bluuebunny/crossref_metadata_2025 huggingface dataset:
Local and systemic immunomodulatory mechanisms triggered by Human Papillomavirus transformed cells: a potential role for G-CSF and neutrophils
Authors: Alvarez Karla Lucia Fernandez , Beldi Mariana , Sarmanho Fabiane , Rossetti Renata Ariza Marques , Silveira Caio Raony Farina , Mota Giana Rabello , Andreoli Maria Antonieta , Caruso Eliana Dias de Carvalho , Kamillos Marcia Ferreira , Souza Ana Marta , Mastrocalla Haydee , Clavijo-Salomon Maria Alejandra , Barbuto José Alexandre Marzagão , Lorenzi Noely Paula , Longatto-Filho Adhemar , Baracat Edmund , Lopez Rossana Verónica Mendoza , Villa Luisa Lina , Tacla Maricy , Lepique Ana Paula
Published: August 2017

Cervical cancer is the last stage of a series of molecular and cellular alterations initiated with Human Papillomavirus (HPV) infection. The process involves immune responses and evasion mechanisms, which culminates with tolerance toward tumor antigens. Our objective was to understand local and systemic changes in the interactions between HPV associated cervical lesions and the immune system as lesions progress to cancer. Locally, we observed higher cervical leukocyte infiltrate, reflected by the increase in the frequency of T lymphocytes, neutrophils and M2 macrophages, in cancer patients. We observed a strong negative correlation between the frequency of neutrophils and T cells in precursor and cancer samples, but not cervicitis. In 3D tumor cell cultures, neutrophils inhibited T cell activity, displayed longer viability and longer CD16 expression half-life than neat neutrophil cultures. Systemically, we observed higher plasma G-CSF concentration, higher frequency of immature low density neutrophils, and tolerogenic monocyte derived dendritic cells, MoDCs, also in cancer patients. Interestingly, there was a negative correlation between T cell activation by MoDCs and G-CSF concentration in the plasma. Our results indicate that neutrophils and G-CSF may be part of the immune escape mechanisms triggered by cervical cancer cells, locally and systemically, respectively.
Establishing PNB-qPCR for quantifying minimal ctDNA concentrations during tumour resection
Authors: Ehlert T. , Tug S. , Brahmer A. , Neef V. , Heid F. , Werner C. , Jansen-Winkeln B. , Kneist W. , Lang H. , Gockel I. , Simon P.
Published: August 2017

The analysis of blood plasma or serum as a non-invasive alternative to tissue biopsies is a much-pursued goal in cancer research. Various methods and approaches have been presented to determine a patient’s tumour status, chances of survival, and response to therapy from serum or plasma samples. We established PNB-qPCR (Pooled, Nested, WT-Blocking qPCR), a highly specific nested qPCR with various modifications to detect and quantify minute amounts of circulating tumour DNA (ctDNA) from very limited blood plasma samples. PNB-qPCR is a nested qPCR technique combining ARMS primers, blocking primers, LNA probes, and pooling of multiple first round products for sensitive quantification of the seven most frequent point mutations in KRAS exon 2. Using this approach, we were able to characterize ctDNA and total cell-free DNA (cfDNA) kinetics by selective amplification of KRAS mutated DNA fragments in the blood plasma over the course of tumour resection and the surrounding days. Whereas total cfDNA concentrations increased over the surgical and regenerative process, ctDNA levels showed a different scheme, rising only directly after tumour resection and about three days after the surgery. For the first time, we present insights into the impact of surgery on the release of ctDNA and total cfDNA.
First-principles study of crystallographic slip modes in ω-Zr
Authors: Kumar Anil , Kumar M. Arul , Beyerlein Irene J.
Published: August 2017

We use first-principles density functional theory to study the preferred modes of slip in the high-pressure ω phase of Zr. The generalized stacking fault energy surfaces associated with shearing on nine distinct crystallographic slip modes in the hexagonal ω-Zr crystal are calculated, from which characteristics such as ideal shear stress, the dislocation Burgers vector, and possible accompanying atomic shuffles, are extracted. Comparison of energy barriers and ideal shear stresses suggests that the favorable modes are prismatic 〈c〉, prismatic-II $$\langle 10\bar{1}0\rangle $$
〈

10

1
¯

0

〉
and pyramidal-II 〈c + a〉, which are distinct from the ground state hexagonal close packed α phase of Zr. Operation of these three modes can accommodate any deformation state. The relative preferences among the identified slip modes are examined using a mean-field crystal plasticity model and comparing the calculated deformation texture with the measurement. Knowledge of the basic crystallographic modes of slip is critical to understanding and analyzing the plastic deformation behavior of ω-Zr or mixed α-ω phase-Zr.
Sensitivity enhancement of flexible gas sensors via conversion of inkjet-printed silver electrodes into porous gold counterparts
Authors: Fang Yunnan , Akbari Mitra , Hester Jimmy G. D. , Sydänheimo Lauri , Ukkonen Leena , Tentzeris Manos M.
Published: August 2017

This work describes a facile, mild and general wet chemical method to change the material and the geometry of inkjet-printed interdigitated electrodes (IDEs) thus drastically enhancing the sensitivity of chemiresistive sensors. A novel layer-by-layer chemical method was developed and used to uniformly deposit semiconducting single-wall carbon nanotube (SWCNT)-based sensing elements on a Kapton® substrate. Flexible chemiresistive sensors were then fabricated by inkjet-printing fine-featured silver IDEs on top of the sensing elements. A mild and facile two-step process was employed to convert the inkjet-printed dense silver IDEs into their highly porous gold counterparts under ambient conditions without losing the IDE-substrate adhesion. A proof-of-concept gas sensor equipped with the resulting porous gold IDEs featured a sensitivity to diethyl ethylphosphonate (DEEP, a simulant of the nerve agent sarin) of at least 5 times higher than a similar sensor equipped with the original dense silver IDEs, which suggested that the electrode material and/or the Schottky contacts between the electrodes and the SWCNTs might have played an important role in the gas sensing process.
Real-time EEG-based brain-computer interface to a virtual avatar enhances cortical involvement in human treadmill walking
Authors: Luu Trieu Phat , Nakagome Sho , He Yongtian , Contreras-Vidal Jose L.
Published: August 2017

