rapid cSCC development in the mouse. Mutation of Tp53 (which is commonly mutated in sporadic cSCC) coupled with Tgfbr1 deletion in LGR5+ve cells also results in cSCC development. These findings indicate that LGR5+ve stem cells may act as cells of origin for cSCC, and that RAS/RAF/MAPK pathway hyperactivation or Tp53 mutation, coupled with loss of TGFβ signalling, are driving events of skin tumorigenesis.
Microglia contact induces synapse formation in developing somatosensory cortex
Authors: Miyamoto Akiko , Wake Hiroaki , Ishikawa Ayako Wendy , Eto Kei , Shibata Keisuke , Murakoshi Hideji , Koizumi Schuichi , Moorhouse Andrew J. , Yoshimura Yumiko , Nabekura Junichi
Published: August 2016

Microglia are the immune cells of the central nervous system that play important roles in brain pathologies. Microglia also help shape neuronal circuits during development, via phagocytosing weak synapses and regulating neurogenesis. Using in vivo multiphoton imaging of layer 2/3 pyramidal neurons in the developing somatosensory cortex, we demonstrate here that microglial contact with dendrites directly induces filopodia formation. This filopodia formation occurs only around postnatal day 8–10, a period of intense synaptogenesis and when microglia have an activated phenotype. Filopodia formation is preceded by contact-induced Ca2+ transients and actin accumulation. Inhibition of microglia by genetic ablation decreases subsequent spine density, functional excitatory synapses and reduces the relative connectivity from layer 4 neurons. Our data provide the direct demonstration of microglial-induced spine formation and provide further insights into immune system regulation of neuronal circuit development, with potential implications for developmental disorders of immune and brain dysfunction.
Single-point single-molecule FRAP distinguishes inner and outer nuclear membrane protein distribution
Authors: Mudumbi Krishna C , Schirmer Eric C , Yang Weidong
Published: August 2016

The normal distribution of nuclear envelope transmembrane proteins (NETs) is disrupted in several human diseases. NETs are synthesized on the endoplasmic reticulum and then transported from the outer nuclear membrane (ONM) to the inner nuclear membrane (INM). Quantitative determination of the distribution of NETs on the ONM and INM is limited in available approaches, which moreover provide no information about translocation rates in the two membranes. Here we demonstrate a single-point single-molecule FRAP microscopy technique that enables determination of distribution and translocation rates for NETs in vivo.
Metal-responsive promoter DNA compaction by the ferric uptake regulator
Authors: Roncarati Davide , Pelliciari Simone , Doniselli Nicola , Maggi Stefano , Vannini Andrea , Valzania Luca , Mazzei Luca , Zambelli Barbara , Rivetti Claudio , Danielli Alberto
Published: August 2016

Short-range DNA looping has been proposed to affect promoter activity in many bacterial species and operator configurations, but only few examples have been experimentally investigated in molecular detail. Here we present evidence for a metal-responsive DNA condensation mechanism controlled by the Helicobacter pylori ferric uptake regulator (Fur), an orthologue of the widespread Fur family of prokaryotic metal-dependent regulators. H. pylori Fur represses the transcription of the essential arsRS acid acclimation operon through iron-responsive oligomerization and DNA compaction, encasing the arsR transcriptional start site in a repressive macromolecular complex. A second metal-dependent regulator NikR functions as nickel-dependent anti-repressor at this promoter, antagonizing the binding of Fur to the operator elements responsible for the DNA condensation. The results allow unifying H. pylori metal ion homeostasis and acid acclimation in a mechanistically coherent model, and demonstrate, for the first time, the existence of a selective metal-responsive DNA compaction mechanism controlling bacterial transcriptional regulation.
Targeting of Fzr/Cdh1 for timely activation of the APC/C at the centrosome during mitotic exit
Authors: Meghini Francesco , Martins Torcato , Tait Xavier , Fujimitsu Kazuyuki , Yamano Hiroyuki , Glover David M. , Kimata Yuu
Published: August 2016

A multi-subunit ubiquitin ligase, the anaphase-promoting complex/cyclosome (APC/C), regulates critical cellular processes including the cell cycle. To accomplish its diverse functions, APC/C activity must be precisely regulated in time and space. The interphase APC/C activator Fizzy-related (Fzr or Cdh1) is localized at centrosomes in animal cells. However, neither the mechanism of its localization nor its importance is clear. Here we identify the centrosome component Spd2 as a major partner of Fzr in Drosophila. The localization of Fzr to the centriole during interphase depends on direct interaction with Spd2. By generating Spd2 mutants unable to bind Fzr, we show that centrosomal localization of Fzr is essential for optimal APC/C activation towards its centrosomal substrate Aurora A. Finally, we show that Spd2 is also a novel APC/CFzr substrate. Our study is the first to demonstrate the critical importance of distinct subcellular pools of APC/C activators in the spatiotemporal control of APC/C activity.
YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4–NOT deadenylase complex
Authors: Du Hao , Zhao Ya , He Jinqiu , Zhang Yao , Xi Hairui , Liu Mofang , Ma Jinbiao , Wu Ligang
Published: August 2016

