bluuebunny/crossref_metadata_2025_split huggingface dataset:
N-Terminomics TAILS Identifies Host Cell Substrates of Poliovirus and Coxsackievirus B3 3C Proteinases That Modulate Virus Infection
Authors: Jagdeo Julienne M. , Dufour Antoine , Klein Theo , Solis Nestor , Kleifeld Oded , Kizhakkedathu Jayachandran , Luo Honglin , Overall Christopher M. , Jan Eric 
Published: February 2018

ABSTRACT

Enteroviruses encode proteinases that are essential for processing of the translated viral polyprotein. In addition, viral proteinases also target host proteins to manipulate cellular processes and evade innate antiviral responses to promote replication and infection. Although some host protein substrates of enterovirus proteinases have been identified, the full repertoire of targets remains unknown. We used a novel quantitative
in vitro
proteomics-based approach, termed
t
erminal
a
mine
i
sotopic
l
abeling of
s
ubstrates (TAILS), to identify with high confidence 72 and 34 new host protein targets of poliovirus and coxsackievirus B3 (CVB3) 3C proteinases (3C
pro
s) in HeLa cell and cardiomyocyte HL-1 cell lysates, respectively. We validated a subset of candidate substrates that are targets of poliovirus 3C
pro
in vitro
including three common protein targets, phosphoribosylformylglycinamidine synthetase (PFAS), hnRNP K, and hnRNP M, of both proteinases. 3C
pro
-targeted substrates were also cleaved in virus-infected cells but not noncleavable mutant proteins designed from the TAILS-identified cleavage sites. Knockdown of TAILS-identified target proteins modulated infection both negatively and positively, suggesting that cleavage by 3C
pro
promotes infection. Indeed, expression of a cleavage-resistant mutant form of the endoplasmic reticulum (ER)-Golgi vesicle-tethering protein p115 decreased viral replication and yield. As the first comprehensive study to identify and validate functional enterovirus 3C
pro
substrates
in vivo
, we conclude that N-terminomics by TAILS is an effective strategy to identify host targets of viral proteinases in a nonbiased manner.

IMPORTANCE
Enteroviruses are positive-strand RNA viruses that encode proteases that cleave the viral polyprotein into the individual mature viral proteins. In addition, viral proteases target host proteins in order to modulate cellular pathways and block antiviral responses in order to facilitate virus infection. Although several host protein targets have been identified, the entire list of proteins that are targeted is not known. In this study, we used a novel unbiased proteomics approach to identify ∼100 novel host targets of the enterovirus 3C protease, thus providing further insights into the network of cellular pathways that are modulated to promote virus infection.
Gut microbiota modulate T cell trafficking into human colorectal cancer
Authors: Cremonesi Eleonora , Governa Valeria , Garzon Jesus Francisco Glaus , Mele Valentina , Amicarella Francesca , Muraro Manuele Giuseppe , Trella Emanuele , Galati-Fournier Virginie , Oertli Daniel , Däster Silvio Raffael , Droeser Raoul A , Weixler Benjamin , Bolli Martin , Rosso Raffaele , Nitsche Ulrich , Khanna Nina , Egli Adrian , Keck Simone , Slotta-Huspenina Julia , Terracciano Luigi M , Zajac Paul , Spagnoli Giulio Cesare , Eppenberger-Castori Serenella , Janssen Klaus-Peter , Borsig Lubor , Iezzi Giandomenica 
Published: February 2018

