bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of autophagy increases susceptibility of glioblastoma stem cells to temozolomide by igniting ferroptosis
Authors: Buccarelli Mariachiara , Marconi Matteo , Pacioni Simone , De Pascalis Ivana , D’Alessandris Quintino Giorgio , Martini Maurizio , Ascione Barbara , Malorni Walter , Larocca Luigi Maria , Pallini Roberto , Ricci-Vitiani Lucia , Matarrese Paola
Published: August 2018

The role of autophagy in cancer onset and progression appears still controversial. On one hand, autophagy allows cancer cell to survive in unfavorable environmental conditions, on the other hand, once internal energy resources are exhausted, it leads to cell death. In addition, autophagy interpheres with cell cycle progression, de facto exerting a cytostatic activity. Hence, it represents an important target for anticancer therapy. For example, temozolomide (TMZ), of use for glioblastoma (GBM) treatment, appears as capable of inducing autophagy partially inhibiting cancer cell proliferation. However, GBM, a very aggressive brain tumor with poor prognosis even after surgery and radio-chemotherapy, invariably recurs and leads to patient death. Since cancer stem cells have been hypothesized to play a role in refractory/relapsing cancers, in the present work we investigated if autophagy could represent a constitutive cytoprotection mechanism for glioblastoma stem-like cells (GSCs) and if the modulation of autophagic process could affect GBM growth and survival. Thus, in the present study we first evaluated the relevance of autophagy in GBM tumor specimens, then its occurrence in GSCs and, finally, if modulation of autophagy could influence GSC response to TMZ. Our results suggested that, in vitro, the impairing autophagic process with quinacrine, a compound able to cross the blood-brain barrier, increased GSC susceptibility to TMZ. Death of GSCs was apparently due to the iron dependent form of programmed cell death characterized by the accumulation of lipid peroxides called ferroptosis. These results underscore the relevance of the modulation of autophagy in the GSC survival and death and suggest that triggering of ferroptosis in GSCs could represent a novel and important target for the management of glioblastoma.
DBC1 regulates Wnt/β-catenin-mediated expression of MACC1, a key regulator of cancer progression, in colon cancer
Authors: Kim Hwa Jin , Moon Sue Jin , Kim Seok-Hyung , Heo Kyu , Kim Jeong Hoon
Published: August 2018

Metastasis-associated in colon cancer 1 (MACC1) has been reported to be overexpressed in multiple cancers and promote proliferation, metastasis, cancer stem cell-like properties, and drug resistance of cancer cells. Despite its significance and the considerable knowledge accumulated on the function of MACC1 in various types of human malignancies, regulatory mechanisms underlying MACC1 expression remain unclear. Here we report that MACC1 is a direct target of Wnt/β-catenin signaling pathway in colon cancer cells and that DBC1 functions as a coactivator for Wnt-mediated MACC1 expression by promoting the activity of a LEF1/β-catenin-dependent enhancer located in intron 1 of MACC1 gene. DBC1 is required for LEF1/β-catenin complex formation on the MACC1 enhancer and for long-distance enhancer-promoter interaction of the MACC1 locus. MACC1 expression was increased in colonosphere cells compared to adherent colon cancer cells, and DBC1 overexpression further increased MACC1 expression in colonospheres and promoted sphere-forming abilities of colon cancer cells and drug resistance of colonospheres. Importantly, expressions of MACC1 and DBC1 are positively correlated with each other, upregulated in high-risk groups of colorectal cancer patients, and associated with poor survival. Our results establish MACC1 as a transcriptional target of Wnt/β-catenin signaling and suggest that DBC1 plays a key role in colorectal cancer progression through Wnt/β-catenin-MACC1 signaling axis.
Notch3/VEGF-A axis is involved in TAT-mediated proliferation of pulmonary artery smooth muscle cells: Implications for HIV-associated PAH
Authors: Guo Ming-Lei , Kook Yeon Hee , Shannon Callen E. , Buch Shilpa
Published: August 2018

The incidence of pulmonary arterial hypertension (PAH) is a significant co-morbidity observed in HIV (+) individuals. Pulmonary artery smooth muscle cells (PASMCs)—key components of the arterial vessel wall that regulate vessel diameter, demonstrate increased proliferation and hypertrophy in the lungs of HIV infected individuals, underscoring the role of these cells in the pathogenesis of HIV-associated PAH. While several pathways have been implicated in enhanced proliferation of PASMCs, detailed molecular mechanism(s) underlying HIV-associated PASMC proliferation still remain elusive. In the current study, we sought to investigate the effects HIV protein transactivator of transcription (TAT)-mediated proliferation on PASMCs. In agreement with earlier findings, our results also demonstrated TAT-mediated proliferation of human PASMCs. We identified activation of a novel Notch3 signaling pathway in TAT-mediated proliferation of PASMCs. Further validation of the Notch 3 pathway was demonstrated using both pharmacological (γ-secretase inhibitor, DAPT), as well as genetic approaches (Notch3 siRNA). Vascular endothelial growth factor A (VEGF-A) was identified as a novel downstream molecule that was induced following Notch activation. Findings from in vitro studies were further validated in archived simian immunodeficiency virus (SIV)-infected monkey lung tissues. There was increased activation of Notch3 signaling as well as enhanced expression of VEGF-A in the lungs of SIV-infected macaques compared with the lungs of SIV(−) controls. Taken together, we demonstrated that HIV-TAT increased the proliferation of PASMCs via the Notch3/VEGF-A axis. Targeting the Notch3/VEGF-A axis could thus be considered a potential therapeutic approach for the treatment of HIV-associated PAH.
Notch3-dependent β-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC
Authors: Arasada Rajeswara Rao , Shilo Konstantin , Yamada Tadaaki , Zhang Jianying , Yano Seiji , Ghanem Rashelle , Wang Walter , Takeuchi Shinji , Fukuda Koji , Katakami Nobuyuki , Tomii Keisuke , Ogushi Fumitaka , Nishioka Yasuhiko , Talabere Tiffany , Misra Shrilekha , Duan Wenrui , Fadda Paolo , Rahman Mohammad A. , Nana-Sinkam Patrick , Evans Jason , Amann Joseph , Tchekneva Elena E. , Dikov Mikhail M. , Carbone David P.
Published: August 2018