Methylation at the N6 position of adenosine (m6A) is the most abundant RNA modification within protein-coding and long noncoding RNAs in eukaryotes and is a reversible process with important biological functions. YT521-B homology domain family (YTHDF) proteins are the readers of m6A, the binding of which results in the alteration of the translation efficiency and stability of m6A-containing RNAs. However, the mechanism by which YTHDF proteins cause the degradation of m6A-containing RNAs is poorly understood. Here we report that m6A-containing RNAs exhibit accelerated deadenylation that is mediated by the CCR4–NOT deadenylase complex. We further show that YTHDF2 recruits the CCR4–NOT complex through a direct interaction between the YTHDF2 N-terminal region and the SH domain of the CNOT1 subunit, and that this recruitment is essential for the deadenylation of m6A-containing RNAs by CAF1 and CCR4. Therefore, we have uncovered the mechanism of YTHDF2-mediated degradation of m6A-containing RNAs in mammalian cells.
Ubiquitin ligase RNF20/40 facilitates spindle assembly and promotes breast carcinogenesis through stabilizing motor protein Eg5
Authors: Duan Yang , Huo Dawei , Gao Jie , Wu Heng , Ye Zheng , Liu Zhe , Zhang Kai , Shan Lin , Zhou Xing , Wang Yue , Su Dongxue , Ding Xiang , Shi Lei , Wang Yan , Shang Yongfeng , Xuan Chenghao
Published: August 2016

Whether transcriptional regulators are functionally involved in mitosis is a fundamental question in cell biology. Here we report that the RNF20/40 complex, a major ubiquitin ligase catalysing histone H2B monoubiquitination, interacts with the motor protein Eg5 during mitosis and participates in spindle assembly. We show that the RNF20/40 complex monoubiquitinates and stabilizes Eg5. Loss of RNF20/40 results in spindle assembly defects, cell cycle arrest and apoptosis. Consistently, depletion of either RNF20/40 or Eg5 suppresses breast cancer in vivo. Significantly, RNF20/40 and Eg5 are concurrently upregulated in human breast carcinomas and high Eg5 expression is associated with poorer overall survival of patients with luminal A, or B, breast cancer. Our study uncovers an important spindle assembly role of the RNF20/40 complex, and implicates the RNF20/40-Eg5 axis in breast carcinogenesis, supporting the pursuit of these proteins as potential targets for breast cancer therapeutic interventions.
Comparative genomics reveals convergent rates of evolution in ant–plant mutualisms
Authors: Rubin Benjamin E. R. , Moreau Corrie S.
Published: August 2016

Symbiosis—the close and often long-term interaction of species—is predicted to drive genome evolution in a variety of ways. For example, parasitic interactions have been shown to increase rates of molecular evolution, a trend generally attributed to the Red Queen Hypothesis. However, it is much less clear how mutualisms impact the genome, as both increased and reduced rates of change have been predicted. Here we sequence the genomes of seven species of ants, three that have convergently evolved obligate plant–ant mutualism and four closely related species of non-mutualists. Comparing these sequences, we investigate how genome evolution is shaped by mutualistic behaviour. We find that rates of molecular evolution are higher in the mutualists genome wide, a characteristic apparently not the result of demography. Our results suggest that the intimate relationships of obligate mutualists may lead to selective pressures similar to those seen in parasites, thereby increasing rates of evolution.
Correction: Corrigendum: Identifying a set of influential spreaders in complex networks
Authors: Zhang Jian-Xiong , Chen Duan-Bing , Dong Qiang , Zhao Zhi-Dan
Published: August 2016

Scientific Reports 6: Article number: 27823; published online: 14 June 2016; updated: 25 August 2016 This Article contains errors in the Acknowledgements section. “This work is partially supported by the National Natural Science Foundation of China under Grant Nos 61433014 and 61300018, by the National High Technology Research and Development Program under Grant No.
Correction: Corrigendum: Exploration of acetanilide derivatives of 1-(ω-phenoxyalkyl)uracils as novel inhibitors of Hepatitis C Virus replication
Authors: Magri Andrea , Ozerov Alexander A. , Tunitskaya Vera L. , Valuev-Elliston Vladimir T. , Wahid Ahmed , Pirisi Mario , Simmonds Peter , Ivanov Alexander V. , Novikov Mikhail S. , Patel Arvind H.
Published: August 2016

Scientific Reports 6: Article number: 29487; published online: 12 July 2016; updated: 25 August 2016 In this Article, Figure 3 is incorrect. The correct Figure 3 appears below as Figure 1. As a result, the accompanying legend should read: “Antiviral activity on a replicon cell line. Huh-J17 cells expressing the N17/JFH1 subgenomic replicon were seeded in the presence of the drugs at the concentration of 10 μM each, or an equivalent amount of DMSO as a vehicle control, and then incubated at 37 °C for 24 h, 48 h or 72 h.
Whole Genome Sequencing Identifies a Missense Mutation in HES7 Associated with Short Tails in Asian Domestic Cats
Authors: Xu Xiao , Sun Xin , Hu Xue-Song , Zhuang Yan , Liu Yue-Chen , Meng Hao , Miao Lin , Yu He , Luo Shu-Jin
Published: August 2016

