bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel cancer vaccine with the ability to simultaneously produce anti-PD-1 antibody and GM-CSF in cancer cells and enhance Th1-biased antitumor immunity
Authors: Tian Hongwei , Shi Gang , Wang Qin , Li Yiming , Yang Qianmei , Li Chunlei , Yang Guoyou , Wu Min , Xie Qian , Zhang Shuang , Yang Yang , Xiang Rong , Yu Dechao , Wei Yuquan , Deng Hongxin
Published: December 2016

Tumor escape from immune-mediated destruction has been associated with immunosuppressive mechanisms that inhibit T-cell activation. A promising strategy for cancer immunotherapy is to disrupt key pathways regulating immune tolerance, such as program death-1 (PD-1/PD-L1) pathway in the tumor environment. However, the determinants of response to anti-PD-1 monoclonal antibodies (mAbs) treatment remain incompletely understood. In murine models, PD-1 blockade alone fails to induce effective immune responses to poorly immunogenic tumors, but is successful when combined with additional interventions, such as cancer vaccines. Novel cancer vaccines combined with antibody may offer promising control of cancer development and progression. In this investigation, we generated a novel tumor cell vaccine simultaneously expressing anti-PD-1 mAbs and granulocyte-macrophage colony stimulating factor (GM-CSF) in CT26 colon cancer and B16-F10 melanoma. The antitumor effect of the vaccine was verified by therapeutic and adoptive animal experiments in vivo. The antitumor mechanism was analyzed using Flow cytometry, Elispot and in vivo intervention approaches. The results showed that tumor cell vaccine secreting PD-1 neutralizing antibodies and GM-CSF induced remarkable antitumor immune effects and prolonged the survival of tumor-bearing animals compared with animals treated with either PD-1 mAbs or GM-CSF alone. Antitumor effects and prolonged survival correlated with strong antigen-specific T-cell responses by analyzing CD11c+CD86+ DC, CD11b+F4/80+ MΦ cells, increased ratio of Teff/Treg in the tumor microenvironment, and higher secretion levels of Th1 proinflammatory cytokines in serum. Furthermore, the results of ELISPOT and in vivo blocking strategies further confirmed that the antitumor immune response is acquired by CD4 and CD8 T immune responses, primarily dependent on CD4 Th1 immune response, not NK innate immune response. The combination of PD-1 blockade with GM-CSF secretion potency creates a novel tumor cell vaccine immunotherapy, affording significantly improved antitumor responses by releasing the state of immunosuppressive microenvironment and augmenting the tumor-reactive T-cell responses.
Compressive Sensing with Optical Chaos
Authors: Rontani D. , Choi D. , Chang C.-Y. , Locquet A. , Citrin D. S.
Published: December 2016

Compressive sensing (CS) is a technique to sample a sparse signal below the Nyquist-Shannon limit, yet still enabling its reconstruction. As such, CS permits an extremely parsimonious way to store and transmit large and important classes of signals and images that would be far more data intensive should they be sampled following the prescription of the Nyquist-Shannon theorem. CS has found applications as diverse as seismology and biomedical imaging. In this work, we use actual optical signals generated from temporal intensity chaos from external-cavity semiconductor lasers (ECSL) to construct the sensing matrix that is employed to compress a sparse signal. The chaotic time series produced having their relevant dynamics on the 100 ps timescale, our results open the way to ultrahigh-speed compression of sparse signals.
SAG/RBX2 E3 ligase complexes with UBCH10 and UBE2S E2s to ubiquitylate β-TrCP1 via K11-linkage for degradation
Authors: Kuang Peng , Tan Mingjia , Zhou Weihua , Zhang Qiang , Sun Yi
Published: December 2016

SAG/RBX2 and RBX1 are two family members of RING components of Cullin-RING ligases (CRLs), required for their enzymatic activity. Previous studies showed that SAG prefers to bind with CUL5, as well as CUL1, whereas RBX1 binds exclusively to CULs1–4. Detailed biochemical difference between SAG and RBX1, and whether SAG mediates cross-talk between CRL5 and CRL1 are previously unknown. Here we report that the levels of SAG and β-TrCP1 are inversely correlated, and SAG-CUL5-βTrCP1 forms a complex under physiological condition. SAG-CUL5, but not RBX1-CUL1, negatively modulates β-TrCP1 levels by shortening its protein half-life through promoting its ubiquitylation via atypical K11-linkage. Consistently, chemical inducers of SAG reduced β-TrCP1 level. Furthermore, SAG mainly binds to E2s UBCH10 and UBE2S known to mediate K11 linkage of ubiquitin, whereas RBX1 exclusively binds to E2s CDC34 and UBCH5C, known to mediate K48 linkage of ubiquitin. Finally, silencing of either UBCH10 or UBE2S, but not UBCH5C, caused accumulation of endogenous β-TrCP1, suggesting that β-TrCP1 is a physiological substrate of SAG-UBCH10C/UBE2S. Our study, for the first time, differentiates SAG and RBX1 biochemically via their respective binding to different E2s; and shows a negative cross-talk between CRL5 and CRL1 through SAG mediated ubiquitylation of β-TrCP1.
An updated dose–response meta-analysis of coffee consumption and liver cancer risk
Authors: Yu Chengbo , Cao Qing , Chen Ping , Yang Shigui , Deng Min , Wang Yugang , Li Lanjuan
Published: December 2016