Recent advances in non-invasive brain-computer interface (BCI) technologies have shown the feasibility of neural decoding for both users’ gait intent and continuous kinematics. However, the dynamics of cortical involvement in human upright walking with a closed-loop BCI has not been investigated. This study aims to investigate the changes of cortical involvement in human treadmill walking with and without BCI control of a walking avatar. Source localization revealed significant differences in cortical network activity between walking with and without closed-loop BCI control. Our results showed sustained α/µ suppression in the Posterior Parietal Cortex and Inferior Parietal Lobe, indicating increases of cortical involvement during walking with BCI control. We also observed significant increased activity of the Anterior Cingulate Cortex (ACC) in the low frequency band suggesting the presence of a cortical network involved in error monitoring and motor learning. Additionally, the presence of low γ modulations in the ACC and Superior Temporal Gyrus may associate with increases of voluntary control of human gait. This work is a further step toward the development of a novel training paradigm for improving the efficacy of rehabilitation in a top-down approach.
Epidemiological characteristics of hand, foot, and mouth disease in Shandong, China, 2009–2016
Authors: Wang Jing , Hu Tao , Sun Dapeng , Ding Shujun , Carr Michael J. , Xing Weijia , Li Shixue , Wang Xianjun , Shi Weifeng
Published: August 2017

In the past decade, hand, foot, and mouth disease (HFMD) has posed a serious threat to childhood health in China; however, no epidemiological data from large HFMD epidemics have been described since 2013. In the present study, we described the epidemiological patterns of HFMD in Shandong province during 2009–2016 from a large number of symptomatic cases (n = 839,483), including >370,000 HFMD cases since 2013. Our results revealed that HFMD activity has remained at a high level and continued to cause annual epidemics in Shandong province from 2013 onwards. Although the incidence rate was significantly higher in urban areas than in rural areas, no significantly higher case-severity and case-fatality rates were found in urban areas. Furthermore, the seventeen cities of Shandong province could be classified into three distinct epidemiological groups according to the different peak times from southwest (inland) to northeast (coastal) regions. Notably, a replacement of the predominant HFMD circulating agent was seen and non-EVA71/Coxsackievirus A16 enteroviruses became dominant in 2013 and 2015, causing approximately 30% of the severe cases. Our study sheds light on the latest epidemiological characteristics of HFMD in Shandong province and should prove helpful for the prevention and control of the disease in Shandong and elsewhere.
miR-125a, miR-139 and miR-324 contribute to Urocortin protection against myocardial ischemia-reperfusion injury
Authors: Díaz Ignacio , Calderón-Sánchez Eva , Toro Raquel Del , Ávila-Médina Javier , de Rojas-de Pedro Eva Sánchez , Domínguez-Rodríguez Alejandro , Rosado Juan Antonio , Hmadcha Abdelkrim , Ordóñez Antonio , Smani Tarik
Published: August 2017

Urocortin 1 and 2 (Ucn-1 and Ucn-2) have established protective actions against myocardial ischemia-reperfusion (I/R) injuries. However, little is known about their role in posttranscriptional regulation in the process of cardioprotection. Herein, we investigated whether microRNAs play a role in urocortin-induced cardioprotection. Administration of Ucn-1 and Ucn-2 at the beginning of reperfusion significantly restored cardiac function, as evidenced ex vivo in Langendorff-perfused rat hearts and in vivo in rat subjected to I/R. Experiments using microarray and qRT-PCR determined that the addition of Ucn-1 at reperfusion modulated the expression of several miRNAs with unknown role in cardiac protection. Ucn-1 enhanced the expression of miR-125a-3p, miR-324-3p; meanwhile it decreased miR-139-3p. Similarly, intravenous infusion of Ucn-2 in rat model of I/R mimicked the effect of Ucn-1 on miR-324-3p and miR-139-3p. The effect of Ucn-1 involves the activation of corticotropin-releasing factor receptor-2, Epac2 and ERK1/2. Moreover, the overexpression of miR-125a-3p, miR-324-3p and miR-139-3p promoted dysregulation of genes expression involved in cell death and apoptosis (BRCA1, BIM, STAT2), in cAMP and Ca2+ signaling (PDE4a, CASQ1), in cell stress (NFAT5, XBP1, MAP3K12) and in metabolism (CPT2, FoxO1, MTRF1, TAZ). Altogether, these data unveil a novel role of urocortin in myocardial protection, involving posttranscriptional regulation with miRNAs.
Harnessing out-of-plane deformation to design 3D architected lattice metamaterials with tunable Poisson’s ratio
Authors: Li Tiantian , Hu Xiaoyi , Chen Yanyu , Wang Lifeng
Published: August 2017