Domestic cats exhibit abundant variations in tail morphology and serve as an excellent model to study the development and evolution of vertebrate tails. Cats with shortened and kinked tails were first recorded in the Malayan archipelago by Charles Darwin in 1868 and remain quite common today in Southeast and East Asia. To elucidate the genetic basis of short tails in Asian cats, we built a pedigree of 13 cats segregating at the trait with a founder from southern China and performed linkage mapping based on whole genome sequencing data from the pedigree. The short-tailed trait was mapped to a 5.6 Mb region of Chr E1, within which the substitution c. 5T > C in the somite segmentation-related gene HES7 was identified as the causal mutation resulting in a missense change (p.V2A). Validation in 245 unrelated cats confirmed the correlation between HES7-c. 5T > C and Chinese short-tailed feral cats as well as the Japanese Bobtail breed, indicating a common genetic basis of the two. In addition, some of our sampled kinked-tailed cats could not be explained by either HES7 or the Manx-related T-box, suggesting at least three independent events in the evolution of domestic cats giving rise to short-tailed traits.
Topology of chromosome centromeres in human sperm nuclei with high levels of DNA damage
Authors: Wiland Ewa , Fraczek Monika , Olszewska Marta , Kurpisz Maciej
Published: August 2016

Several studies have shown that the ‘poor’ sperm DNA quality appears to be an important factor affecting male reproductive ability. In the case of sperm cells from males with the correct somatic karyotype but with deficient spermatogenesis, resulting in a high degree of sperm DNA fragmentation, we observed changes in the preferential topology of the chromosome 7, 9, 15, 18, X and Y centromeres. The changes occurred in radial localization and may have been directly linked to the sperm chromatin damage. This conclusion is mainly based on a comparison of FISH signals that were observed simultaneously in the TUNEL-positive and TUNEL-negative sperm cells. The analyzed cells originated from the same ejaculated sample and FISH was performed on the same slides, after in situ TUNEL reaction. Based on the observed changes and previous data, it appears that the sperm nucleus architecture can be disrupted by a variety of factors and has a negative influence on spermatogenesis at the same time. Often, these factors coexist (e.g. chromosomal translocations, aneuploidies, a higher DNA fragmentation, abnormal seminology), but no direct correlations between the factors were observed.
Neuregulin 1 improves cognitive deficits and neuropathology in an Alzheimer’s disease model
Authors: Xu Jiqing , de Winter Fred , Farrokhi Catherine , Rockenstein Edward , Mante Michael , Adame Anthony , Cook Jonathan , Jin Xin , Masliah Eliezer , Lee Kuo-Fen
Published: August 2016

Several lines of evidence suggest that neuregulin 1 (NRG1) signaling may influence cognitive function and neuropathology in Alzheimer’s disease (AD). To test this possibility, full-length type I or type III NRG1 was overexpressed via lentiviral vectors in the hippocampus of line 41 AD mouse. Both type I and type III NRG1 improves deficits in the Morris water-maze behavioral task. Neuropathology was also significantly ameliorated. Decreased expression of the neuronal marker MAP2 and synaptic markers PSD95 and synaptophysin in AD mice was significantly reversed. Levels of Aβ peptides and plaques were markedly reduced. Furthermore, we showed that soluble ectodomains of both type I and type III NRG1 significantly increased expression of Aβ-degrading enzyme neprilysin (NEP) in primary neuronal cultures. Consistent with this finding, immunoreactivity of NEP was increased in the hippocampus of AD mice. These results suggest that NRG1 provides beneficial effects in candidate neuropathologic substrates of AD and, therefore, is a potential target for the treatment of AD.
Formation mechanism of guided resonances and bound states in the continuum in photonic crystal slabs
Authors: Gao Xingwei , Hsu Chia Wei , Zhen Bo , Lin Xiao , Joannopoulos John D. , Soljačić Marin , Chen Hongsheng
Published: August 2016

We develop a formalism, based on the mode expansion method, to describe the guided resonances and bound states in the continuum (BICs) in photonic crystal slabs with one-dimensional periodicity. This approach provides analytic insights to the formation mechanisms of these states: the guided resonances arise from the transverse Fabry–Pérot condition and the divergence of the resonance lifetimes at the BICs is explained by a destructive interference of radiation from different propagating components inside the slab. We show BICs at the center and on the edge of the Brillouin zone protected by symmetry, BICs at generic wave vectors not protected by symmetry and the annihilation of BICs at low-symmetry wave vectors.
AAV8-Mediated Angiotensin-Converting Enzyme 2 Gene Delivery Prevents Experimental Autoimmune Uveitis by Regulating MAPK, NF-κB and STAT3 Pathways
Authors: Qiu Yiguo , Tao Lifei , Zheng Shijie , Lin Ru , Fu Xinyu , Chen Zihe , Lei Chunyan , Wang Jiaming , Li Hongwei , Li Qiuhong , Lei Bo
Published: August 2016