Prospective cohort studies of the relationship between coffee consumption and liver cancer risk have drawn different conclusions. Therefore, a dose-response meta-analysis of prospective cohort studies was performed to disentangle this causal relationship. Prospective cohort studies of the association between coffee consumption and liver cancer risk published prior to Jan 9, 2016 were identified by searching in the PubMed and EMBASE databases. Extracted data were analyzed using a random-effects model. Of the 2892 records identified using the search strategy, a total of twenty cohort studies from ten publications were included in the final meta-analysis. The pooled estimate of relative risk (RR) with 95% confidence interval (CI) for highest vs. non/occasional coffee drinkers was 0.55(0.44–0.67). No evidence of publication bias was observed (p for Egger’s test = 0.229). Sensitivity analysis indicated the results were robust. Dose-response analysis revealed a significant linear dose-response relationship between coffee consumption and liver cancer risk (p = 0.36). Subgroup analyses stratified by pre-specified variables (gender, geographic region, and adjusted factors) indicated similar results within individual subgroups. Our meta-analysis suggested that coffee consumption is inversely associated with liver cancer risk.
Auditory evoked potential could reflect emotional sensitivity and impulsivity
Authors: Kim Ji Sun , Kim Sungkean , Jung Wookyoung , Im Chang-Hwan , Lee Seung-Hwan
Published: December 2016

Emotional sensitivity and impulsivity could cause interpersonal conflicts and neuropsychiatric problems. Serotonin is correlated with behavioral inhibition and impulsivity. This study evaluated whether the loudness dependence of auditory evoked potential (LDAEP), a potential biological marker of central serotonergic activity, could reflect emotional sensitivity and impulsivity. A total of 157 healthy individuals were recruited, who performed LDAEP and Go/Nogo paradigms during electroencephalogram measurement. Barratt impulsivity scale (BIS), Conners’ Adult ADHD rating scale (CAARS), and affective lability scale (ALS) were evaluated. Comparison between low and high LDAEP groups was conducted for behavioural, psychological, and event-related potential (ERP) measures. The high LDAEP group showed significantly increased BIS, a subscale of the CAARS, ALS, and false alarm rate of Nogo stimuli compared to the low LDAEP group. LDAEP showed significant positive correlations with the depression scale, ALS scores, subscale of the CAARS and Nogo-P3 amplitude. In the source activity of Nogo-P3, the cuneus, lingual gyrus, and precentral gyrus activities were significantly increased in the high LDAEP group. Our study revealed that LDAEP could reflect emotional sensitivity and impulsivity. LDAEP, an auditory evoked potential could be a useful tool to evaluate emotional regulation.
Antinociceptive Profile of Levo-tetrahydropalmatine in Acute and Chronic Pain Mice Models: Role of spinal sigma-1 receptor
Authors: Kang Dong-Wook , Moon Ji-Young , Choi Jae-Gyun , Kang Suk-Yun , Ryu Yeonhee , Park Jin Bong , Lee Jang-Hern , Kim Hyun-Woo
Published: December 2016

We have recently reported that repeated systemic treatments of extract from Corydalis yanhusuo alleviate neuropathic pain and levo-tetrahydropalmatine (l-THP) is one of active components from Corydalis. We designed this study to investigate antinociceptive effect of l-THP in acute and chronic pain models and related mechanism within the spinal cord. We found that intraperitoneal pretreatment with l-THP significantly inhibited the second phase of formalin-induced pain behavior. In addition, intrathecal as well as intraperitoneal pretreatment with l-THP reduced the mechanical allodynia (MA) induced by direct activation of sigma-1 receptor (Sig-1). In chronic constriction injury mice, these treatments remarkably suppressed the increase in MA and spinal phosphorylation of the NMDA receptor NR1 subunit expression on day 7 after surgery. Intrathecal treatment with l-THP combined with the Sig-1R antagonist, BD1047 synergistically blocked MA suggesting that l-THP modulates spinal Sig-1R activation. CatWalk gait analysis also supported that antinociceptive effect of l-THP as demonstrated by restoration of percentages of print area and single stance. Meanwhile, intrathecal pretreatment with naloxone, non-selective opioid receptor antagonist, did not affect the effect of l-THP. In conclusion, these results demonstrate that l-THP possesses antinociceptive effects through spinal Sig-1R mechanism and may be a useful analgesic in the management of neuropathic pain.
Noncontact and Wide-Field Characterization of the Absorption and Scattering Properties of Apple Fruit Using Spatial-Frequency Domain Imaging
Authors: Hu Dong , Fu Xiaping , He Xueming , Ying Yibin
Published: December 2016

Spatial-frequency domain imaging (SFDI), as a noncontact, low-cost and wide-field optical imaging technique, offers great potential for agro-product safety and quality assessment through optical absorption (μa) and scattering (μ"Equation missing") property measurements. In this study, a laboratory-based SFDI system was constructed and developed for optical property measurement of fruits and vegetables. The system utilized a digital light projector to generate structured, periodic light patterns and illuminate test samples. The diffuse reflected light was captured by a charge coupled device (CCD) camera with the resolution of 1280 × 960 pixels. Three wavelengths (460, 527, and 630 nm) were selected for image acquisition using bandpass filters in the system. The μa and μ"Equation missing" were calculated in a region of interest (ROI, 200 × 300 pixels) via nonlinear least-square fitting. Performance of the system was demonstrated through optical property measurement of ‘Redstar’ apples. Results showed that the system was able to acquire spatial-frequency domain images for demodulation and calculation of the μa and μ"Equation missing". The calculated μa of apple tissue experiencing internal browning (IB) were much higher than healthy apple tissue, indicating that the SFDI technique had potential for IB tissue characterization.
Renin–angiotensin–aldosterone system gene polymorphisms in gestational hypertension and preeclampsia: A case–control gene-association study
Authors: Li Xun , Tan Hongzhuan , Zhou Shujin , Hu Shimin , Zhang Tianyi , Li Yangfen , Dou Qianru , Lai Zhiwei , Chen Fenglei
Published: December 2016