Auxetic materials exhibiting a negative Poisson’s ratio are of great research interest due to their unusual mechanical responses and a wide range of potential deployment. Efforts have been devoted to exploring novel 2D and 3D auxetic structures through rational design, optimization, and taking inspiration from nature. Here we report a 3D architected lattice system showing a negative Poisson’s ratio over a wide range of applied uniaxial stretch. 3D printing, experimental tests, numerical simulation, and analytical modeling are implemented to quantify the evolution of the Poisson’s ratio and reveal the underlying mechanisms responsible for this unusual behavior. We further show that the auxetic behavior can be controlled by tailoring the geometric features of the ligaments. The findings reported here provide a new routine to design architected metamaterial systems exhibiting unusual properties and having a wide range of potential applications.
Glucocorticoid Receptor-mediated transactivation is hampered by Striatin-3, a novel interaction partner of the receptor
Authors: Petta Ioanna , Bougarne Nadia , Vandewalle Jolien , Dejager Lien , Vandevyver Sofie , Ballegeer Marlies , Desmet Sofie , Thommis Jonathan , De Cauwer Lode , Lievens Sam , Libert Claude , Tavernier Jan , De Bosscher Karolien
Published: August 2017

The transcriptional activity of the glucocorticoid receptor (GR) is co-determined by its ability to recruit a vast and varying number of cofactors. We here identify Striatin-3 (STRN3) as a novel interaction partner of GR that interferes with GR’s ligand-dependent transactivation capacity. Remarkably, STRN3 selectively affects only GR-dependent transactivation and leaves GR-dependent transrepression mechanisms unhampered. We found that STRN3 down-regulates GR transactivation by an additional recruitment of the catalytic subunit of protein phosphatase 2A (PPP2CA) to GR. We hypothesize the existence of a functional trimeric complex in the nucleus, able to dephosphorylate GR at serine 211, a known marker for GR transactivation in a target gene-dependent manner. The presence of STRN3 appears an absolute prerequisite for PPP2CA to engage in a complex with GR. Herein, the C-terminal domain of GR is essential, reflecting ligand-dependency, yet other receptor parts are also needed to create additional contacts with STRN3.
Revisiting optical properties of MgB2 with a high-quality sample prepared by a HPCVD method
Authors: Seo Yu-Seong , Lee Jae Hak , Kang Won Nam , Hwang Jungseek
Published: August 2017

We investigated a high-quality MgB2 thin film with a thickness of ~1000 nm on an Al2O3 substrate using optical spectroscopy. We measured the reflectance spectra of the film at various temperatures both below, and above, the superconducting transition temperature, T
c
 
$$\simeq $$
≃
 40 K. An earlier study showed that when the sample surface is exposed to air the optical properties of the surface change immediately, however, the saturated change is negligibly small in the far-infrared region. The optical conductivity spectrum in the normal state shows two (narrow and broad) Drude modes, with the narrow Drude mode being dominant in the low frequency region below 1000 cm−1. Our study, which uses a good-quality sample, provides more reliable data on the optical properties of MgB2, in a similar spectral range. The optical data is analyzed further using an extended Drude model, and the electron-phonon spectral density function, α2F(ω), is extracted. The spectral density function α2F(ω) features two peaks: a small one near 114 cm−1, and a strong peak around the 550 cm−1 where the B-B bond stretching phonon exists. Our data in the superconducting state does not show the expected energy shift of the onset of scattering associated with the α2F(ω) peaks.
Effect of aortic regurgitant jet direction on mitral valve leaflet remodeling: a real-time three-dimensional transesophageal echocardiography study
Authors: Hirasawa Kensuke , Izumo Masaki , Sasaoka Taro , Ashikaga Takashi , Suzuki Kengo , Harada Tomoo , Isobe Mitsuaki , Akashi Yoshihiro J
Published: August 2017

Chronic aortic regurgitation (AR) induces mitral valve (MV) leaflet enlargement, although, its mechanism still remains unclear. This study aimed to clarify the influence of AR jet directions on the MV apparatus in patients with chronic AR. This study included 69 consecutive patients with severe chronic AR and 17 controls who underwent three-dimensional (3D) transesophageal echocardiography (TEE). The anterior mitral leaflet (AML), posterior mitral leaflet (PML) and MV annulus areas were measured at mid-diastole. All AR patients were classified into the posterior (Group A, n = 38) or non-posterior (Group B, n = 31) group based on the AR jet directions. Both two groups revealed the increased total leaflet areas compared with the controls. No significant differences in the left ventricular volumes, PML or MV annulus area were observed between Group A and B; however, Group A had the larger AML area and greater AML/PML area ratio than Group B (both P < 0.01). The multivariate analysis indicated that the posterior AR jet was independently associated with the AML/PML area (P < 0.01). 3D TEE depicted geometric differences in the MV apparatus between the different types of AR jet directions. These results may be helpful in understanding the mechanism of MV leaflet remodeling in chronic AR.
miRNA-584-3p inhibits gastric cancer progression by repressing Yin Yang 1- facilitated MMP-14 expression
Authors: Zheng Liduan , Chen Yajun , Ye Lin , Jiao Wanju , Song Huajie , Mei Hong , Li Dan , Yang Feng , Li Huanhuan , Huang Kai , Tong Qiangsong
Published: August 2017