Renin angiotensin system (RAS) is a key hormonal system which regulates the cardiovascular function and is implicated in several autoimmune diseases. With the discovery of the angiotensin-converting enzyme 2 (ACE2), a protective axis of RAS namely ACE2/Ang-(1–7)/Mas that counteracts the deleterious ACE/AngII/AT1R axis has been established. This axis is emerging as a novel target to attenuate ocular inflammation. However, the underlying molecular mechanisms remain unclear. We investigated the hypothesis that enhancing the activity of the protective axis of RAS by subretinal delivery of an AAV8 (Y733F)-ACE2 vector would protect against the ocular inflammation in experimental autoimmune uveitis (EAU) mice through regulating the local immune responses. Our studies demonstrated that increased ACE2 expression exerts protective effects on inflammation in EAU mouse by modulating ocular immune responses, including the differentiation of Th1/Th17 cells and the polarization of M1/M2 macrophages; whereas the systemic immune responses appeared not affected. These effects were mediated by activating the Ang-(1–7)/Mas and inhibiting the MAPK, NF-κB and STAT3 signaling pathways. This proof-of-concept study suggests that activation of ocular ACE2/Ang-(1–7)/Mas axis with AAV gene transfer modulates local immune responses and may be a promising, long-lasting therapeutic strategy for refractory and recurrent uveitis, as well as other inflammatory eye diseases.
A ruthenium polypyridyl intercalator stalls DNA replication forks, radiosensitizes human cancer cells and is enhanced by Chk1 inhibition
Authors: Gill Martin R. , Harun Siti Norain , Halder Swagata , Boghozian Ramon A. , Ramadan Kristijan , Ahmad Haslina , Vallis Katherine A.
Published: August 2016

Ruthenium(II) polypyridyl complexes can intercalate DNA with high affinity and prevent cell proliferation; however, the direct impact of ruthenium-based intercalation on cellular DNA replication remains unknown. Here we show the multi-intercalator [Ru(dppz)2(PIP)]2+ (dppz = dipyridophenazine, PIP = 2-(phenyl)imidazo[4,5-f][1,10]phenanthroline) immediately stalls replication fork progression in HeLa human cervical cancer cells. In response to this replication blockade, the DNA damage response (DDR) cell signalling network is activated, with checkpoint kinase 1 (Chk1) activation indicating prolonged replication-associated DNA damage, and cell proliferation is inhibited by G1-S cell-cycle arrest. Co-incubation with a Chk1 inhibitor achieves synergistic apoptosis in cancer cells, with a significant increase in phospho(Ser139) histone H2AX (γ-H2AX) levels and foci indicating increased conversion of stalled replication forks to double-strand breaks (DSBs). Normal human epithelial cells remain unaffected by this concurrent treatment. Furthermore, pre-treatment of HeLa cells with [Ru(dppz)2(PIP)]2+ before external beam ionising radiation results in a supra-additive decrease in cell survival accompanied by increased γ-H2AX expression, indicating the compound functions as a radiosensitizer. Together, these results indicate ruthenium-based intercalation can block replication fork progression and demonstrate how these DNA-binding agents may be combined with DDR inhibitors or ionising radiation to achieve more efficient cancer cell killing.
Higher FT4 or TSH below the normal range are associated with increased risk of dementia: a meta-analysis of 11 studies
Authors: Wu Yue , Pei Yuqing , Wang Fei , Xu Danfei , Cui Wei
Published: August 2016

Observational studies of thyroid function and dementia have reported conflicting results. We reviewed cohort and case-control studies from MEDLINE, EMBASE, Web of Science and the Cochrane Library that focused on the association between serum thyroxine, thyrotropin and dementia. A total of 24,952 participants from three case-control and eight cohort studies were included. The relationships between dementia and the per standard deviation (SD) increment of free thyroxine (FT4) (random relative ratio (RR) = 1.08, 95% confidence interval (CI) 1.00–1.17) and thyroid-stimulating hormone (TSH) (fixed RR = 0.91, 95% CI 0.84–0.99) were well established. TSH levels in the low category were associated with an increased risk of dementia (fixed RR = 1.60, 95% CI 1.27–2.00). However, the positive association was confined to TSH levels below the normal range (fixed RR = 1.77, 95% CI 1.31–2.39), not those in the lower tertile of the normal range (fixed RR = 1.39, 95% CI 0.98–1.97). Additionally, dementia was not significantly associated with high TSH levels (fixed RR = 0.99, 95% CI 0.76–1.29). Furthermore, there was no positive association between dementia and the low or high categories of TSH in men. Thus, individuals with higher FT4 levels or those with TSH levels below the normal range have an increased risk of dementia.
A fast multispectral light synthesiser based on LEDs and a diffraction grating
Authors: Belušič Gregor , Ilić Marko , Meglič Andrej , Pirih Primož
Published: August 2016