Pregnancy-induced hypertension (PIH, including preeclampsia [PE] and gestational hypertension [GH]) and cardiovascular diseases (CVDs) have some metabolic changes and risk factors in common. Many studies have reported associations between single nucleotide polymorphisms (SNPs) of renin–angiotensin–aldosterone system (RAAS) genes and CVDs (particularly hypertension), and their findings have provided candidate SNPs for research on genetic correlates of PIH. We explored the association between hypertension-related RAAS SNPs and PIH in a Chinese population. A total of 130 cases with PE, 67 cases with GH, and 316 controls were recruited. Six candidate SNPs of the RAAS system were selected. Multiple logistic regression analysis adjusting for maternal age, fetal sex, and gestational diabetes mellitus showed significant associations between angiotensinogen (AGT) rs3789678 T/C and GH (p = 0.0088) and between angiotensin II receptor type 1 (AGTR1) rs275645 G/A and PE (p = 0.0082). The study population was further stratified by maternal age (<30 and ≥30 years), and stratified and crossover analyses were conducted to determine genetic associations in different age groups. Our findings suggest that the impacts of different SNPs might be affected by maternal age; however, the effect of this potential gene–age interaction on PIH needs further exploration.
Hyperthermia enhances 17-DMAG efficacy in hepatocellular carcinoma cells with aggravated DNA damage and impaired G2/M transition
Authors: Huang Zhizhou , Zhou Xueqiong , He Yangfan , Ke Xiangyu , Wen Ying , Zou Fei , Chen Xuemei
Published: December 2016

Due to the lack of effective treatment, hepatocellular carcinoma (HCC) is one of the malignancies with low survival rates worldwide. Combination of hyperthermia and chemotherapy has shown promising results in several abdominal tumours, but high expression of HSP90 in tumours attenuated the efficacy of hyperthermia. Thus a combination of hyperthermia and inhibition of HSP90 might be a feasible therapeutic strategy for HCC. One hepatic cell line (L02) and two HCC cell lines (Huh7 and HepG2) were heated at 42 °C for 0, 0.5 or 4 h with or without 100 nM 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). HCC cells of the combination group exhibited more G2/M arrest and higher apoptotic rates which might result from suffering from more reactive oxygen species and serious DNA damage. Heat shock/17-DMAG co-treatment of HCC cells also destabilized CDK1, Cyclin B1 and CDC25C with a concomitant decreased proportion of cells in the M phase. Furthermore, co-treatment impaired the interaction of HSP90α with CDC37 and with CDK1, accompanied with decreased soluble CDK1. Combination of 17-DMAG with a 1.5-h whole body hyperthermia treatment attenuated tumour growth in xenograft mice models. These results suggest hyperthermia sensitize HCC to 17-DMAG, and combination of hyperthermia with 17-DMAG might be a potential therapeutic strategy for HCC.
J-curve relation between daytime nap duration and type 2 diabetes or metabolic syndrome: A dose-response meta-analysis
Authors: Yamada Tomohide , Shojima Nobuhiro , Yamauchi Toshimasa , Kadowaki Takashi
Published: December 2016

Adequate sleep is important for good health, but it is not always easy to achieve because of social factors. Daytime napping is widely prevalent around the world. We performed a meta-analysis to investigate the association between napping (or excessive daytime sleepiness: EDS) and the risk of type 2 diabetes or metabolic syndrome, and to quantify the potential dose-response relation using cubic spline models. Electronic databases were searched for articles published up to 2016, with 288,883 Asian and Western subjects. Pooled analysis revealed that a long nap (≥60 min/day) and EDS were each significantly associated with an increased risk of type 2 diabetes versus no nap or no EDS (odds ratio 1.46 (95% CI 1.23–1.74, p < 0.01) for a long nap and 2.00 (1.58–2.53) for EDS). In contrast, a short nap (<60 min/day) was not associated with diabetes (p = 0.75). Dose-response meta-analysis showed a J-curve relation between nap time and the risk of diabetes or metabolic syndrome, with no effect of napping up to about 40 minutes/day, followed by a sharp increase in risk at longer nap times. In summary, longer napping is associated with an increased risk of metabolic disease. Further studies are needed to confirm the benefit of a short nap.
Transmission of Multiple HIV-1 Subtype C Transmitted/founder Viruses into the Same Recipients Was not Determined by Modest Phenotypic Differences
Authors: Song Hongshuo , Hora Bhavna , Giorgi Elena E. , Kumar Amit , Cai Fangping , Bhattacharya Tanmoy , Perelson Alan S. , Gao Feng
Published: December 2016

A severe bottleneck exists during HIV-1 mucosal transmission. However, viral properties that determine HIV-1 transmissibility are not fully elucidated. We identified multiple transmitted/founder (T/F) viruses in six HIV-1-infected subjects by analyzing whole genome sequences. Comparison of biological phenotypes of different T/F viruses from the same individual allowed us to more precisely identify critical determinants for viral transmissibility since they were transmitted under similar conditions. All T/F viruses used coreceptor CCR5, while no T/F viruses used CXCR4 or GPR15. However, the efficiency for different T/F viruses from the same individual to use CCR5 was significantly variable, and the differences were even more significant for usage of coreceptors FPRL1, CCR3 and APJ. Resistance to IFN-α was also different between T/F viruses in 2 of 3 individuals. The relative fitness between T/F viruses from the same subject was highly variable (2–6%). Importantly, the levels of coreceptor usage efficiency, resistance to IFN-α and viral fitness were not associated with proportions of T/F viruses in each individual during acute infection. Our results show that the modest but significant differences in coreceptor usage efficiency, IFN-α sensitivity and viral fitness each alone may not play a critical role in HIV-1 transmission.
Intracellular mechanisms of solar water disinfection
Authors: Castro-Alférez María , Polo-López María Inmaculada , Fernández-Ibáñez Pilar
Published: December 2016