EGFR tyrosine kinase inhibitors cause dramatic responses in EGFR-mutant lung cancer, but resistance universally develops. The involvement of β-catenin in EGFR TKI resistance has been previously reported, however, the precise mechanism by which β-catenin activation contributes to EGFR TKI resistance is not clear. Here, we show that EGFR inhibition results in the activation of β-catenin signaling in a Notch3-dependent manner, which facilitates the survival of a subset of cells that we call “adaptive persisters”. We previously reported that EGFR-TKI treatment rapidly activates Notch3, and here we describe the physical association of Notch3 with β-catenin, leading to increased stability and activation of β-catenin. We demonstrate that the combination of EGFR-TKI and a β-catenin inhibitor inhibits the development of these adaptive persisters, decreases tumor burden, improves recurrence free survival, and overall survival in xenograft models. These results supports combined EGFR-TKI and β-catenin inhibition in patients with EGFR mutant lung cancer.
Fossil lemurs from Egypt and Kenya suggest an African origin for Madagascar’s aye-aye
Authors: Gunnell Gregg F. , Boyer Doug M. , Friscia Anthony R. , Heritage Steven , Manthi Fredrick Kyalo , Miller Ellen R. , Sallam Hesham M. , Simmons Nancy B. , Stevens Nancy J. , Seiffert Erik R.
Published: August 2018

In 1967 G.G. Simpson described three partial mandibles from early Miocene deposits in Kenya that he interpreted as belonging to a new strepsirrhine primate, Propotto. This interpretation was quickly challenged, with the assertion that Propotto was not a primate, but rather a pteropodid fruit bat. The latter interpretation has not been questioned for almost half a century. Here we re-evaluate the affinities of Propotto, drawing upon diverse lines of evidence to establish that this strange mammal is a strepsirrhine primate as originally suggested by Simpson. Moreover, our phylogenetic analyses support the recognition of Propotto, together with late Eocene Plesiopithecus from Egypt, as African stem chiromyiform lemurs that are exclusively related to the extant aye-aye (Daubentonia) from Madagascar. Our results challenge the long-held view that all lemurs are descended from a single ancient colonization of Madagascar, and present an intriguing alternative scenario in which two lemur lineages dispersed from Africa to Madagascar independently, possibly during the later Cenozoic.
Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma
Authors: Chen Huihui , Cho Kin-Sang , Vu T. H. Khanh , Shen Ching-Hung , Kaur Mandeep , Chen Guochun , Mathew Rose , McHam M. Lisa , Fazelat Ahad , Lashkari Kameran , Au Ngan Pan Bennett , Tse Joyce Ka Yu , Li Yingqian , Yu Honghua , Yang Lanbo , Stein-Streilein Joan , Ma Chi Him Eddie , Woolf Clifford J. , Whary Mark T. , Jager Martine J. , Fox James G. , Chen Jianzhu , Chen Dong F.
Published: August 2018

Glaucoma is the most prevalent neurodegenerative disease and a leading cause of blindness worldwide. The mechanisms causing glaucomatous neurodegeneration are not fully understood. Here we show, using mice deficient in T and/or B cells and adoptive cell transfer, that transient elevation of intraocular pressure (IOP) is sufficient to induce T-cell infiltration into the retina. This T-cell infiltration leads to a prolonged phase of retinal ganglion cell degeneration that persists after IOP returns to a normal level. Heat shock proteins (HSP) are identified as target antigens of T-cell responses in glaucomatous mice and human glaucoma patients. Furthermore, retina-infiltrating T cells cross-react with human and bacterial HSPs; mice raised in the absence of commensal microflora do not develop glaucomatous T-cell responses or the associated neurodegeneration. These results provide compelling evidence that glaucomatous neurodegeneration is mediated in part by T cells that are pre-sensitized by exposure to commensal microflora.
Growth tradeoffs produce complex microbial communities on a single limiting resource
Authors: Manhart Michael , Shakhnovich Eugene I.
Published: August 2018

The relationship between the dynamics of a community and its constituent pairwise interactions is a fundamental problem in ecology. Higher-order ecological effects beyond pairwise interactions may be key to complex ecosystems, but mechanisms to produce these effects remain poorly understood. Here we model microbial growth and competition to show that higher-order effects can arise from variation in multiple microbial growth traits, such as lag times and growth rates, on a single limiting resource with no other interactions. These effects produce a range of ecological phenomena: an unlimited number of strains can exhibit multistability and neutral coexistence, potentially with a single keystone strain; strains that coexist in pairs do not coexist all together; and a strain that wins all pairwise competitions can go extinct in a mixed competition. Since variation in multiple growth traits is ubiquitous in microbial populations, our results indicate these higher-order effects may also be widespread, especially in laboratory ecology and evolution experiments.
A balance between aerodynamic and olfactory performance during flight in Drosophila
Authors: Li Chengyu , Dong Haibo , Zhao Kai
Published: August 2018