Optical experiments often require fast-switching light sources with adjustable bandwidths and intensities. We constructed a wavelength combiner based on a reflective planar diffraction grating and light emitting diodes with emission peaks from 350 to 630 nm that were positioned at the angles corresponding to the first diffraction order of the reversed beam. The combined output beam was launched into a fibre. The spacing between 22 equally wide spectral bands was about 15 nm. The time resolution of the pulse-width modulation drivers was 1 ms. The source was validated with a fast intracellular measurement of the spectral sensitivity of blowfly photoreceptors. In hyperspectral imaging of Xenopus skin circulation, the wavelength resolution was adequate to resolve haemoglobin absorption spectra. The device contains no moving parts, has low stray light and is intrinsically capable of multi-band output. Possible applications include visual physiology, biomedical optics, microscopy and spectroscopy.
The efficacy and safety of immunotherapy in patients with advanced NSCLC: a systematic review and meta-analysis
Authors: Zhou Liang , Wang Xi-Ling , Deng Qing-Long , Du Yan-Qiu , Zhao Nai-Qing
Published: August 2016

Immunotherapy is a novel treatment for advanced non-small cell lung cancer (NSCLC) patients. Immunotherapy includes two main broad classes of therapeutic vaccines and immune checkpoint inhibitors, as well as cytokines, biological response modifiers and cellular therapy. The present systematic review and meta-analysis aims to evaluate the efficacy and safety of different classes of immunotherapy in patients with advanced NSCLC. Literature search was done on Medline, Embase and Cochrane Library. The primary endpoints were overall survival (OS) and grade ≥3 adverse events. Twenty randomized controlled trials were finally identified in our study. Efficacy analysis indicated an improvement of OS in advanced NSCLC patients after treating by therapeutic vaccines and immune checkpoint inhibitors, but not for other immunomodulators. Safety analysis showed that immunotherapy was well-tolerated. All kinds of grade ≥3 adverse events were similar between experimental group and control group except that neutropenia and thrombocytopenia had a higher incidence in patients received vaccines. In conclusion, immunotherapy is a promising treatment for advanced NSCLC patients. Our findings will be further confirmed and supplemented by several phase II and phase III RCTs which are going to complete in near future.
Prognostic significance of nuclear expression of UMP-CMP kinase in triple negative breast cancer patients
Authors: Liu Ning Qing , De Marchi Tommaso , Timmermans Annemieke , Trapman-Jansen Anita M. A. C. , Foekens Renée , Look Maxime P. , Smid Marcel , van Deurzen Carolien H. M. , Span Paul N. , Sweep Fred C. G. J. , Brask Julie Benedicte , Timmermans-Wielenga Vera , Foekens John A. , Martens John W. M. , Umar Arzu
Published: August 2016

We have previously identified UMP-CMP kinase (CMPK1) as a prognostic marker for triple negative breast cancer (TNBC) by mass spectrometry (MS). In this study we evaluated CMPK1 association to prognosis in an independent set of samples by immunohistochemistry (IHC) and assessed biological pathways associated to its expression through gene set enrichment analysis (GSEA). A total of 461 TNBC paraffin-embedded tissues were collected from different academic hospitals in Europe, incorporated into tissue micro-arrays (TMA), and stained for CMPK1 expression. We also collected gene expression data of 60 samples, which were also present in the TMA, for GSEA correlation analysis. CMPK1 IHC staining showed both cytoplasmic and nuclear components. While cytoplasmic CMPK1 did not show any association to metastasis free survival (MFS), nuclear CMPK1 was associated to poor prognosis independently from other prognostic factors in stratified Cox regression analyses. GSEA correlation analysis of the nuclear CMPK1-stratified gene expression dataset showed a significant enrichment of extracellular matrix (ECM; positive correlation) and cell cycle (negative correlation) associated genes. We have shown here that nuclear CMPK1 is indicative of poor prognosis in TNBCs and that its expression may be related to dysregulation of ECM and cell cycle molecules.
Experiment and simulation of novel liquid crystal plasma mirrors for high contrast, intense laser pulses
Authors: Poole P. L. , Krygier A. , Cochran G. E. , Foster P. S. , Scott G. G. , Wilson L. A. , Bailey J. , Bourgeois N. , Hernandez-Gomez C. , Neely D. , Rajeev P. P. , Freeman R. R. , Schumacher D. W.
Published: August 2016

We describe the first demonstration of plasma mirrors made using freely suspended, ultra-thin films formed dynamically and in-situ. We also present novel particle-in-cell simulations that for the first time incorporate multiphoton ionization and dielectric models that are necessary for describing plasma mirrors. Dielectric plasma mirrors are a crucial component for high intensity laser applications such as ion acceleration and solid target high harmonic generation because they greatly improve pulse contrast. We use the liquid crystal 8CB and introduce an innovative dynamic film formation device that can tune the film thickness so that it acts as its own antireflection coating. Films can be formed at a prolonged, high repetition rate without the need for subsequent realignment. High intensity reflectance above 75% and low-field reflectance below 0.2% are demonstrated, as well as initial ion acceleration experimental results that demonstrate increased ion energy and yield on shots cleaned with these plasma mirrors.
Large fluctuations at the lasing threshold of solid- and liquid-state dye lasers
Authors: Basak Supratim , Blanco Alvaro , López Cefe
Published: August 2016