Solar water disinfection (SODIS) is a zero-cost intervention measure to disinfect drinking water in areas of poor access to improved water sources, used by more than 6 million people in the world. The bactericidal action of solar radiation in water has been widely proven, nevertheless the causes for this remain still unclear. Scientific literature points out that generation of reactive oxygen species (ROS) inside microorganisms promoted by solar light absorption is the main reason. For the first time, this work reports on the experimental measurement of accumulated intracellular ROS in E. coli during solar irradiation. For this experimental achievement, a modified protocol based on the fluorescent probe dichlorodihydrofluorescein diacetate (DCFH-DA), widely used for oxidative stress in eukaryotic cells, has been tested and validated for E. coli. Our results demonstrate that ROS and their accumulated oxidative damages at intracellular level are key in solar water disinfection.
Lignin-AuNPs liquid marble for remotely-controllable detection of Pb2+
Authors: Han Guocheng , Wang Xiaoying , Hamel Jonathan , Zhu Hongli , Sun Runcang
Published: December 2016

This work reported the green and facile fabrication of a versatile lignin-AuNP composite, which was readily and remotely encapsulated to form novel liquid marbles. The marbles can stay suspended in water, and show excellent photothermal conversion properties, as well as visual detection and adsorption towards Pb2+. More importantly, the marbles can simultaneously remotely detect and adsorb Pb2+ via co-precipitation by simply controlling the near infrared (NIR) irradiation. It is believed that the remotely-controllable NIR-responsive lignin-AuNPs liquid marble can be used in Pb2+-related reactions. The liquid marble can be placed in the system at the very beginning of the reaction and stably stays on the surface until the reaction has ended. After reacting, upon remote NIR irradiation, the liquid marble bursts to adsorb Pb2+, and the residual Pb2+ can be collected. This facile manipulation strategy does not use complicated nanostructures or sophisticated equipment, so it has potential applications for channel-free microfluidics, smart microreactors, microengines, and so on.
Adjuvant radiotherapy for locally advanced upper tract urothelial carcinoma
Authors: Huang Yun-Ching , Chang Ying-Hsu , Chiu Kuo-Hsiung , Shindel Alan W. , Lai Chia-Hsuan
Published: December 2016

There is relatively little literature on adjuvant radiotherapy after radical nephroureterectomy with bladder cuff excision (RNU) for patients with upper tract urothelial carcinoma (UTUC). This study was designed to determine the efficacy of adjuvant radiotherapy for patients with pT3N0M0 UTUC. We retrospectively reviewed 198 patients treated with RNU between December 2001 and January 2015. Postoperative radiotherapy was administered in 40 (20.2%) of patients. Patients who received radiotherapy were younger than those that did not (65.2 vs. 70.5 years, p = 0.023). With median follow up of 29.1 months, Kaplan-Meier analysis with the log-rank test demonstrated no significant differences between those omitting vs receiving adjuvant radiotherapy in regards to 2-year rates of overall survival (72.0% vs. 73.4%, p = 0.979), cancer-specific survival (73.2% vs. 75.3%, p = 0.844), and recurrence-free survival (61.2% vs. 66.3%, p = 0.742). However, in multivariable analysis with Cox regression, young age, absence of chronic kidney disease, negative lymphovascular invasion, negative surgical margin, and adjuvant chemotherapy were also associated with better cancer-specific survival. In conclusion, adjuvant radiotherapy did not offer any significant benefit in terms of overall, cancer-specific, and recurrence-free survivals in patients with pT3N0M0 UTUC after RNU. More effective systemic adjuvant chemotherapy is necessary to improve the outcome of these patients.
Improved bi-allelic modification of a transcriptionally silent locus in patient-derived iPSC by Cas9 nickase
Authors: Eggenschwiler Reto , Moslem Mohsen , Fráguas Mariane Serra , Galla Melanie , Papp Oliver , Naujock Maximilian , Fonfara Ines , Gensch Ingrid , Wähner Annabell , Beh-Pajooh Abbas , Mussolino Claudio , Tauscher Marcel , Steinemann Doris , Wegner Florian , Petri Susanne , Schambach Axel , Charpentier Emmanuelle , Cathomen Toni , Cantz Tobias
Published: December 2016

Homology directed repair (HDR)-based genome editing via selectable long flanking arm donors can be hampered by local transgene silencing at transcriptionally silent loci. Here, we report efficient bi-allelic modification of a silent locus in patient-derived hiPSC by using Cas9 nickase and a silencing-resistant donor construct that contains an excisable selection/counter-selection cassette. To identify the most active single guide RNA (sgRNA)/nickase combinations, we employed a lentiviral vector-based reporter assay to determine the HDR efficiencies in cella. Next, we used the most efficient pair of sgRNAs for targeted integration of an improved, silencing-resistant plasmid donor harboring a piggyBac-flanked puroΔtk cassette. Moreover, we took advantage of a dual-fluorescence selection strategy for bi-allelic targeting and achieved 100% counter-selection efficiency after bi-allelic excision of the selection/counter-selection cassette. Together,
we present an improved system for efficient bi-allelic modification of transcriptionally silent loci in human pluripotent stem cells.
Three millennia of heavy rainfalls in Western Mediterranean: frequency, seasonality and atmospheric drivers
Authors: Corella J. P. , Valero-Garcés B. L. , Vicente- Serrano S. M. , Brauer A. , Benito G.
Published: December 2016