The ability to track odor plumes to their source (food, mate, etc.) is key to the survival of many insects. During this odor-guided navigation, flapping wings could actively draw odorants to the antennae to enhance olfactory sensitivity, but it is unclear if improving olfactory function comes at a cost to aerodynamic performance. Here, we computationally quantify the odor plume features around a fruit fly in forward flight and confirm that the antenna is well positioned to receive a significant increase of odor mass flux (peak 1.8 times), induced by wing flapping, vertically from below the body but not horizontally. This anisotropic odor spatial sampling may have important implications for behavior and the algorithm during plume tracking. Further analysis also suggests that, because both aerodynamic and olfactory functions are indispensable during odor-guided navigation, the wing shape and size may be a balance between the two functions.
Nuclear-resident RIG-I senses viral replication inducing antiviral immunity
Authors: Liu GuanQun , Lu Yao , Thulasi Raman Sathya N. , Xu Fang , Wu Qi , Li Zhubing , Brownlie Robert , Liu Qiang , Zhou Yan
Published: August 2018

The nucleus represents a cellular compartment where the discrimination of self from non-self nucleic acids is vital. While emerging evidence establishes a nuclear non-self DNA sensing paradigm, the nuclear sensing of non-self RNA, such as that from nuclear-replicating RNA viruses, remains unexplored. Here, we report the identification of nuclear-resident RIG-I actively involved in nuclear viral RNA sensing. The nuclear RIG-I, along with its cytoplasmic counterpart, senses influenza A virus (IAV) nuclear replication leading to a cooperative induction of type I interferon response. Its activation signals through the canonical signaling axis and establishes an effective antiviral state restricting IAV replication. The exclusive signaling specificity conferred by nuclear RIG-I is reinforced by its inability to sense cytoplasmic-replicating Sendai virus and appreciable sensing of hepatitis B virus pregenomic RNA in the nucleus. These results refine the RNA sensing paradigm for nuclear-replicating viruses and reveal a previously unrecognized subcellular milieu for RIG-I-like receptor sensing.
Elongator mutation in mice induces neurodegeneration and ataxia-like behavior
Authors: Kojic Marija , Gaik Monika , Kiska Bence , Salerno-Kochan Anna , Hunt Sarah , Tedoldi Angelo , Mureev Sergey , Jones Alun , Whittle Belinda , Genovesi Laura A. , Adolphe Christelle , Brown Darren L. , Stow Jennifer L. , Alexandrov Kirill , Sah Pankaj , Glatt Sebastian , Wainwright Brandon J.
Published: August 2018

Cerebellar ataxias are severe neurodegenerative disorders with an early onset and progressive and inexorable course of the disease. Here, we report a single point mutation in the gene encoding Elongator complex subunit 6 causing Purkinje neuron degeneration and an ataxia-like phenotype in the mutant wobbly mouse. This mutation destabilizes the complex and compromises its function in translation regulation, leading to protein misfolding, proteotoxic stress, and eventual neuronal death. In addition, we show that substantial microgliosis is triggered by the NLRP3 inflammasome pathway in the cerebellum and that blocking NLRP3 function in vivo significantly delays neuronal degeneration and the onset of ataxia in mutant animals. Our data provide a mechanistic insight into the pathophysiology of a cerebellar ataxia caused by an Elongator mutation, substantiating the increasing body of evidence that alterations of this complex are broadly implicated in the onset of a number of diverse neurological disorders.
Publisher Correction: The photoelastic coefficient $${P}_{12}$$ of H+ implanted GaAs as a function of defect density
Authors: Baydin Andrey , Krzyzanowska Halina , Gatamov Rustam , Garnett Joy , Tolk Norman
Published: August 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.
Isocorroles as Homoaromatic NIR-Absorbing Chromophores: A First Quantum Chemical Study
Authors: Foroutan-Nejad Cina , Larsen Simon , Conradie Jeanet , Ghosh Abhik
Published: August 2018

Density functional theory calculations of magnetically induced current densities have revealed high diatropic ring currents in unsubstituted isocorrole consistent with homoaromatic character. An examination of the Kohn-Sham molecular orbitals showed clear evidence of homoconjugative interactions in four occupied π-type molecular orbitals as well as in the LUMO. Remarkably, substituents at the saturated meso position were found to exert a dramatic influence on the overall current density pattern. Thus, whereas bis(trimethylsilyl)-substitution strongly enhanced the peripheral diatropic current (consistent with enhanced homoaromaticity), difluoro-substitution engendered a strong, net paratropic current (consistent with antihomoaromaticity). In this respect, isocorroles stand in sharp contrast to benzenoid aromatics, for which substituents typically exert a small influence on the current density distribution.
Enzyme-modified non-oxidized LDL (ELDL) induces human coronary artery smooth muscle cell transformation to a migratory and osteoblast-like phenotype
Authors: Chellan Bijoy , Rojas Elizabeth , Zhang Chunling , Hofmann Bowman Marion A.
Published: August 2018