Intensity fluctuations in lasers are commonly studied above threshold in some special configurations (especially when emission is fed back into the cavity or when two lasers are coupled) and related with their chaotic behaviour. Similar fluctuating instabilities are usually observed in random lasers, which are open systems with plenty of quasi-modes whose non orthogonality enables them to exchange energy and provides the sort of loss mechanism whose interplay with pumping leads to replica symmetry breaking. The latter however, had never been observed in plain cavity lasers where disorder is absent or not intentionally added. Here we show a fluctuating lasing behaviour at the lasing threshold both in solid and liquid dye lasers. Above and below a narrow range around the threshold the spectral line-shape is well correlated with the pump energy. At the threshold such correlation disappears, and the system enters a regime where emitted laser fluctuates between narrow, intense and broad, weak peaks. The immense number of modes and the reduced resonator quality favour the coupling of modes and prepares the system so that replica symmetry breaking occurs without added disorder.
Exploration of pathological prediction of chronic kidney diseases by a novel theory of bi-directional probability
Authors: Yang Yuan , Luo Min , Xiao Li , Zhu Xue-jing , Wang Chang , Fu Xiao , Yuan Shu-guang , Xiao Fang , Liu Hong , Dong Zheng , Liu Fu-you , Sun Lin
Published: August 2016

In the clinic, the pathological types of chronic kidney diseases (CKD) are considered references for choosing treatment protocols. From a statistical viewpoint, a non-invasive method to predict pathological types of CKD is a focus of our work. In the current study, following a frequency analysis of the clinical indices of 588 CKD patients in the department of nephrology, a third-grade class-A hospital, a novel theory is proposed: “bi-directional cumulative probability dichotomy”. Further, two models for the prediction and differential diagnosis of CKD pathological type are established. The former indicates an occurrence probability of the pathological types, and the latter indicates an occurrence of CKD pathological type according to logistic binary regression. To verify the models, data were collected from 135 patients, and the results showed that the highest accuracy rate on membranous nephropathy (MN-100%), followed by IgA nephropathy (IgAN-83.33%) and mild lesion type (MLN-73.53%), whereas lower prediction accuracy was observed for mesangial proliferative glomerulonephritis (0%) and focal segmental sclerosis type (21.74%). The models of bi-directional probability prediction and differential diagnosis indicate a good prediction value in MN, IgAN and MLN and may be considered alternative methods for the pathological discrimination of CKD patients who are unable to undergo renal biopsy.
Characterization of mammary epithelial stem/progenitor cells and their changes with aging in common marmosets
Authors: Wu Anqi , Dong Qiaoxiang , Gao Hui , Shi Yuanshuo , Chen Yuanhong , Zhang Fuchuang , Bandyopadhyay Abhik , Wang Danhan , Gorena Karla M. , Huang Changjiang , Tardif Suzette , Nathanielsz Peter W. , Sun Lu-Zhe
Published: August 2016

Age is the number one risk factor for breast cancer, yet the underlying mechanisms are unexplored. Age-associated mammary stem cell (MaSC) dysfunction is thought to play an important role in breast cancer carcinogenesis. Non-human primates with their close phylogenetic relationship to humans provide a powerful model system to study the effects of aging on human MaSC. In particular, the common marmoset monkey (Callithrix jacchus) with a relatively short life span is an ideal model for aging research. In the present study, we characterized for the first time the mammary epithelial stem/progenitor cells in the common marmoset. The MaSC-enriched cells formed four major types of morphologically distinct colonies when cultured on plates pre-seeded with irradiated NIH3T3 fibroblasts and were also capable of forming mammospheres in suspension culture and subsequent formation of 3D organoids in Matrigel culture. Most importantly, these 3D organoids were found to contain stem/progenitor cells that can undergo self-renewal and multi-lineage differentiation bothin vitroandin vivo. We also observed a significant decrease of luminal-restricted progenitors with age. Our findings demonstrate that common marmoset mammary stem/progenitor cells can be isolated and quantified with establishedin vitroandin vivoassays used for mouse and human studies.
A mir-231-Regulated Protection Mechanism against the Toxicity of Graphene Oxide in Nematode Caenorhabditis elegans
Authors: Yang Ruilong , Ren Mingxia , Rui Qi , Wang Dayong
Published: August 2016