Documenting subdecadal-scale heavy rainfall (HR) variability over several millennia can rarely be accomplished due to the paucity of high resolution, homogeneous and continuous proxy records. Here, using a unique, seasonally resolved lake record from southern Europe, we quantify temporal changes in extreme HR events for the last 2,800 years in this region and their correlation with negative phases of the Mediterranean Oscillation (MO). Notably, scarce HR dominated by a persistent positive MO mode characterizes the so-called Migration period (CE 370–670). Large hydroclimatic variability, particularly between CE 1012 and 1164, singles out the Medieval Climatic Anomaly, whereas more stationary HR conditions occurred between CE 1537 and 1805 coinciding with the Little Ice Age. This exceptional paleohydrological record highlights that the present-day trend towards strengthened hydrological deficit and less HR in the western Mediterranean is neither acute nor unusual in the context of Late Holocene hydrometeorological variability at centennial to decadal time scales.
Interference with Protease-activated Receptor 1 Alleviates Neuronal Cell Death Induced by Lipopolysaccharide-Stimulated Microglial Cells through the PI3K/Akt Pathway
Authors: Li Yuxin , Yang Wuyang , Quinones-Hinojosa Alfredo , Wang Baocheng , Xu Shujun , Zhu Weijie , Yu Feng , Yuan Shaoji , Lu Peigang
Published: December 2016

Excessive microglial cells activation in response to inflammatory stimuli leads to synaptic loss, dysfunction, and neuronal cell death. Activated microglia are involved in the pathogenesis of neurological conditions and frequently contribute to several complications. Accumulating evidence suggests that signaling through PAR-1 is involved in inflammation, however, its function has yet to be fully elucidated. Here, we have demonstrated that the suppression of PAR-1 leads to down-regulation of inflammatory factors including IL-1β, IL-6, TNF-α, NO, as well as the prevention of activation of NF-κB in BV2 cells. In addition, we found that a PAR-1 antagonist, SCH, prevented LPS-induced excessive microglial activation in a dose-dependent manner. As a result of SCH treatment, neuronal cell death via up-regulation of Akt-mediated pathways was reduced. Our results demonstrate that the beneficial effects of SCH are linked to its ability to block an inflammatory response. Further, we found that SCH inhibited the death of PC12 neurons from the cytotoxicity of activated BV2 cells via activation of the PI3K/Akt pathway. These neuro-protective effects appear to be related to inhibition of PAR-1, and represents a novel neuroprotective strategy that could has potential for use in therapeutic interventions of neuroinflammatory disease.
Glial pannexin1 contributes to tactile hypersensitivity in a mouse model of orofacial pain
Authors: Hanstein Regina , Hanani Menachem , Scemes Eliana , Spray David C.
Published: December 2016

Drug studies in animal models have implicated pannexin1 (Panx1) in various types of pain, including trigeminal hypersensitivity, neuropathic pain and migraine. However, the tested drugs have limited specificity and efficacy so that direct evidence for Panx1 contribution to pain has been lacking. We here show that tactile hypersensitivity is markedly attenuated by deletion of Panx1 in a mouse model of chronic orofacial pain; in this model, trigeminal ganglion Panx1 expression and function are markedly enhanced. Targeted deletion of Panx1 in GFAP-positive glia or in neurons revealed distinct effects. Panx1 deletion in GFAP-positive glia cells prevented hypersensitivity completely, whereas deletion of neuronal Panx1 reduced baseline sensitivity and the duration of hypersensitivity. In trigeminal ganglia with genetically encoded Ca2+ indicator in GFAP-positive glia or in neurons, both cell populations were found to be hyperactive and hyper-responsive to ATP. These novel findings reveal unique roles for GFAP-positive glial and neuronal Panx1 and describe new chronic pain targets for cell-type specific intervention in this often intractable disease.
Human Mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE2-dependent mechanism
Authors: Vasandan Anoop Babu , Jahnavi Sowmya , Shashank Chandanala , Prasad Priya , Kumar Anujith , Prasanna S. Jyothi
Published: December 2016

Mesenchymal stem cells (MSCs) are speculated to act at macrophage-injury interfaces to mediate efficient repair. To explore this facet in-depth this study evaluates the influence of MSCs on human macrophages existing in distinct functional states. MSCs promoted macrophage differentiation, enhanced respiratory burst and potentiated microbicidal responses in naïve macrophages (Mφ). Functional attenuation of inflammatory M1 macrophages was associated with a concomitant shift towards alternatively activated M2 state in MSC-M1 co-cultures. In contrast, alternate macrophage (M2) activation was enhanced in MSC-M2 co-cultures. Elucidation of key macrophage metabolic programs in Mo/MSC, M1/MSC and M2/MSC co-cultures indicated changes in Glucose transporter1 (GLUT1 expression/glucose uptake, IDO1 protein/activity, SIRTUIN1 and alterations in AMPK and mTOR activity, reflecting MSC-instructed metabolic shifts. Inability of Cox2 knockdown MSCs to attenuate M1 macrophages and their inefficiency in instructing metabolic shifts in polarized macrophages establishes a key role for MSC-secreted PGE2 in manipulating macrophage metabolic status and plasticity. Functional significance of MSC-mediated macrophage activation shifts was further validated on human endothelial cells prone to M1 mediated injury. In conclusion, we propose a novel role for MSC secreted factors induced at the MSC-macrophage interface in re-educating macrophages by manipulating metabolic programs in differentially polarized macrophages.
Mal-Lys: prediction of lysine malonylation sites in proteins integrated sequence-based features with mRMR feature selection
Authors: Xu Yan , Ding Ya-Xin , Ding Jun , Wu Ling-Yun , Xue Yu
Published: December 2016