Recent evidence shows the emerging roles of promoter-targeting endogenous microRNAs (miRNAs) in regulating gene transcription. However, miRNAs affecting the transcription of matrix metalloproteinase 14 (MMP-14) in gastric cancer remain unknown. Herein, through integrative mining of public datasets, we identified the adjacent targeting sites of Yin Yang 1 (YY1) and miRNA-584-3p (miR-584-3p) within MMP-14 promoter. We demonstrated that YY1 directly targeted the MMP-14 promoter to facilitate its expression in gastric cancer cells. In contrast, miR-584-3p recognized its complementary site within MMP-14 promoter to suppress its expression. Mechanistically, miR-584-3p interacted with Argonaute 2 to recruit enhancer of zeste homolog 2 and euchromatic histone lysine methyltransferase 2, resulting in enrichment of repressive epigenetic markers and decreased binding of YY1 to MMP-14 promoter. miR-584-3p inhibited the in vitro and in vivo tumorigenesis and aggressiveness of gastric cancer cells through repressing YY1-facilitated MMP-14 expression. In clinical gastric cancer tissues, the expression of YY1 and miR-584-3p was positively or negatively correlated with MMP-14 levels. In addition, miR-584-3p and YY1 were independent prognostic factors associated with favorable and unfavorable outcome of gastric cancer patients, respectively. These data demonstrate that miR-584-3p directly targets the MMP-14 promoter to repress YY1-facilitated MMP-14 expression and inhibits the progression of gastric cancer.
Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis
Authors: Srinivasan Sundararajan , Severa Martina , Rizzo Fabiana , Menon Ramesh , Brini Elena , Mechelli Rosella , Martinelli Vittorio , Hertzog Paul , Salvetti Marco , Furlan Roberto , Martino Gianvito , Comi Giancarlo , Coccia Eliana M. , Farina Cinthia
Published: August 2017

Recent evidence indicates that single multiple sclerosis (MS) susceptibility genes involved in interferon (IFN) signaling display altered transcript levels in peripheral blood of untreated MS subjects, suggesting that responsiveness to endogenous IFN is dysregulated during neuroinflammation. To prove this hypothesis we exploited the systematic collection of IFN regulated genes (IRG) provided by the Interferome database and mapped Interferome changes in experimental and human MS. Indeed, central nervous system tissue and encephalitogenic CD4 T cells during experimental autoimmune encephalomyelitis were characterized by massive changes in Interferome transcription. Further, the analysis of almost 500 human blood transcriptomes showed that (i) several IRG changed expression at distinct MS stages with a core of 21 transcripts concordantly dysregulated in all MS forms compared with healthy subjects; (ii) 100 differentially expressed IRG were validated in independent case-control cohorts; and (iii) 53 out of 100 dysregulated IRG were targeted by IFN-beta treatmentin vivo. Finally,ex vivoandin vitroexperiments established that IFN-beta administration modulated expression of two IRG, ARRB1 and CHP1, in immune cells. Our study confirms the impairment of Interferome in experimental and human MS, and describes IRG signatures at distinct disease stages which can represent novel therapeutic targets in MS.
Increased role of E prostanoid receptor-3 in prostacyclin-evoked contractile activity of spontaneously hypertensive rat mesenteric resistance arteries
Authors: Liu Bin , Zhan Mengyi , Zhang Yingzhan , Li Hui , Wu Xiangzhong , Zhuang Fengfeng , Luo Wenhong , Zhou Yingbi
Published: August 2017

This study aimed to determine whether E prostanoid receptor-3 (EP3) is involved in prostacyclin (PGI2)-evoked vasoconstrictor activity of resistance arteries and if so, how it changes under hypertensive conditions. Mesenteric resistance arteries from Wistar-Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) were isolated for functional and biochemical studies. Here we show that in vessels from WKYs, PGI2or the endothelial muscarinic agonist ACh (which stimulatesin vitroPGI2synthesis) evoked vasoconstrictor activity, which increased in SHRs. The thromboxane-prostanoid receptor (TP) antagonist SQ29548 partially removed the vasoconstrictor activity, and an increased contractile activity of PGI2resistant to SQ29548 was observed in SHRs. Interestingly, L798106, an antagonist of EP3 (whose expression was higher in SHRs than in WKYs), not only added to the effect of SQ29548 but also caused relaxation to PGI2more than that obtained with SQ29548. In accordance, EP3 deletion, which reduced PGI2–evoked contraction, together with SQ29548 resulted in relaxation evoked by the agonist in mouse aortas. These results thus demonstrate an explicit involvement of EP3 in PGI2-evoked vasoconstrictor activity in rat mesenteric resistance arteries and suggest that up-regulation of the receptor contributes significantly to the increased contractile activity evoked by PGI2under hypertensive conditions.
Phellodendron chinense Schneid: A novel yellow-emitting luminescent material for white light-emitting diodes
Authors: Lin Pin-Chun , Hsu Kuei-Ting , Shiu Ming-Hsiu , Liu Wei-Ren
Published: August 2017

To facilitate the next generation of environmental material for white light emitting diodes, the discovery of natural luminesce is essential. In this study, we disclose a rare-earth free and yellow-emission phosphor, Phellodendron, which could be both excited by near ultraviolet light and blue light. The new yellow phosphor is obtained by extraction of Phellodendron chinense Schneid. The emission wavelength, full width at half maximum and CIE coordinates of extracted Phellodendron are 540 nm, 120 nm and (0.41, 0.55), respectively. The corresponding luminescent properties of Phellodendron are characterized by PL, PLE, reflection spectra, FITR and decay lifetime. Surprising thing is luminous intensity of Phellodendron phosphors excited at 380 nm was stronger than YAG:Ce phosphor by more than 139%. In addition, we firstly introduce the yellow phosphor in white LED fabrication by combining blue chip and Y3Al5O12:Ce3+ phosphor, to create warm white. For comparison, red-emission CaAlSiN3:Eu2+ phosphors are also introduced for LED package tests. The results demonstrate that Phellodendron is a potential candidate for white LED applications.
A new standard model for milk yield in dairy cows based on udder physiology at the milking-session level
Authors: Gasqui Patrick , Trommenschlager Jean-Marie
Published: August 2017