ObjectiveTumour-infiltrating lymphocytes (TILs) favour survival in human colorectal cancer (CRC). Chemotactic factors underlying their recruitment remain undefined. We investigated chemokines attracting T cells into human CRCs, their cellular sources and microenvironmental triggers.DesignExpression of genes encoding immune cell markers, chemokines and bacterial 16S ribosomal RNA (16SrRNA) was assessed by quantitative reverse transcription-PCR in fresh CRC samples and corresponding tumour-free tissues. Chemokine receptor expression on TILs was evaluated by flow cytometry on cell suspensions from digested tissues. Chemokine production by CRC cells was evaluated in vitro and in vivo, on generation of intraperitoneal or intracecal tumour xenografts in immune-deficient mice. T cell trafficking was assessed on adoptive transfer of human TILs into tumour-bearing mice. Gut flora composition was analysed by 16SrRNA sequencing.ResultsCRC infiltration by distinct T cell subsets was associated with defined chemokine gene signatures, including CCL5, CXCL9 and CXCL10 for cytotoxic T lymphocytes and T-helper (Th)1 cells; CCL17, CCL22 and CXCL12 for Th1 and regulatory T cells; CXCL13 for follicular Th cells; and CCL20 and CCL17 for interleukin (IL)-17-producing Th cells. These chemokines were expressed by tumour cells on exposure to gut bacteria in vitro and in vivo. Their expression was significantly higher in intracecal than in intraperitoneal xenografts and was dramatically reduced by antibiotic treatment of tumour-bearing mice. In clinical samples, abundance of defined bacteria correlated with high chemokine expression, enhanced T cell infiltration and improved survival.ConclusionsGut microbiota stimulate chemokine production by CRC cells, thus favouring recruitment of beneficial T cells into tumour tissues.
Downregulation of exosomal miR-204-5p and miR-632 as a biomarker for FTD: a GENFI study
Authors: Schneider Raphael , McKeever Paul , Kim TaeHyung , Graff Caroline , van Swieten John Cornelis , Karydas Anna , Boxer Adam , Rosen Howie , Miller Bruce L , Laforce Jr Robert , Galimberti Daniela , Masellis Mario , Borroni Barbara , Zhang Zhaolei , Zinman Lorne , Rohrer Jonathan Daniel , Tartaglia Maria Carmela , Robertson Janice 
Published: February 2018

ObjectiveTo determine whether exosomal microRNAs (miRNAs) in cerebrospinal fluid (CSF) of patients with frontotemporal dementia (FTD) can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort and in sporadic FTD.MethodsGENFI participants were either carriers of a pathogenic mutation in progranulin, chromosome 9 open reading frame 72 or microtubule-associated protein tau or were at risk of carrying a mutation because a first-degree relative was a known symptomatic mutation carrier. Exosomes were isolated from CSF of 23 presymptomatic and 15 symptomatic mutation carriers and 11 healthy non-mutation carriers. Expression of 752 miRNAs was measured using quantitative PCR (qPCR) arrays and validated by qPCR using individual primers. MiRNAs found differentially expressed in symptomatic compared with presymptomatic mutation carriers were further evaluated in a cohort of 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer’s disease (AD) and 10 healthy controls (HCs) of similar age.ResultsIn the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared with presymptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 (90% CI 0.79 to 0.98) and 0.81 (90% CI 0.68 to 0.93), respectively, and when combined an area of 0.93 (90% CI 0.87 to 0.99). In sporadic FTD, only miR-632 was significantly decreased compared with AD and HCs. Decrease of miR-632 revealed an area of 0.90 (90% CI 0.81 to 0.98).ConclusionsExosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD.
A Phase I Study of CPI-613 in Combination with High-Dose Cytarabine and Mitoxantrone for Relapsed or Refractory Acute Myeloid Leukemia
Authors: Pardee Timothy S. , Anderson Rebecca G. , Pladna Kristin M. , Isom Scott , Ghiraldeli Lais P. , Miller Lance D. , Chou Jeff W. , Jin Guangxu , Zhang Wei , Ellis Leslie R. , Berenzon Dmitriy , Howard Dianna S. , Hurd David D. , Manuel Megan , Dralle Sarah , Lyerly Susan , Powell Bayard L. 
Published: February 2018