Enzyme modified non-oxidative LDL (ELDL) is effectively taken up by vascular smooth muscle cells (SMC) and mediates transition into foam cells and produces phenotypic changes in SMC function. Our data show that incubation of human coronary artery SMC (HCASMC) with low concentration of ELDL (10 μg/ml) results in significantly enhanced foam cell formation compared to oxidized LDL (200 μg/ml; p < 0.01) or native LDL (200 μg/ml; p < 0.01). Bioinformatic network analysis identified activation of p38 MAPK, NFkB, ERK as top canonical pathways relevant for biological processes linked to cell migration and osteoblastic differentiation in ELDL-treated cells. Functional studies confirmed increased migration of HCASMC upon stimulation with ELDL (10 μg/ml) or Angiopoietin like protein 4, (ANGPTL4, 5 μg/ml), and gain in osteoblastic gene profile with significant increase in mRNA levels for DMP-1, ALPL, RUNX2, OPN/SPP1, osterix/SP7, BMP and reduction in mRNA for MGP and ENPP1. Enhanced calcification of HCASMC by ELDL was demonstrated by Alizarin Red staining. In summary, ELDL is highly potent in inducing foam cells in HCASMC and mediates a phenotypic switch with enhanced migration and osteoblastic gene profile. These results point to the potential of ELDL to induce migratory and osteoblastic effects in human smooth muscle cells with potential implications for migration and calcification of SMCs in human atherosclerosis.
Millennial soil retention of terrestrial organic matter deposited in the Bengal Fan
Authors: French Katherine L. , Hein Christopher J. , Haghipour Negar , Wacker Lukas , Kudrass Hermann R. , Eglinton Timothy I. , Galy Valier
Published: August 2018

The abundance of organic carbon (OC) in vegetation and soils (~2,600 PgC) compared to carbon in the atmosphere (~830 PgC) highlights the importance of terrestrial OC in global carbon budgets. The residence time of OC in continental reservoirs, which sets the rates of carbon exchange between land and atmosphere, represents a key uncertainty in global carbon cycle dynamics. Retention of terrestrial OC can also distort bulk OC- and biomarker-based paleorecords, yet continental storage timescales remain poorly quantified. Using “bomb” radiocarbon (14C) from thermonuclear weapons testing as a tracer, we model leaf-wax fatty acid and bulk OC 14C signatures in a river-proximal marine sediment core from the Bay of Bengal in order to constrain OC storage timescales within the Ganges-Brahmaputra (G-B) watershed. Our model shows that 79–83% of the leaf-waxes in this core were stored in continental reservoirs for an average of 1,000–1,200 calendar years, while the remainder was stored for an average of 15 years. This age structure distorts high-resolution organic paleorecords across geologically rapid events, highlighting that compound-specific proxy approaches must consider storage timescales. Furthermore, these results show that future environmental change could destabilize large stores of old - yet reactive - OC currently stored in tropical basins.
Rapid and reversible impairment of episodic memory by a high-fat diet in mice
Authors: McLean Fiona H. , Grant Christine , Morris Amanda C. , Horgan Graham W. , Polanski Alex J. , Allan Kevin , Campbell Fiona M. , Langston Rosamund F. , Williams Lynda M.
Published: August 2018

Alzheimer’s disease is a leading cause of morbidity and mortality with no cure and only limited treatment available. Obesity and type 2 diabetes are positively associated with the development of premature cognitive decline and Alzheimer’s disease, linking diet with these conditions. Here we demonstrate that in mice episodic memory, together with spatial and contextual associative memory, is compromised after only one day of high-fat diet. However, object memory remains intact. This shows not only a more rapid effect than previously reported but also that more complex memories are at higher risk of being compromised by a high-fat diet. In addition, we show that these memory deficits are rapidly reversed by switching mice from a high-fat diet back to a low-fat diet. These findings have important implications for the contribution of nutrition to the development of cognitive decline and Alzheimer’s disease.
Effect of patterned polyacrylamide hydrogel on morphology and orientation of cultured NRVMs
Authors: Sanzari I. , Humphrey E. J. , Dinelli F. , Terracciano C. M. , Prodromakis T.
Published: August 2018

We recently demonstrated that patterned Parylene C films could be effectively used as a mask for directly copolymerizing proteins on polyacrylamide hydrogel (PAm). In this work, we have proved the applicability of this technique for studying the effect such platforms render on neonatal rat ventricular myocytes (NRVMs). Firstly, we have characterised topographically and mechanically the scaffolds in liquid at the nano-scale level. We thus establish that such platforms have physical properties that closely mimics thein vivoextracellular environment of cells. We have then studied the cell morphology and physiology by comparing cultures on flat uniformly-covered and collagen-patterned scaffolds. We show that micro-patterns promote the elongation of cells along the principal axis of the ridges coated with collagen. In several cases, cells also tend to create bridges across the grooves. We have finally studied cell contraction, monitoring Ca2+cycling at a certain stimulation. Cells seeded on patterned scaffolds present significant responses in comparison to the isotropic ones.
Hypoalbuminemia as a predictor of acute kidney injury during colistin treatment
Authors: Giacobbe Daniele Roberto , di Masi Alessandra , Leboffe Loris , Del Bono Valerio , Rossi Marianna , Cappiello Dario , Coppo Erika , Marchese Anna , Casulli Annarita , Signori Alessio , Novelli Andrea , Perrone Katja , Principe Luigi , Bandera Alessandra , Vender Luca Enrico , Misin Andrea , Occhilupo Pierpaolo , Melone Marcello , Ascenzi Paolo , Gori Andrea , Luzzati Roberto , Viscoli Claudio , Di Bella Stefano
Published: August 2018