Milk production in dairy cow udders is a complex and dynamic physiological process that has resisted explanatory modelling thus far. The current standard model, Wood’s model, is empirical in nature, represents yield in daily terms, and was published in 1967. Here, we have developed a dynamic and integrated explanatory model that describes milk yield at the scale of the milking session. Our approach allowed us to formally represent and mathematically relate biological features of known relevance while accounting for stochasticity and conditional elements in the form of explicit hypotheses, which could then be tested and validated using real-life data. Using an explanatory mathematical and biological model to explore a physiological process and pinpoint potential problems (i.e., “problem finding”), it is possible to filter out unimportant variables that can be ignored, retaining only those essential to generating the most realistic model possible. Such modelling efforts are multidisciplinary by necessity. It is also helpful downstream because model results can be compared with observed data, via parameter estimation using maximum likelihood and statistical testing using model residuals. The process in its entirety yields a coherent, robust, and thus repeatable, model.
Improved efficacy and in vivo cellular properties of human embryonic stem cell derivative in a preclinical model of bladder pain syndrome
Authors: Kim Aram , Yu Hwan Yeul , Lim Jisun , Ryu Chae-Min , Kim Yong Hwan , Heo Jinbeom , Han Ju-Young , Lee Seungun , Bae Yoon Sung , Kim Jae Young , Bae Dong-Jun , Kim Sang-Yeob , Noh Byeong-Joo , Hong Ki-Sung , Han Ji-Yeon , Lee Sang Wook , Song Miho , Chung Hyung-Min , Kim Jun Ki , Shin Dong-Myung , Choo Myung-Soo
Published: August 2017

Interstitial cystitis/bladder pain syndrome (IC/BPS) is an intractable disease characterized by severe pelvic pain and urinary frequency. Mesenchymal stem cell (MSC) therapy is a promising approach to treat incurable IC/BPS. Here, we show greater therapeutic efficacy of human embryonic stem cell (hESC)-derived multipotent stem cells (M-MSCs) than adult bone-marrow (BM)-derived counterparts for treating IC/BPS and also monitor long-term safety and in vivo properties of transplanted M-MSCs in living animals. Controlled hESC differentiation and isolation procedures resulted in pure M-MSCs displaying typical MSC behavior. In a hydrochloric-acid instillation-induced IC/BPS animal model, a single local injection of M-MSCs ameliorated bladder symptoms of IC/BPS with superior efficacy compared to BM-derived MSCs in ameliorating bladder voiding function and histological injuries including urothelium denudation, mast-cell infiltration, tissue fibrosis, apoptosis, and visceral hypersensitivity. Little adverse outcomes such as abnormal growth, tumorigenesis, or immune-mediated transplant rejection were observed over 12-months post-injection. Intravital confocal fluorescence imaging tracked the persistence of the transplanted cells over 6-months in living animals. The infused M-MSCs differentiated into multiple cell types and gradually integrated into vascular-like structures. The present study provides the first evidence for improved therapeutic efficacy, long-term safety, and in vivo distribution and cellular properties of hESC derivatives in preclinical models of IC/BPS.
Protein structure shapes immunodominance in the CD4 T cell response to yellow fever vaccination
Authors: Koblischke Maximilian , Mackroth Maria S. , Schwaiger Julia , Fae Ingrid , Fischer Gottfried , Stiasny Karin , Heinz Franz X. , Aberle Judith H.
Published: August 2017

The live attenuated yellow fever (YF) vaccine is a highly effective human vaccine and induces long-term protective neutralizing antibodies directed against the viral envelope protein E. The generation of such antibodies requires the help of CD4 T cells which recognize peptides derived from proteins in virus particles internalized and processed by E-specific B cells. The CD4 T helper cell response is restricted to few immunodominant epitopes, but the mechanisms of their selection are largely unknown. Here, we report that CD4 T cell responses elicited by the YF-17D vaccine are focused to hotspots of two helices of the viral capsid protein and to exposed strands and loops of E. We found that the locations of immunodominant epitopes within three-dimensional protein structures exhibit a high degree of overlap between YF virus and the structurally homologous flavivirus tick-borne encephalitis virus, although amino acid sequence identity of the epitope regions is only 15–45%. The restriction of epitopes to exposed E protein surfaces and their strikingly similar positioning within proteins of distantly related flaviviruses are consistent with a strong influence of protein structure that shapes CD4 T cell responses and provide leads for a rational design of immunogens for vaccination.
Lateralized scale-eating behaviour of cichlid is acquired by learning to use the naturally stronger side
Authors: Takeuchi Yuichi , Oda Yoichi
Published: August 2017

The scale-eating cichlid Perissodus microlepis exhibits significant lateralised predation behaviour using an asymmetric mouth. But how the acquisition of the behavioural laterality depends, if at all, on experience during development remains obscure. Here, naïve juveniles were tested in a series of predation sessions. Initially, they attacked both sides of the prey, but during subsequent sessions, attack direction gradually lateralised to the skewed mouth (dominant) side. Attack side preference of juveniles that had accumulated scale-eating experience during successive sessions was significantly higher than that of naïve juveniles at the same age and naïve adults. Thus, the lateralised behaviour was a learned experience, and did not develop with age. Surprisingly, however, both maximum amplitude and angular velocity of body flexion during attack of naïve fish was dominant on one side. Therefore, scale-eating fish have a naturally stronger side for attacking prey fish, and they learn to use the dominant side through experience.
A Simple Noninvasive Index Can Predict Hepatocellular Carcinoma in Patients with Chronic Hepatitis B
Authors: Zhu Lihui , Li Tao , Ma Xiaomin , Qiu Yumin , Ma Xiaoxiao , Lin Yueke , Han Lihui , Qin Chengyong
Published: August 2017