Recently, several dysregulated microRNAs (miRNAs) have been identified in organisms exposed to graphene oxide (GO). However, their biological functions and mechanisms of the action are still largely unknown. Here, we investigated the molecular mechanism of mir-231 in the regulation of GO toxicity using in vivo assay system of Caenorhabditis elegans. We found that GO exposure inhibited the expression of mir-231::GFP in multiple tissues, in particular in the intestine. mir-231 acted in intestine to regulate the GO toxicity and overexpression of mir-231 in intestine caused a susceptible property of nematodes to GO toxicity. smk-1 encoding a homologue to mammalian SMEK functioned as a targeted gene for mir-231 and was also involved in the intestinal regulation of GO toxicity. Mutation of smk-1 gene induced a susceptible property to GO toxicity, whereas the intestinal overexpression of smk-1 resulted in a resistant property to GO toxicity. Moreover, mutation of smk-1 gene suppressed the resistant property of mir-231 mutant to GO toxicity. In nematodes, SMK-1 further acted upstream of the transcriptional factor DAF-16/FOXO in insulin signaling pathway to regulate GO toxicity. Therefore, mir-231 may encode a GO-responsive protection mechanism against the GO toxicity by suppressing the function of the SMK-1 - DAF-16 signaling cascade in nematodes.
Oxidized (non)-regenerated cellulose affects fundamental cellular processes of wound healing
Authors: Wagenhäuser M. U. , Mulorz J. , Ibing W. , Simon F. , Spin J. M. , Schelzig H. , Oberhuber A.
Published: August 2016

In this study we investigated how hemostats such as oxidized regenerated cellulose (ORC, TABOTAMP) and oxidized non-regenerated cellulose (ONRC, RESORBA CELL) influence local cellular behavior and contraction of the extracellular matrix (ECM). Human stromal fibroblasts were inoculated in vitro with ORC and ONRC. Cell proliferation was assayed over time and migration was evaluated by Live Cell imaging microscopy. Fibroblasts grown in collagen-gels were treated with ORC or ONRC and ECM contraction was measured utilizing a contraction assay. An absolute pH decline was observed with both ORC and ONRC after 1 hour. Mean daily cell proliferation, migration and matrix contraction were more strongly inhibited by ONRC when compared with ORC (p < 0.05). When control media was pH-lowered to match the lower pH values typically seen with ORC and ONRC, significant differences in cell proliferation and migration were still observed between ONRC and ORC (p < 0.05). However, in these pH conditions, inhibition of matrix contraction was only significant for ONRC (p < 0.05). We find that ORC and ONRC inhibit fibroblast proliferation, migration and matrix contraction and stronger inhibition of these essential cellular processes of wound healing were observed for ONRC when compared with ORC. These results will require further validation in future in vivo experiments to clarify the clinical implications for hemostat use in post-surgical wound healing.
Red Mud as an Efficient, Stable and Cost-Free Catalyst for COx-Free Hydrogen Production from Ammonia
Authors: Kurtoğlu Samira Fatma , Uzun Alper
Published: August 2016

Red mud, one of the mostly produced industrial wastes, was converted into a catalyst with exceptionally high and stable performance for hydrogen production from ammonia. Results showed that iron species produced after reduction of the HCl digested red mud were converted into ε-Fe2N during the induction period of ammonia decomposition reaction at 700 °C. The catalytic performance measurements indicated that the modified red mud catalyst provides a record high hydrogen production rate for a non-noble metal catalyst at this temperature. For instance, stable hydrogen production rates were measured as 72 and 196 mmol H2 min−1 gcat−1 for the corresponding space velocities of 72 000 and 240 000 cm3 NH3 h−1 gcat−1, respectively, at 700 °C. These results offer opportunities to utilize one of the key hazardous industrial wastes as an eco-friendly, efficient, stable and almost cost-free catalyst for COx-free hydrogen production from ammonia decomposition.
Mechanism and role of MCP-1 upregulation upon chikungunya virus infection in human peripheral blood mononuclear cells
Authors: Ruiz Silva Mariana , van der Ende-Metselaar Heidi , Mulder H. Lie , Smit Jolanda M. , Rodenhuis-Zybert Izabela A.
Published: August 2016

Monocyte chemoattractant protein-1 (MCP-1/CCL2)-mediated migration of monocytes is essential for immunological surveillance of tissues. During chikungunya virus (CHIKV) infection however, excessive production of MCP-1 has been linked to disease pathogenesis. High MCP-1 serum levels are detected during the viremic phase of CHIKV infection and correlate with the virus titre. In vitro CHIKV infection was also shown to stimulate MCP-1 production in whole blood; yet the role and the mechanism of MCP-1 production upon infection of human peripheral blood mononuclear cells remain unknown. Here we found that active CHIKV infection stimulated production of MCP-1 in monocytes. Importantly however, we found that communication with other leukocytes is crucial to yield MCP-1 by monocytes upon CHIKV infection. Indeed, blocking interferon-α/β receptor or the JAK1/JAK2 signalling downstream of the receptor abolished CHIKV-mediated MCP-1 production. Additionally, we show that despite the apparent correlation between IFN type I, CHIKV replication and MCP-1, modulating the levels of the chemokine did not influence CHIKV infection. In summary, our data disclose the complexity of MCP-1 regulation upon CHIKV infection and point to a crucial role of IFNβ in the chemokine secretion. We propose that balance between these soluble factors is imperative for an appropriate host response to CHIKV infection.
Functionalized HgTe nanoparticles promote laser-induced solid phase ionization/dissociation for comprehensive glycan sequencing
Authors: Primadona Indah , Lai Yin-Hung , Capangpangan Rey Y. , Obena Rofeamor P. , Tseng Mei-Chun , Huang Ming-Feng , Chang Huan-Tsung , Li Shiou-Ting , Wu Chung-Yi , Chien Wei-Ting , Lin Chun-Cheng , Wang Yi-Sheng , Chen Yu-Ju
Published: August 2016