Lysine malonylation is an important post-translational modification (PTM) in proteins, and has been characterized to be associated with diseases. However, identifying malonyllysine sites still remains to be a great challenge due to the labor-intensive and time-consuming experiments. In view of this situation, the establishment of a useful computational method and the development of an efficient predictor are highly desired. In this study, a predictor Mal-Lys which incorporated residue sequence order information, position-specific amino acid propensity and physicochemical properties was proposed. A feature selection method of minimum Redundancy Maximum Relevance (mRMR) was used to select optimal ones from the whole features. With the leave-one-out validation, the value of the area under the curve (AUC) was calculated as 0.8143, whereas 6-, 8- and 10-fold cross-validations had similar AUC values which showed the robustness of the predictor Mal-Lys. The predictor also showed satisfying performance in the experimental data from the UniProt database. Meanwhile, a user-friendly web-server for Mal-Lys is accessible at http://app.aporc.org/Mal-Lys/.
Switchable 3D optofluidic Y-branch waveguides tuned by Dean flows
Authors: Li L. , Zhu X.Q. , Liang L. , Zuo Y. F. , Xu Y. S. , Yang Y. , Yuan Y. J. , Huang Q. Q.
Published: December 2016

Optical branch waveguides are one of the most important optical elements and have been widely exploited for optical communication systems. However, prevailing devices are typically solid and have limit in tunability. Liquid optical devices have attracted more interest for the advantage of tunability of liquid media, but their signals suffer serious leakage if the refractive index (RI) of liquid is smaller than that of solid channels. This paper demonstrates the tunable three-dimensional (3D) optofluidic Y-branch waveguides in plannar microchannels by simply introducing Dean flow. This device can reconfigure 3D Y-branch profiles and separate the intensity of light as tunable ratio from 0 to 1 by adjusting the flow rates with low loss. Different from the prevailing 2D liquid counterparts, the 3D configuration offer much more freedom in the selection of liquid media as liquid’s RI can be totally independent to the solid channel structure. The transmission loss through the device is estimated to 0.97 db when the splitting angle is 10°, which shows the light is confined better in the 3D liquid structures than traditional 2D liquid counterparts. The Y-branch waveguides show potential in applications of integrated optofluidic devices.
Locating the quantum critical point of the Bose-Hubbard model through singularities of simple observables
Authors: Łącki Mateusz , Damski Bogdan , Zakrzewski Jakub
Published: December 2016

We show that the critical point of the two-dimensional Bose-Hubbard model can be easily found through studies of either on-site atom number fluctuations or the nearest-neighbor two-point correlation function (the expectation value of the tunnelling operator). Our strategy to locate the critical point is based on the observation that the derivatives of these observables with respect to the parameter that drives the superfluid-Mott insulator transition are singular at the critical point in the thermodynamic limit. Performing the quantum Monte Carlo simulations of the two-dimensional Bose-Hubbard model, we show that this technique leads to the accurate determination of the position of its critical point. Our results can be easily extended to the three-dimensional Bose-Hubbard model and different Hubbard-like models. They provide a simple experimentally-relevant way of locating critical points in various cold atomic lattice systems.
Loss of EGFR-ASAP1 signaling in metastatic and unresectable hepatoblastoma
Authors: Ranganathan Sarangarajan , Ningappa Mylarappa , Ashokkumar Chethan , Higgs Brandon W. , Min Jun , Sun Qing , Schmitt Lori , Subramaniam Shankar , Hakonarson Hakon , Sindhi Rakesh
Published: December 2016

Hepatoblastoma (HBL), the most common childhood liver cancer is cured with surgical resection after chemotherapy or with liver transplantation if local invasion and multifocality preclude resection. However, variable survival rates of 60–80% and debilitating chemotherapy sequelae argue for more informed treatment selection, which is not possible by grading the Wnt-β-catenin over activity present in most HBL tumors. A hypothesis-generating whole transcriptome analysis shows that HBL tumors removed at transplantation are enriched most for cancer signaling pathways which depend predominantly on epidermal growth factor (EGF) signaling, and to a lesser extent, on aberrant Wnt-β-catenin signaling. We therefore evaluated whether EGFR, ASAP1, ERBB2 and ERBB4, which signal downstream after ligation of EGF, and which show aberrant expression in several other invasive cancers, would also predict HBL tumor invasiveness. Immunohistochemistry of HBL tumors (n = 60), which are histologically heterogeneous, shows that compared with well-differentiated fetal cells, less differentiated embryonal and undifferentiated small cells (SCU) progressively lose EGFR and ASAP1 expression. This trend is exaggerated in unresectable, locally invasive or metastatic tumors, in which embryonal tumor cells are EGFR-negative, while SCU cells are EGFR-negative and ASAP1-negative. Loss of EGFR-ASAP1 signaling characterizes undifferentiated and invasive HBL. EGFR-expressing HBL tumors present novel therapeutic targeting opportunities.
Superficial vimentin mediates DENV-2 infection of vascular endothelial cells
Authors: Yang Jie , Zou Lingyun , Yang Yi , Yuan Jizhen , Hu Zhen , Liu Hui , Peng Huagang , Shang Weilong , Zhang Xiaopeng , Zhu Junmin , Rao Xiancai
Published: December 2016

Damage to vascular endothelial cells (VECs) is a critical hallmark of hemorrhagic diseases caused by dengue virus (DENV). However, the precise molecular event involved in DENV binding and infection of VECs has yet to be clarified. In this study, vimentin (55 kDa) was identified to be involved in DENV-2 adsorption into VECs. This protein is located on the surface of VECs and interacts with DENV-2 envelope protein domain III (EDIII). The expression level of the superficial vimentin on VECs was not affected by viral infection or siRNA interference, indicating that the protein exists in a particular mode. Furthermore, the rod domain of the vimentin protein mainly functions in DENV-2 adsorption into VECs. Molecular docking results predicted several residues in vimentin rod and DENV EDIII; these residues may be responsible for cell–virus interactions. We propose that the superficial vimentin could be a novel molecule involved in DENV binding and infection of VECs. DENV EDIII directly interacts with the rod domain of vimentin on the VEC surface and thus mediates the infection.
Modulated switching current density and spin-orbit torques in MnGa/Ta films with inserting ferromagnetic layers
Authors: Meng Kangkang , Miao Jun , Xu Xiaoguang , Wu Yong , Xiao Jiaxing , Zhao Jianhua , Jiang Yong
Published: December 2016