Screening for possible development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) is essential for risk prediction and early therapy. This study reported a novel model comprised of routine laboratory variables for predicting HCC from CHB. A retrospective study was performed among 463 participants. alpha-fetoprotein (AFP), platelet and alanine aminotransferase (ALT) ratio (APAR) was constructed to differentiate HCC from CHB or non-cancer with area under the receiver operating characteristic curves (AUC) of 0.815 and 0.868 in the training set, 0.831 and 0.861 in the validation set, respectively. In participants with low or normal AFP (<100 ng/mL), the diagnostic efficacy of APAR measured by AUC were 0.817 and 0.809 for predicting HCC from CHB or non-cancer, and at a cutoff of 0.47, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 89%, 60%, 67% and 86%, respectively. For participants with normal AFP (<20 ng/mL), the AUC of APAR were 0.839 and 0.746 accompanied by a cutoff of 0.36 with sensitivity, specificity, PPV, and NPV of 88%, 69%, 71%, and 87%, respectively. In conclusion, APAR is an effective model for HCC screening especially in those with low even normal serum AFP levels.
Excess α-synuclein compromises phagocytosis in iPSC-derived macrophages
Authors: Haenseler Walther , Zambon Federico , Lee Heyne , Vowles Jane , Rinaldi Federica , Duggal Galbha , Houlden Henry , Gwinn Katrina , Wray Selina , Luk Kelvin C. , Wade-Martins Richard , James William S. , Cowley Sally A.
Published: August 2017

To examine the pathogenic role of α-synuclein (αS) in Parkinson’s Disease, we have generated induced Pluripotent Stem Cell lines from early onset Parkinson’s Disease patients with SNCA A53T and SNCA Triplication mutations, and in this study have differentiated them to PSC-macrophages (pMac), which recapitulate many features of their brain-resident cousins, microglia. We show that SNCA Triplication pMac, but not A53T pMac, have significantly increased intracellular αS versus controls and release significantly more αS to the medium. SNCA Triplication pMac, but not A53T pMac, show significantly reduced phagocytosis capability and this can be phenocopied by adding monomeric αS to the cell culture medium of control pMac. Fibrillar αS is taken up by pMac by actin-rearrangement-dependent pathways, and monomeric αS by actin-independent pathways. Finally, pMac degrade αS and this can be arrested by blocking lysosomal and proteasomal pathways. Together, these results show that macrophages are capable of clearing αS, but that high levels of exogenous or endogenous αS compromise this ability, likely a vicious cycle scenario faced by microglia in Parkinson’s disease.
Free energy of a chemotactic model with nonlinear diffusion
Authors: Baek Seung Ki , Kim Beom Jun
Published: August 2017

The Patlak-Keller-Segel equation is a canonical model of chemotaxis to describe self-organized aggregation of organisms interacting with chemical signals. We investigate a variant of this model, assuming that the organisms exert effective pressure proportional to the number density. From the resulting set of partial differential equations, we derive a Lyapunov functional that can also be regarded as the free energy of this model, and minimize it with a Monte Carlo method to detect the condition for self-organized aggregation. Focusing on radially symmetric solutions on a two-dimensional disc, we find that the chemical interaction competes with diffusion so that aggregation occurs when the relative interaction strength exceeds a certain threshold. Based on the analysis of the free-energy landscape, we argue that the transition from a homogeneous state to aggregation is abrupt yet continuous.
Risk Model for Prostate Cancer Using Environmental and Genetic Factors in the Spanish Multi-Case-Control (MCC) Study
Authors: Gómez-Acebo Inés , Dierssen-Sotos Trinidad , Fernandez-Navarro Pablo , Palazuelos Camilo , Moreno Víctor , Aragonés Nuria , Castaño-Vinyals Gemma , Jiménez-Monleón Jose J. , Ruiz-Cerdá Jose Luis , Pérez-Gómez Beatriz , Ruiz-Dominguez José Manuel , Molero Jessica Alonso , Pollán Marina , Kogevinas Manolis , Llorca Javier
Published: August 2017

Prostate cancer (PCa) is the second most common cancer among men worldwide. Its etiology remains largely unknown compared to other common cancers. We have developed a risk stratification model combining environmental factors with family history and genetic susceptibility. 818 PCa cases and 1,006 healthy controls were compared. Subjects were interviewed on major lifestyle factors and family history. Fifty-six PCa susceptibility SNPs were genotyped. Risk models based on logistic regression were developed to combine environmental factors, family history and a genetic risk score. In the whole model, compared with subjects with low risk (reference category, decile 1), those carrying an intermediate risk (decile 5) had a 265% increase in PCa risk (OR = 3.65, 95% CI 2.26 to 5.91). The genetic risk score had an area under the ROC curve (AUROC) of 0.66 (95% CI 0.63 to 0.68). When adding the environmental score and family history to the genetic risk score, the AUROC increased by 0.05, reaching 0.71 (95% CI 0.69 to 0.74). Genetic susceptibility has a stronger risk value of the prediction that modifiable risk factors. While the added value of each SNP is small, the combination of 56 SNPs adds to the predictive ability of the risk model.
Opposite feedback from mTORC1 to H-ras and K-ras4B downstream of SREBP1
Authors: Posada Itziar M. D. , Lectez Benoit , Siddiqui Farid A. , Oetken-Lindholm Christina , Sharma Mukund , Abankwa Daniel
Published: August 2017