This study aimed to assess the predictors of acute kidney injury (AKI) during colistin therapy in a cohort of patients with bloodstream infections (BSI) due to colistin-susceptible Gram-negative bacteria, focusing on the role of serum albumin levels. The study consisted of two parts: (1) a multicentre retrospective clinical study to assess the predictors of AKI during colistin therapy, defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria; and (2) bioinformatic and biochemical characterization of the possible interaction between human serum albumin and colistin. Among the 170 patients included in the study, 71 (42%), 35 (21%), and 11 (6%) developed KDIGO stage 1 (K1-AKI), KDIGO stage 2 (K2-AKI), and KDIGO stage 3 (K3-AKI), respectively. In multivariable analyses, serum albumin <2.5 g/dL was independently associated with K1-AKI (subdistribution hazard ratio [sHR] 1.85, 95% confidence interval [CI] 1.17–2.93, p = 0.009) and K2-AKI (sHR 2.37, 95% CI 1.15–4.87, p = 0.019). Bioinformatic and biochemical analyses provided additional information nurturing the discussion on how hypoalbuminemia favors development of AKI during colistin therapy. In conclusion, severe hypoalbuminemia independently predicted AKI during colistin therapy in a large cohort of patients with BSI due to colistin-susceptible Gram-negative bacteria. Further study is needed to clarify the underlying causal pathways.
Cortical signatures of wakeful somatosensory processing
Authors: Song Chenchen , Piscopo Denise M. , Niell Cristopher M. , Knöpfel Thomas
Published: August 2018

Sensory inputs carry critical information for the survival of an organism. In mice, tactile information conveyed by the whiskers is of high behavioural relevance, and is broadcasted across cortical areas beyond the primary somatosensory cortex. Mesoscopic voltage sensitive dye imaging (VSDI) of cortical population response to whisker stimulations has shown that seemingly ‘simple’ sensory stimuli can have extended impact on cortical circuit dynamics. Here we took advantage of genetically encoded voltage indicators (GEVIs) that allow for cell type-specific monitoring of population voltage dynamics in a chronic dual-hemisphere transcranial windowed mouse preparation to directly compare the cortex-wide broadcasting of sensory information in wakening (lightly anesthetized to sedated) and awake mice. Somatosensory-evoked cortex-wide dynamics is altered across brain states, with anatomically sequential hyperpolarising activity observed in the awake cortex. GEVI imaging revealed cortical activity maps with increased specificity, high spatial coverage, and at the timescale of cortical information processing.
Niche dissociated assembly drives insular lizard community organization
Authors: Harikrishnan Surendran , Vasudevan Karthikeyan
Published: August 2018

Interspecific competition for resources leading to niche partitioning is considered as one of the major drivers of community assembly. Competitive niche partitioning is diagnosed from species co-occurrence, species abundance distributions (SADs), and body size distributions of species. For several decades, studies have explored these patterns for the relative significance of interspecific competition in shaping communities. We explored these patterns in a finite assemblage of insectivorous lizards in the Andaman & Nicobar Islands, both at the level of archipelago and individual islands. Negative geographic co-occurrences occurred only between species pairs in islands separated by deep ocean channels. Ecologically similar species did not show positive co-occurrence in guild co-occurrence analyses, indicating that the negative geographical co-occurrences between species in islands were due to historical allopatry. Species abundance distribution was best explained by a Pareto distribution in both metacommunity and local communities. There was no predictable spacing of body sizes among co-existing species in local communities. The empirical data on insular lizard community on species co-occurrence, SADs, and body size ratios does not lend support to assortment of species in islands caused by niche subdivision. Such niche-dissociated assembly of species in islands might be an important factor in formation of biological communities, regardless of geographic scale.
Temperature-dependent excitonic superfluid plasma frequency evolution in an excitonic insulator, Ta2NiSe5
Authors: Seo Yu-Seong , Eom Man Jin , Kim Jun Sung , Kang Chang-Jong , Min Byung Il , Hwang Jungseek
Published: August 2018

An interesting van der Waals material, Ta2NiSe5 has been known one of strong excitonic insulator candidates since it has very small or zero bandgap and can have a strong exciton binding energy because of its quasi-one-dimensional crystal structure. Here we investigate a single crystal Ta2NiSe5 using optical spectroscopy. Ta2NiSe5 has quasi-one-dimensional chains along the a-axis. We have obtained anisotropic optical properties of a single crystal Ta2NiSe5 along the a- and c-axes. The measured a- and c-axis optical conductivities exhibit large anisotropic electronic and phononic properties. With regard to the a-axis optical conductivity, a sharp peak near 3050 cm−1 at 9 K, with a well-defined optical gap ($${{\boldsymbol{\Delta }}}_{{\boldsymbol{o}}{\boldsymbol{p}}}^{{\boldsymbol{E}}{\boldsymbol{I}}}\,{\boldsymbol{\simeq }}$$ΔopEI≃ 1800 cm−1) and a strong temperature-dependence, is observed. With an increase in temperature, this peak broadens and the optical energy gap closes around ∼325 K ($${{\boldsymbol{T}}}_{{\boldsymbol{c}}}^{{\boldsymbol{E}}{\boldsymbol{I}}}$$TcEI). The spectral weight redistribution with respect to the frequency and temperature indicates that the normalized optical energy gap $$({{\boldsymbol{\Delta }}}_{{\boldsymbol{o}}{\boldsymbol{p}}}^{{\boldsymbol{E}}{\boldsymbol{I}}}({\boldsymbol{T}})/\,{{\boldsymbol{\Delta }}}_{{\boldsymbol{o}}{\boldsymbol{p}}}^{{\boldsymbol{E}}{\boldsymbol{I}}}{\bf{(0)}})$$(ΔopEI(T)/ΔopEI(0)) is $${\bf{1}}{\boldsymbol{-}}{({\boldsymbol{T}}/{{\boldsymbol{T}}}_{{\boldsymbol{c}}}^{{\boldsymbol{E}}{\boldsymbol{I}}})}^{{\bf{2}}}$$1−(T/TcEI)2. The temperature-dependent superfluid plasma frequency of the excitonic condensation in Ta2NiSe5 has been determined from measured optical data. Our study may pave new avenues in the future research on excitonic insulators.
Computer-Guided Surface Engineering for Enzyme Improvement
Authors: Wilding Matthew , Scott Colin , Warden Andrew C.
Published: August 2018