Unambiguous glycan characterization is facilitated by the use of functionalized HgTe nanoparticles.
Discrimination of adulterants in UHT milk samples by NIRS coupled with supervision discrimination techniques
Authors: Luna Aderval S. , Pinho Jéssica S. A. , Machado Luciana C.
Published: August 2016

A methodology was developed for distinguishing different ultra-high temperature (UHT) milk adulterants (water, urea, and formaldehyde) at various levels using NIR spectroscopy (NIRS) coupled with supervision discrimination techniques (SIMCA, SVM-DA, and PLS-DA).
Simultaneous determination of As, Bi, Sb, Se, Sn and Te in lead alloy using flow injection-hydride generation-inductively coupled plasma mass spectrometry
Authors: Soares J. , Nunes M. A. G. , Flores E. M. M. , Paniz J. N. G. , Dressler V. L.
Published: August 2016

A method based on flow injection-hydride generation-inductively coupled plasma mass spectrometry (FI-HG-ICP-MS) for the determination of trace amounts of As, Bi, Sb, Se, Sn and Te in lead alloys was developed.
The fast detection of streptavidin based on the initial reaction rate of the binding-induced DNA strand-displacement reaction
Authors: Li Chenxi , Lin Ruoyun , Li Tian , Liu Feng , Li Na
Published: August 2016

Binding-induced DNA strand-displacement reactions diversify the applications beyond nucleic acids and small molecules.
Naphthalene-fused BODIPY near-infrared dye as a stable contrast agent for in vivo photoacoustic imaging
Authors: Ni Yong , Kannadorai Ravi K. , Peng Juanjuan , Yu Sidney W.-K. , Chang Young-Tae , Wu Jishan
Published: August 2016

Naphthalene-fused BODIPY near infrared dye (Na-BD) was synthesized and used as a stable contrast agent for in vivo photoacoustic imaging.
Iodine-promoted cyclization of N-propynyl amides and N-allyl amides via sulfonylation and sulfenylation
Authors: Senadi Gopal Chandru , Guo Bing-Chun , Hu Wan-Ping , Wang Jeh-Jeng
Published: August 2016

Metal-free synthesis via endo carbon functionalization of N-propynyl/allyl amides with sulfonyl hydrazides to afford sulfonylated oxazoles and sulfenylated oxazolines.
Noble-metal loading reverses temperature dependent photocatalytic hydrogen generation in methanol–water solutions
Authors: Ye Liqun , Chu Ka Him , Wang Bo , Wu Dan , Xie Haiquan , Huang Guocheng , Yip Ho Yin , Wong Po Keung
Published: August 2016

Noble-metal (Pt or Au) loading reverses the temperature dependent photocatalytic activity trends of photocatalytic hydrogen generation in water–methanol solutions.
The role of counter-anions in the kinetics and chirality of porphyrin J-aggregates
Authors: Occhiuto I. G. , Zagami R. , Trapani M. , Bolzonello L. , Romeo A. , Castriciano M. A. , Collini E. , Monsù Scolaro L.
Published: August 2016

The structure-making or breaking abilities of different anions, according to the Hofmeister series, play an important role in controlling the kinetics of growth and the chirality in porphyrin J-aggregates.
A selective and sensitive near-infrared fluorescent probe for acetylcholinesterase imaging
Authors: Chao Sovy , Krejci Eric , Bernard Véronique , Leroy Jacqueline , Jean Ludovic , Renard Pierre-Yves
Published: August 2016

HupNIR2 is the first NIR fluorescent probe for acetylcholinesterase imaging in tissues. This probe penetrates easily and deeply into the tissue, and directly labels AChE.
An air-persistent oxyallyl radical cation with simple di(methyl)amino substituents
Authors: Regnier Vianney , Molton Florian , Philouze Christian , Martin David
Published: August 2016

Despite minimal steric hindrance, the 1,1,3,3-tetrakis(dimethylamino) oxyallyl radical cation is persistent for several hours in well-aerated solutions.
A photoactivatable Znsalen complex for super-resolution imaging of mitochondria in living cells
Authors: Tang Juan , Zhang Mingshu , Yin Hao-Yan , Jing Jing , Xie Da , Xu Pingyong , Zhang Jun-Long
Published: August 2016

We report the first transition metal complex, Znsalen J-S-Alk, as a photoactivatable probe for super-resolution imaging of mitochondria.