As a major growth factor transducer, Ras is an upstream activator of mTORC1, which further integrates nutrient and energy inputs. To ensure a contextual coupling of cell division via Ras/MAPK-signalling and growth via mTORC1-signalling, feedback loops from one pathway back to the other are required. Here we describe a novel feedback from mTORC1, which oppositely affects oncogenic H-ras- and K-ras-signalling output, and as a consequence stemness properties of tumourigenic cells. Amino acid stimulation of mTORC1 increases the processed form of SREBP1, a major lipidome regulator. We show that modulation of the SREBP1 levels downstream of S6K1 has opposite effects on oncogenic H-ras and K-ras nanoscale membrane organisation, ensuing signalling output and promotion of mammospheres expressing these oncogenes. Our data suggest that modulation of phosphatidic acid, a major target of SREBP1 controlled lipid metabolism, is sufficient to affect H-ras and K-ras oppositely in the membrane. Thus mTORC1 activation increases H-ras-, but decreases K-ras-signalling output in cells transformed with the respective oncogene. Given the different impact of these two Ras isoforms on stemness, our results could have implications for stem cell biology and inhibition of cancer stem cells.
Eukaryotic transporters for hydroxyderivatives of benzoic acid
Authors: Cillingová Andrea , Zeman Igor , Tóth Renáta , Neboháčová Martina , Dunčková Ivana , Hölcová Mária , Jakúbková Michaela , Gérecová Gabriela , Pryszcz Leszek P. , Tomáška Ľubomír , Gabaldón Toni , Gácser Attila , Nosek Jozef
Published: August 2017

Several yeast species catabolize hydroxyderivatives of benzoic acid. However, the nature of carriers responsible for transport of these compounds across the plasma membrane is currently unknown. In this study, we analyzed a family of genes coding for permeases belonging to the major facilitator superfamily (MFS) in the pathogenic yeast Candida parapsilosis. Our results revealed that these transporters are functionally equivalent to bacterial aromatic acid: H+ symporters (AAHS) such as GenK, MhbT and PcaK. We demonstrate that the genes HBT1 and HBT2 encoding putative transporters are highly upregulated in C. parapsilosis cells assimilating hydroxybenzoate substrates and the corresponding proteins reside in the plasma membrane. Phenotypic analyses of knockout mutants and hydroxybenzoate uptake assays provide compelling evidence that the permeases Hbt1 and Hbt2 transport the substrates that are metabolized via the gentisate (3-hydroxybenzoate, gentisate) and 3-oxoadipate pathway (4-hydroxybenzoate, 2,4-dihydroxybenzoate and protocatechuate), respectively. Our data support the hypothesis that the carriers belong to the AAHS family of MFS transporters. Phylogenetic analyses revealed that the orthologs of Hbt permeases are widespread in the subphylum Pezizomycotina, but have a sparse distribution among Saccharomycotina lineages. Moreover, these analyses shed additional light on the evolution of biochemical pathways involved in the catabolic degradation of hydroxyaromatic compounds.
Combinatory repair strategy to promote axon regeneration and functional recovery after chronic spinal cord injury
Authors: DePaul Marc A. , Lin Ching-Yi , Silver Jerry , Lee Yu-Shang
Published: August 2017

Eight weeks post contusive spinal cord injury, we built a peripheral nerve graft bridge (PNG) through the cystic cavity and treated the graft/host interface with acidic fibroblast growth factor (aFGF) and chondroitinase ABC (ChABC). This combinatorial strategy remarkably enhanced integration between host astrocytes and graft Schwann cells, allowing for robust growth, especially of catecholaminergic axons, through the graft and back into the distal spinal cord. In the absence of aFGF+ChABC fewer catecholaminergic axons entered the graft, no axons exited, and Schwann cells and astrocytes failed to integrate. In sharp contrast with the acutely bridge-repaired cord, in the chronically repaired cord only low levels of serotonergic axons regenerated into the graft, with no evidence of re-entry back into the spinal cord. The failure of axons to regenerate was strongly correlated with a dramatic increase of SOCS3 expression. While regeneration was more limited overall than at acute stages, our combinatorial strategy in the chronically injured animals prevented a decline in locomotor behavior and bladder physiology outcomes associated with an invasive repair strategy. These results indicate that PNG+aFGF+ChABC treatment of the chronically contused spinal cord can provide a permissive substrate for the regeneration of certain neuronal populations that retain a growth potential over time, and lead to functional improvements.
A Mathematical Model for Storage and Recall of Images using Targeted Synchronization of Coupled Maps
Authors: Palaniyandi P. , Rangarajan Govindan
Published: August 2017

We propose a mathematical model for storage and recall of images using coupled maps. We start by theoretically investigating targeted synchronization in coupled map systems wherein only a desired (partial) subset of the maps is made to synchronize. A simple method is introduced to specify coupling coefficients such that targeted synchronization is ensured. The principle of this method is extended to storage/recall of images using coupled Rulkov maps. The process of adjusting coupling coefficients between Rulkov maps (often used to model neurons) for the purpose of storing a desired image mimics the process of adjusting synaptic strengths between neurons to store memories. Our method uses both synchronisation and synaptic weight modification, as the human brain is thought to do. The stored image can be recalled by providing an initial random pattern to the dynamical system. The storage and recall of the standard image of Lena is explicitly demonstrated.
Effect of disorder on transport properties in a tight-binding model for lead halide perovskites
Authors: Ashhab S. , Voznyy O. , Hoogland S. , Sargent E. H. , Madjet M. E.
Published: August 2017

The hybrid organic-inorganic lead halide perovskite materials have emerged as remarkable materials for photovoltaic applications. Their strengths include good electric transport properties in spite of the disorder inherent in them. Motivated by this observation, we analyze the effects of disorder on the energy eigenstates of a tight-binding model of these materials. In particular, we analyze the spatial extension of the energy eigenstates, which is quantified by the inverse participation ratio. This parameter exhibits a tendency, and possibly a phase transition, to localization as the on-site energy disorder strength is increased. However, we argue that the disorder in the lead halide perovskites corresponds to a point in the regime of highly delocalized states. Our results also suggest that the electronic states of mixed-halide materials tend to be more localized than those of pure materials, which suggests a weaker tendency to form extended bonding states in the mixed-halide materials and is therefore not favourable for halide mixing.
Confinement Effects on Carbon Dioxide Methanation: A Novel Mechanism for Abiotic Methane Formation
Authors: Le Thu , Striolo Alberto , Turner C. Heath , Cole David R.
Published: August 2017