Protein engineering strategies are often guided by our understanding of how the structure of a protein determines its function. However, our understanding is generally restricted to small regions of a protein, namely the active site and its immediate vicinity, while the remainder of the protein is something of an enigma. Studying highly homologous transaminases with strictly conserved active sites, but different substrate preferences and activities, we predict and experimentally validate that the surface of the protein far from the active site carries out a decisive role in substrate selectivity and catalytic efficiency. Using a unique molecular dynamics approach and novel trajectory analysis, we demonstrate the phenomenon of surface-directed ligand diffusion in this well-known protein family for the first time. Further, we identify the residues involved in directing substrate, design surface channel variants endowed for improved kinetic properties and establish a broadly applicable new approach for protein engineering.
Gemcitabine treatment promotes immunosuppressive microenvironment in pancreatic tumors by supporting the infiltration, growth, and polarization of macrophages
Authors: Deshmukh Sachin Kumar , Tyagi Nikhil , Khan Mohammad Aslam , Srivastava Sanjeev Kumar , Al-Ghadhban Ahmed , Dugger Kari , Carter James Elliot , Singh Seema , Singh Ajay Pratap
Published: August 2018

Chemotherapy-induced immunosuppression poses an additional challenge to its limited efficacy in pancreatic cancer (PC). Here we investigated the effect of gemcitabine on macrophages, which are the first line of immune-defense mechanisms. We observed an increased presence of macrophages in orthotopic human pancreatic tumor xenografts from mice treated with gemcitabine as compared to those from vehicle only-treated mice. Conditioned media from gemcitabine-treated PC cells (Gem-CM) promoted growth, migration and invasion of RAW264.7 macrophage. In addition, Gem-CM also induced upregulation of M2-polarized macrophage markers, arginase-1 and TGF-β1. Cytokine profiling of gemcitabine-treated PC cells identified IL-8 as the most differentially-expressed cytokine. Incubation of Gem-CM with IL-8 neutralizing antibody diminished its ability to induce growth, migration and invasion of RAW264.7 macrophages, but did not abrogate their M2 polarization. Together, our findings identify IL-8 as an important mediator in the gemcitabine-induced infiltration of macrophages within the pancreatic tumor microenvironment and suggest the requirement of additional mechanism(s) for macrophage polarization.
Autophagy upregulation as a possible mechanism of arsenic induced diabetes
Authors: Zeinvand-Lorestani Marzieh , Kalantari Heibatullah , Khodayar Mohammad Javad , Teimoori Ali , Saki Najmaldin , Ahangarpour Akram , Rahim Fakher , Alboghobeish Soheila
Published: August 2018

The key features of type 2 diabetes mellitus (T2DM) caused by high fat diet (HFD) in combination with arsenic (As) exposure (pronounced glucose intolerance despite a significant decrease in insulin resistance) are different from those expected for T2DM. Autophagy has been considered as a possible link between insulin resistance and obesity. Therefore in this study, we utilized autophagy gene expression profiling via real-time RT-PCR array analysis in livers of NMRI mice exposed to an environmentally relevant and minimally cytotoxic concentration of arsenite (50 ppm) in drinking water while being fed with a HFD for 20 weeks. Out of 84 genes associated with autophagy under study, 21 genes were related to autophagy machinery components of which 13 genes were downregulated when HDF diet was applied. In this study, for the first time, it was shown that the exposure to arsenic in the livers of mice chronically fed with HFD along with increased oxidative stress resulted in the restoration of autophagy [upregulation of genes involved in the early phase of phagophore formation, phagophore expansion and autophagosome-lysosome linkage stages]. Considering the role of arsenic in the induction of autophagy; it can be argued that reduced insulin resistance in HFD − As induced diabetes may be mediated by autophagy upregulation.
Biological significance and prognostic relevance of peripheral blood neutrophil-to-lymphocyte ratio in soft tissue sarcoma
Authors: Chan Jason Yongsheng , Zhang Zewen , Chew Winston , Tan Grace Fangmin , Lim Chloe Liwen , Zhou Lingyue , Goh Wei Lin , Poon Eileen , Somasundaram Nagavalli , Selvarajan Sathiyamoorthy , Sittampalam Kesavan , Chin Francis , Teh Jonathan , Tan Mann Hong , Soo Khee Chee , Teo Melissa , Farid Mohamad , Quek Richard
Published: August 2018

Peripheral blood indices of systemic inflammation such as the neutrophil-lymphocyte ratio (NLR) have been shown to be prognostic in various cancers. We aim to investigate the clinical significance of these indices in patients with soft tissue sarcoma (STS). Seven hundred and twelve patients with available blood counts at diagnosis and/or metastatic relapse were retrospectively examined. An optimal cutoff for NLR-high (>2.5) in predicting overall survival (OS) was determined using receiver operating curve analyses. Survival analyses were performed using the Kaplan-Meier method and multivariate Cox proportional models. Our results show that NLR was significantly higher in patients with distant metastasis at diagnosis (n = 183) compared to those without (n = 529) (median: 4.36 vs 2.85,p < 0.0001). Progression of localized disease at diagnosis to metastatic relapse within the same patients was associated with an interval increase in NLR (median: 3.21 vs 3.74,p = 0.0003). In multivariate analysis, NLR-high was the only consistent factor independently associated with both worse OS (HR 1.53, 95% CI 1.10–2.13,p = 0.0112) and relapse-free survival (HR 1.41, 95% CI 1.08–1.85,p = 0.0125) in localized disease, as well as OS (HR 1.82, 95% CI 1.16–2.85,p = 0.0087) in metastatic/unresectable disease. In conclusion, high NLR is an independent marker of poor prognosis among patients with STS.
Comparison of Radial Artery Occlusion Following Transradial Access for Percutaneous Coronary Intervention Using Sheath-based versus Sheathless Technique
Authors: Mohsen Ala , Alqasrawi Musab , Shantha Ghanshyam Palamaner Subash , DeZorzi Chris , Panaich Sidakpal
Published: August 2018