We report modulated switching current density and spin-orbit torques (SOT) in MnGa/Ta films with inserting very thin Co2FeAl and Co layers. Ferromagnetic coupling has been found in MnGa/Co2FeAl/Ta, resulting in a decreased effective anisotropy field. On the contrary, in MnGa/Co/Ta, antiferromagnetic coupling plays a dominant role. The switching current density Jc in MnGa/Ta is 8.5 × 107 A/cm2. After inserting 0.8-nm-thick Co2FeAl and Co, theJc becomes 5 × 107 A/cm2 and 9 × 107 A/cm2, respectively. By performing adiabatic harmonic Hall voltage measurements, it is demonstrated that the inserted Co2FeAl layer has mainly enhanced the field-like torques, while in MnGa/Co/Ta the damping-like torques have been enhanced. Finally, the enhanced spin Hall effect (SHE) has also been studied using the spin Hall magnetoresistance measurement. The modulated Jc and SOT are ascribed to the combination of magnetic coupling, Rashba effect and SHE at the interfaces.
Novel chemoimmunotherapeutic strategy for hepatocellular carcinoma based on a genome-wide association study
Authors: Goto Kaku , Annan Dorcas A. , Morita Tomoko , Li Wenwen , Muroyama Ryosuke , Matsubara Yasuo , Ito Sayaka , Nakagawa Ryo , Tanoue Yasushi , Jinushi Masahisa , Kato Naoya
Published: December 2016

Pharmacotherapeutic options are limited for hepatocellular carcinoma (HCC). Recently, we identified the anti-tumor ligand MHC class I polypeptide-related sequence A (MICA) gene as a susceptibility gene for hepatitis C virus-induced HCC in a genome-wide association study (GWAS). To prove the concept of HCC immunotherapy based on the results of a GWAS, in the present study, we searched for drugs that could restore MICA expression. A screen of the FDA-approved drug library identified the anti-cancer agent vorinostat as the strongest hit, suggesting histone deacetylase inhibitors (HDACis) as potent candidates. Indeed, the HDACi-induced expression of MICA specific to HCC cells enhanced natural killer (NK) cell-mediated cytotoxicity in co-culture, which was further reinforced by treatment with an inhibitor of MICA sheddase. Similarly augmented anti-tumor activity of NK cells via NK group 2D was observed in vivo. Metabolomics analysis revealed HDACi-mediated alterations in energy supply and stresses for MICA induction and HCC inhibition, providing a mechanism for the chemoimmunotherapeutic actions. These data are indicative of promising strategies for selective HCC innate immunotherapy.
Design of a hydroxyapatite-binding antimicrobial peptide with improved retention and antibacterial efficacy for oral pathogen control
Authors: Huang Zhi-bin , Shi Xin , Mao Jing , Gong Shi-qiang
Published: December 2016

Controlling and reducing the formation of pathogenic biofilm on tooth surface is the key to the prevention and treatment of the biofilm-associated oral diseases. Antimicrobial peptides (AMPs), considered as possible future alternatives for conventional antibiotics, have been extensively studied for the control of bacterial infection. Due to the rapid dilution and degradation by human saliva, AMP preparations designed for oral use with longer retention and higher efficacy are in urgent need. To this end, a hydroxyapatite (HAp)-binding antimicrobial peptide (HBAMP), which is based on the fusion of a specific HAp-binding heptapeptide (HBP7) domain and a broad-spectrum antimicrobial peptide (KSLW) domain, has been developed in our laboratory. HBAMP was supposed to form a contact-active antibacterial interface on tooth surface to inhibit the formation of biofilms. In this study, we investigated its binding behaviour, antibacterial activity against bacteria in both planktonic and sessile states, enzymatic stability in human saliva, and cytocompatibility to human gingival fibroblasts (HGFs). Our findings suggest that HBAMP could adsorb on tooth surface to provide effective antibacterial activity with improved retention. This study provides a proof-of-concept on using conjugated molecules to promote antibacterial efficacy by synergistically actions of HBAMP free in solution and bound on tooth surface.
High-yield fabrication and properties of 1.4 nm nanodiamonds with narrow size distribution
Authors: Stehlik Stepan , Varga Marian , Ledinsky Martin , Miliaieva Daria , Kozak Halyna , Skakalova Viera , Mangler Clemens , Pennycook Timothy J. , Meyer Jannik C. , Kromka Alexander , Rezek Bohuslav
Published: December 2016

Detonation nanodiamonds (DNDs) with a typical size of 5 nm have attracted broad interest in science and technology. Further size reduction of DNDs would bring these nanoparticles to the molecular-size level and open new prospects for research and applications in various fields, ranging from quantum physics to biomedicine. Here we show a controllable size reduction of the DND mean size down to 1.4 nm without significant particle loss and with additional disintegration of DND core agglutinates by air annealing, leading to a significantly narrowed size distribution (±0.7 nm). This process is scalable to large quantities. Such molecular-sized DNDs keep their diamond structure and characteristic DND features as shown by Raman spectroscopy, infrared spectroscopy, STEM and EELS. The size of 1 nm is identified as a limit, below which the DNDs become amorphous.
Thrombomodulin regulates monocye differentiation via PKCδ and ERK1/2 pathway in vitro and in atherosclerotic artery
Authors: Tsai Chien-Sung , Lin Yi-Wen , Huang Chun-Yao , Shih Chun-Min , Tsai Yi-Ting , Tsao Nai-Wen , Lin Chin-Sheng , Shih Chun-Che , Jeng Hellen , Lin Feng-Yen
Published: December 2016