An important scientific debate focuses on the possibility of abiotic synthesis of hydrocarbons during oceanic crust-seawater interactions. While on-site measurements near hydrothermal vents support this possibility, laboratory studies have provided data that are in some cases contradictory. At conditions relevant for sub-surface environments it has been shown that classic thermodynamics favour the production of CO2 from CH4, while abiotic methane synthesis would require the opposite. However, confinement effects are known to alter reaction equilibria. This report shows that indeed thermodynamic equilibrium can be shifted towards methane production, suggesting that thermal hydrocarbon synthesis near hydrothermal vents and deeper in the magma-hydrothermal system is possible. We report reactive ensemble Monte Carlo simulations for the CO2 methanation reaction. We compare the predicted equilibrium composition in the bulk gaseous phase to that expected in the presence of confinement. In the bulk phase we obtain excellent agreement with classic thermodynamic expectations. When the reactants can exchange between bulk and a confined phase our results show strong dependency of the reaction equilibrium conversions, $${{\text{X}}}_{{\bf{C}}{{\bf{O}}}_{{\bf{2}}}}$$

X

C

O

2

, on nanopore size, nanopore chemistry, and nanopore morphology. Some physical conditions that could shift significantly the equilibrium composition of the reactive system with respect to bulk observations are discussed.
Glycerol is synthesized and secreted by adipocytes to dispose of excess glucose, via glycerogenesis and increased acyl-glycerol turnover
Authors: Rotondo Floriana , Ho-Palma Ana Cecilia , Remesar Xavier , Fernández-López José Antonio , Romero María del Mar , Alemany Marià
Published: August 2017

White adipose tissue (WAT) produces large amounts of lactate and glycerol from glucose. We used mature epididymal adipocytes to analyse the relative importance of glycolytic versus lipogenic glycerol in adipocytes devoid of external stimuli. Cells were incubated (24/48 h) with 7/14 mM glucose; half of the wells contained 14C-glucose. We analysed glucose label fate, medium metabolites, and the expression of key genes coding for proteins controlling glycerol metabolism. The effects of initial glucose levels were small, but time of incubation increased cell activity and modified its metabolic focus. The massive efflux of lactate was uniform with time and unrelated to glucose concentration; however, glycerol-3P synthesis was higher in the second day of incubation, being largely incorporated into the glycerides-glycerol fraction. Glycerophosphatase expression was not affected by incubation. The stimulation of glycerogenic enzymes’ expression was mirrored in lipases. The result was a shift from medium glycolytic to lipolytic glycerol released as a consequence of increased triacylglycerol turnover, in which most fatty acids were recycled. Production of glycerol seems to be an important primary function of adipocytes, maintained both by glycerogenesis and acyl-glycerol turnover. Production of 3C fragments may also contribute to convert excess glucose into smaller, more readily usable, 3C metabolites.
Animals can assign novel odours to a known category
Authors: Wright Hannah F. , Wilkinson Anna , Croxton Ruth S. , Graham Deanna K. , Harding Rebecca C. , Hodkinson Hayley L. , Keep Benjamin , Cracknell Nina R. , Zulch Helen E.
Published: August 2017

The ability to identify a novel stimulus as a member of a known category allows an organism to respond appropriately towards it. Categorisation is thus a fundamental component of cognition and an essential tool for processing and responding to unknown stimuli. Therefore, one might expect to observe it throughout the animal kingdom and across sensory domains. There is much evidence of visual categorisation in non-human animals, but we currently know little about this process in other modalities. In this experiment, we investigated categorisation in the olfactory domain. Dogs were trained to discriminate between 40 odours; the presence or absence of accelerants formed the categorical rule. Those in the experimental group were rewarded for responding to substrates with accelerants (either burnt or un-burnt) and inhibit responses to the same substrates (either burnt or un-burnt) without accelerants (S+ counterbalanced). The pseudocategory control group was trained on the same stimuli without the categorical rule. The experimental group learned the discrimination and animals were able to generalise to novel stimuli from the same category. None of the control animals were able to learn the discrimination within the maximum number of trials. This study provides the first evidence that non-human animals can learn to categorise non-biologically relevant odour information.
Turn-on Luminescent Probe for Hydrogen Peroxide Sensing and Imaging in Living Cells based on an Iridium(III) Complex–Silver Nanoparticle Platform
Authors: Liu Jinshui , Dong Zhen-Zhen , Yang Chao , Li Guodong , Wu Chun , Lee Fu-Wa , Leung Chung-Hang , Ma Dik-Lung
Published: August 2017

A sensitive turn-on luminescent sensor for H2O2 based on the silver nanoparticle (AgNP)-mediated quenching of an luminescent Ir(III) complex (Ir-1) has been designed. In the absence of H2O2, the luminescence intensity of Ir-1 can be quenched by AgNPs via non-radiative energy transfer. However, H2O2 can oxidize AgNPs to soluble Ag+ cations, which restores the luminescence of Ir-1. The sensing platform displayed a sensitive response to H2O2 in the range of 0−17 μM, with a detection limit of 0.3 μM. Importantly, the probe was successfully applied to monitor intracellular H2O2 in living cells, and it also showed high selectivity for H2O2 over other interfering substances.