We compared the risk of radial artery occlusion (RAO) in patients undergoing coronary intervention with introducer sheath (SG) or without introducer sheath (SLG). 1251 consecutive patients, from 2 tertiary care center in Pennsylvania, USA, undergoing percutaneous coronary interventions (PCI) between 2008–2013 formed the study cohort (SLG: 161 patients, SG: 1090 patients). Radial artery patency was assessed using plethysmography. The association between sheath use and RAO was assessed using unadjusted, adjusted and propensity macthed logistic regression analyses. Mean age: 65 years, men: 63%, diabetics: 37%. SG was associated with lower RAO at band removal [unadjusted (OR: 0.31, 95% CI: 0.21–0.46), adjusted (OR: 0.10, 95% CI: 0.05–0.20) and propensity matched (OR: 0.20, 95% CI: 0.13–0.32)], at 24 hours [unadjusted (OR: 0.20, 95% CI: 0.12–0.34), adjusted (OR: 0.12, 95% CI: 0.06–0.24) and propensity matched (OR: 0.13, 95% CI: 0.07–0.25)] and 30 days [unadjusted (OR: 0.28, 95% CI: 0.14–0.54), adjusted (OR: 0.22, 95% CI: 0.10–0.50) and propensity matched (OR: 0.18, 95% CI: 0.10–0.40)], compared to SLG. Sheath use during radial access for PCI is associated with less RAO. It is unclear if use of introducer sheath during radial access for PCI reduces incidence of RAO. In this prospective cohort study involving 1251 concecutive patients undergoing PCI via radial access between 2008–2013, we assessed the difference in incidence of RAO between the SG (n = 1090) and the SLG (n = 161 patients) groups. SG group experienced lower incidence of RAO at band removal, 24 hours and 30 days post PCI in the unadjusted, adjusted, and propensity matched analyses compared to the SLG group. In conclusion sheath use during radial access for PCI is associated with less RAO.
Impact of Body Mass Index on Oncological Outcomes of Prostate Cancer Patients after Radical Prostatectomy
Authors: Yu Young Dong , Byun Seok-Soo , Lee Sang Eun , Hong Sung Kyu
Published: August 2018

Obesity, often represented by higher body mass index (BMI), is not yet fully understood as a potential risk factor for poor clinical outcomes of prostate cancer (PCa) after radical prostatectomy (RP). This study aimed to evaluate the relationship between BMI and biochemical recurrence (BCR)-free survival in RP patients. This study retrospectively reviewed a total of 2.997 PCa patients who underwent RP between 2006 and 2017. The patients were stratified into three BMI groups according to the WHO recommendations for Asian men: normal weight (<23 kg/m2), overweight (≥23 to <27.5 kg/m2) and obese (≥27.5 kg/m2). Multivariable logistic regression analyses were undertaken to evaluate the factors influencing the BCR rates including BMI. Multivariable Cox regression analyses and Kaplan-Meier analyses were performed to test the association of obesity with BCR-free survival. The final pathologic results showed obese patients had greater positive surgical margin rates (13.9%, p < 0.001), extraprostatic invasion (19.9%, p < 0.001), advanced pathological Gleason score (GS) ≥ 8 (50.8%, p = 0.017), and lymph node invasion (LNI) (14.5%, p = 0.021) than overweight and normal weight patients. According to Kaplan-Meier analyses, obese patients, especially with BMI ≥ 27.5, were more likely to have lower BCR-free-survival. Multivariate Cox analysis revealed that diabetes mellitus, LNI status, pT, pathologic GS, extraprostatic invasion, margin positivity and obesity with BMI ≥ 27.5 kg/m2 were significantly associated with BCR-free survival after RP. Obesity (higher BMI) was significantly associated with BCR after RP. BMI ≥ 27.5 kg/m2 was an independent predictor of BCR-free survival.
Fast Na ion transport triggered by rapid ion exchange on local length scales
Authors: Lunghammer S. , Prutsch D. , Breuer S. , Rettenwander D. , Hanzu I. , Ma Q. , Tietz F. , Wilkening H. M. R.
Published: August 2018

The realization of green and economically friendly energy storage systems needs materials with outstanding properties. Future batteries based on Na as an abundant element take advantage of non-flammable ceramic electrolytes with very high conductivities. Na3Zr2(SiO4)2PO4-type superionic conductors are expected to pave the way for inherently safe and sustainable all-solid-state batteries. So far, only little information has been extracted from spectroscopic measurements to clarify the origins of fast ionic hopping on the atomic length scale. Here we combined broadband conductivity spectroscopy and nuclear magnetic resonance (NMR) relaxation to study Na ion dynamics from the µm to the angstrom length scale. Spin-lattice relaxation NMR revealed a very fast Na ion exchange process in Na3.4Sc0.4Zr1.6(SiO4)2PO4 that is characterized by an unprecedentedly high self-diffusion coefficient of 9 × 10−12 m2s−1 at −10 °C. Thus, well below ambient temperature the Na ions have access to elementary diffusion processes with a mean residence time τNMR of only 2 ns. The underlying asymmetric diffusion-induced NMR rate peak and the corresponding conductivity isotherms measured in the MHz range reveal correlated ionic motion. Obviously, local but extremely rapid Na+ jumps, involving especially the transition sites in Sc-NZSP, trigger long-range ion transport and push ionic conductivity up to 2 mS/cm at room temperature.
IPL-M1 interaction shapes pre-reflective social differentiation in the human action system: new insights from TBS and TMS combined
Authors: Ticini Luca F. , Dolk Thomas , Waszak Florian , Schütz-Bosbach Simone
Published: August 2018