Thrombomodulin (TM) modulates the activation of protein C and coagulation. Additionally, TM regulates monocyte migration and inflammation. However, its role on monocyte differentiation is still unknown. We investigated the effects of TM on monocyte differentiation. First, we found that TM was increased when THP-1 cells were treated with phorbol-12-myristate-13-acetate (PMA). Overexpression of TM enhanced the macrophage markers, CD14 and CD68 expression in PMA-induced THP-1. TM siRNA depressed the PMA-induced increase of p21Cip1/WAF1 via ERK1/2-NF-kB p65 signaling. TM regulated cytoskeletal reorganization via its interaction with paxillin, cofilin, LIMK1, and PYK2. In addition, PMA-induced p21Cip1/WAF1 expression, CD14-positive cell labeling intensity and ERK1/2 phosphorylation were markedly inhibited when protein kinase C-δ (PKCδ) was knocked down. We identified that TM directly interacts with PKCδ. PKCδ was highly expressed in human atherosclerotic arteries and colocalized with TM in CD68-positive infiltrated macrophages of plaques, indicating that the coordination between TM and PKCδ in macrophages participated in atherogenesis. TM may act as a scaffold for PKCδ docking, which keeps PKCδ in the region close to the monocyte membrane to promote the activation of ERK1/2. Taken together, our findings suggest that TM-PKCδ interaction may contribute to cardiovascular disorders by affecting monocye differentiation, which may develop future therapeutic applications.
Novel groups and unique distribution of phage phoH genes in paddy waters in northeast China
Authors: Wang Xinzhen , Liu Junjie , Yu Zhenhua , Jin Jian , Liu Xiaobing , Wang Guanghua
Published: December 2016

Although bacteriophages are ubiquitous in various environments, their genetic diversity is primarily investigated in pelagic marine environments. Corresponding studies in terrestrial environments are few. In this study, we conducted the first survey of phage diversity in the paddy ecosystem by targeting a new viral biomarker gene, phoH. A total of 424 phoH sequences were obtained from four paddy waters generated from a pot experiment with different soils collected from open paddy fields in northeast China. The majority of phoH sequences in paddy waters were novel, with the highest identity of ≤70% with known phoH sequences. Four unique groups (Group α, Group β, Group γ and Group δ) and seven new subgroups (Group 2b, Group 3d, Group 3e, Group 6a, Group 6b, Group 6c and Group 6d) were formed exclusively with the clones from the paddy waters, suggesting novel phage phoH groups exist in the paddy ecosystem. Additionally, the distribution proportions of phoH clones in different groups varied among paddy water samples, suggesting the phage community in paddy fields is biogeographically distributed. Furthermore, non-metric multidimensional scaling analysis indicated that phage phoH assemblages in paddy waters were distinct from those in marine waters.
OER activity manipulated by IrO6 coordination geometry: an insight from pyrochlore iridates
Authors: Sun Wei , Liu Ji-Yuan , Gong Xue-Qing , Zaman Waqas-Qamar , Cao Li-Mei , Yang Ji
Published: December 2016

The anodic reaction of oxygen evolution reaction (OER), an important point for electrolysis, however, remains the obstacle due to its complicated reaction at electrochemical interfaces. Iridium oxide (IrO2) is the only currently known 5d transition metal oxide possessing admirable OER activity. Tremendous efforts have been carried out to enhance the activity of iridium oxides. Unfortunately there lies a gap in understanding what factors responsible for the activity in doped IrO2 or the novel crystal structure. Based on two metallic pyrochlores (Bi2Ir2O7 and Pb2Ir2O6.5) and IrO2. It has been found that there exists a strong correlation between the specific OER activity and IrO6 coordination geometry. The more distortion in IrO6 geometry ascends the activity of Ir sites, and generates activity order of Pb-Ir > IrO2 > Bi-Ir. Our characterizations reveal that distorted IrO6 in Pb-Ir induces a disappearance of J = 1/2 subbands in valence band, while Bi-Ir and IrO2 resist this nature probe. The performed DFT calculations indicated the distortion in IrO6 geometry can optimize binding strength between Ir-5d and O-2p due to broader d band width. Based on this insight, enhancement in OER activity is obtained by effects that change IrO6 octahedral geometry through doping or utilizing structural manipulation with nature of distorted octahedral coordination.
Protective effects of ginsenoside Rg1 on intestinal ischemia/reperfusion injury-induced oxidative stress and apoptosis via activation of the Wnt/β-catenin pathway
Authors: Zu Guo , Guo Jing , Che Ningwei , Zhou Tingting , Zhang Xiangwen
Published: December 2016

Ginsenoside Rg1 (Rg1) is one of the major bioactive ingredients in Panax ginseng, and it attenuates inflammation and apoptosis. The aims of our study were to explore the potential of Rg1 for the treatment of intestinal I/R injury and to determine whether the protective effects of Rg1 were exerted through the Wnt/β-catenin signaling pathway. In this study, Rg1 treatment ameliorated inflammatory factors, ROS and apoptosis that were induced by intestinal I/R injury. Cell viability was increased and cell apoptosis was decreased with Rg1 pretreatment following hypoxia/reoxygenation (H/R) in the in vitro study. Rg1 activated the Wnt/β-catenin signaling pathway in both the in vivo and in vitro models, and in the in vitro study, the activation was blocked by DKK1. Our study provides evidence that pretreatment with Rg1 significantly reduces ROS and apoptosis induced by intestinal I/R injury via activation of the Wnt/β-catenin pathway. Taken together, our results suggest that Rg1 could exert its therapeutic effects on intestinal I/R injury through the Wnt/β-catenin signaling pathway and provide a novel treatment modality for intestinal I/R injury.