The conscious experience of being the author of our own actions is thought to be grounded in pre-reflective and low-level sensorimotor representations of the self as different from the other. It has been suggested that the inferior parietal lobe (IPL) is generally involved in self-other differentiation processes and in providing an explicit sense of action authorship. However, direct evidence for its causal and functional role in distinguishing self-related and other-related sensorimotor representations is lacking. The current study employed theta-burst stimulation (TBS) to condition left IPL’s activity before a social version of the rubber hand illusion led participants to illusorily attribute observed finger movements to their own body. We recorded motor evoked potentials to single-pulse transcranial magnetic stimulation over the primary motor cortex (M1) as proxies of action authorship during action observation. The results showed that in a control condition (intermediate TBS over the left IPL) others’ actions facilitated whereas self-attributed movements inhibited the motor system. Critically, continuous TBS disrupted this mismatch between self and other representations. This outcome provides direct evidence for the IPL’s role in providing fundamental authorship signals for social differentiation in the human action system.
Dye-functionalized Sol-gel Matrix on Carbon Nanotubes for Refreshable and Flexible Gas Sensors
Authors: Kim Jeongsu , Yoo Haneul , Pham Ba Viet Anh , Shin Narae , Hong Seunghun
Published: August 2018

We report a colorimetric dye-functionalized sol-gel matrix on carbon nanotubes for use as a refreshable and flexible gas sensor with humidity calibration. Here, we fabricated gas sensors by functionalizing dye molecules on the top of carbon nanotube networks via a sol-gel method. Using hybrid gas sensors with different dye molecules, we could selectively detect various hazardous gases, such as NH3, Cl2 and SO2 gases, via optical and electrical signals. The sensors exhibited rather large conductance changes of more than 50% following exposure to gas species with concentrations even under the permissible exposure limit. Significantly, we could refresh used gas sensors by simply exposing them to fresh N2 gas without any heat treatment. Additionally, our sensors can be bent to form versatile practical sensor devices, such as tube-shape sensors for ventilation tubes. This work shows a simple but powerful method for building refreshable and selective gas sensors for versatile industrial and academic applications.
The Springtime Influence of Natural Tropical Pacific Variability on the Surface Climate of the Ross Ice Shelf, West Antarctica: Implications for Ice Shelf Thinning
Authors: Clem Kyle R. , Orr Andrew , Pope James O.
Published: August 2018

Observational records starting in the 1950s show West Antarctica is amongst the most rapidly warming regions on the planet. Together with increased intrusions of warm circumpolar deep water (CDW) onto the continental shelf due to local wind forcing (the primary mechanism in recent decades), this has resulted in enhanced surface and basal melting of floating ice shelves and an associated acceleration and thinning of West Antarctic outlet glaciers, increasing the rate of global sea level rise. In this study, it is shown that during the austral spring season, significant surface warming across West Antarctica has shifted westward to the Ross Ice Shelf in recent decades in response to enhanced cyclonic circulation over the Ross Sea. These circulation changes are caused by a Rossby wave train forced by increasing sea surface temperatures in the western tropical Pacific, which is tied to the springtime shift of the Interdecadal Pacific Oscillation (IPO) to its negative phase after 1992. While the local wind trends enhance warm air advection and surface warming across the Ross Ice Shelf, the strong easterly component of the wind trends reduces the likelihood for intrusions of CDW onto the continental shelf in this region. This suggests that during spring there are competing mechanisms of surface and basal melting of the Ross Ice Shelf, both of which are closely tied to natural tropical Pacific decadal variability. Moreover, that the projected transition of the IPO back to its positive phase in the coming decade, though likely to reduce surface warming on the Ross Ice Shelf, could increase the risk of disintegration of Ross Sea ice shelves due to increased intrusions of CDW and enhanced basal melting.
Associative plasticity in supplementary motor area - motor cortex pathways in Tourette syndrome
Authors: Tübing Jennifer , Gigla Bettina , Brandt Valerie Cathérine , Verrel Julius , Weissbach Anne , Beste Christian , Münchau Alexander , Bäumer Tobias
Published: August 2018

The important role of the supplementary motor area (SMA) in the generation of tics and urges in Gilles de la Tourette syndrome (GTS) is underscored by an increased SMA-motor cortex (M1) connectivity. However, whether plasticity is also altered in SMA-M1 pathways is unclear. We explored whether SMA-M1 plasticity is altered in patients with Tourette syndrome. 15 patients with GTS (mean age of 33.4 years, SD = 9.9) and 19 age and sex matched healthy controls were investigated with a paired association stimulation (PAS) protocol using three transcranial magnetic stimulation (TMS) coils stimulating both M1 and the SMA. Standard clinical measures for GTS symptoms were collected. There was a significant PAS effect showing that MEP amplitudes measured in blocks during and after PAS were significantly higher compared to those in the first block. However, the degree of PAS was not differentially modulated between patients and controls as shown by a Bayesian data analysis. PAS effects in GTS correlated positively with the YGTSS motor tic severity. Plasticity previously reported to be altered in sensorimotor pathways in GTS is normal in SMA-M1 projections suggesting that the dysfunction of the SMA in GTS is not primarily related to altered plasticity in SMA-M1 connections.