Abstract
Purpose: CPI-613, a lipoate analogue that inhibits pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase (KGDH), has activity in patients with myeloid malignancies. This study explored the role of mitochondrial metabolism in chemotherapy response and determined the MTD, efficacy, and safety of CPI-613 combined with high-dose cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia.
Experimental Design: The role of mitochondrial response to chemotherapy was assessed in cell lines and animal models. A phase I study of CPI-613 plus cytarabine and mitoxantrone was conducted in patients with relapsed or refractory AML.
Results: Exposure to chemotherapy induced mitochondrial oxygen consumption that depended on PDH. CPI-613 sensitized AML cells to chemotherapy indicating that mitochondrial metabolism is a source of resistance. Loss of p53 did not alter response to CPI-613. The phase I study enrolled 67 patients and 62 were evaluable for response. The overall response rate was 50% (26CR+5CRi/62). Median survival was 6.7 months. In patients over 60 years old, the CR/CRi rate was 47% (15/32) with a median survival of 6.9 months. The response rate for patients with poor-risk cytogenetics also was encouraging with 46% (11/24 patients) achieving a CR or CRi. RNA sequencing analysis of a subset of baseline bone marrow samples revealed a gene expression signature consistent with the presence of B cells in the pretreatment marrow of responders.
Conclusions: The addition of CPI-613 to chemotherapy is a promising approach in older patients and those with poor-risk cytogenetics. Clin Cancer Res; 24(9); 2060–73. ©2018 AACR.
REGγ Controls Hippo Signaling and Reciprocal NF-κB–YAP Regulation to Promote Colon Cancer
Authors: Wang Qingwei , Gao Xiao , Yu Tong , Yuan Lei , Dai Jie , Wang Weicang , Chen Geng , Jiao Chan , Zhou Wang , Huang Quan , Cui Long , Zhang Pei , Moses Robb E. , Yang Jianhua , Chen Fengyuan , Fu Junjiang , Xiao Jianru , Li Lei , Dang Yongyan , Li Xiaotao 
Published: February 2018

AbstractPurpose: Colorectal cancer is one of the most commonly diagnosed cancers closely associated with inflammation and hyperactive growth. We previously demonstrated a regulatory circuit between the proteasome activator REGγ and NF-kappaB (NF-κB) during colon inflammation, known to be important in the development of colitis-associated cancer as well as sporadic colorectal cancer. How the inflammatory microenvironment affects the Hippo pathway during colorectal cancer development is largely unknown.Experimental Design: Here, we used REGγ-deficient colon cancer cell lines, REGγ knockout mice, and human colorectal cancer samples to identify the novel molecular mechanism by which REGγ functions as an oncoprotein in the development of colorectal cancer.Results: REGγ can directly interact with Lats1 and promote its degradation, which facilitates Yes-associated protein (YAP) activation in colon cancer cells. REGγ deficiency significantly attenuated colon cancer growth, associated with decreased YAP activity. Suppression of tumor growth due to REGγ depletion was overcome by constitutively active YAP. Surprisingly, reciprocal activation of the YAP and NF-κB pathways was observed in human colon cancer cells. REGγ overexpression was found in over 60% of 172 colorectal cancer specimens, highly correlating with the elevation of YAP and p65. Postoperative follow-up revealed a significantly lower survival rate in patients with concomitantly high expression of REGγ, YAP, and p-p65.Conclusions: REGγ could be a master regulator during colorectal cancer development to promote YAP signaling and reinforce cross-talks between inflammation and growth pathways, and REGγ might be a new marker for prognosis of colorectal cancer patients. Clin Cancer Res; 24(8); 2015–25. ©2018 AACR.
Second-Generation Hydrogel Coils for the Endovascular Treatment of Intracranial Aneurysms
Authors: Taschner Christian A. , Chapot René , Costalat Vincent , Machi Paolo , Courthéoux Patrick , Barreau Xavier , Berge Jérôme , Pierot Laurent , Kadziolka Krzysztof , Jean Betty , Blanc Raphaël , Biondi Alessandra , Brunel Hervé , Gallas Sophie , Berlis Ansgar , Herbreteau Denis , Berkefeld Joachim , Urbach Horst , Elsheikh Samer , Fiehler Jens , Desal Hubert , Graf Erika , Bonafé Alain 
Published: February 2018

Background and Purpose—
Endovascular embolization of intracranial aneurysms with hydrogel-coated coils lowers the risk of major recurrence, but technical limitations (coil stiffness and time restriction for placement) have prevented their wider clinical use. We aimed to assess the efficacy of softer, second-generation hydrogel coils.

Methods—
A randomized controlled trial was conducted at 22 centers in France and Germany. Patients aged 18 to 75 years with untreated ruptured or unruptured intracranial aneurysms measuring 4 to 12 mm in diameter were eligible and randomized (1:1 using a web-based system, stratified by rupture status) to coiling with either second-generation hydrogel coils or bare platinum coils. Assist devices were allowed as clinically required. Independent imaging core laboratory was masked to allocation. Primary end point was a composite outcome measure including major aneurysm recurrence, aneurysm retreatment, morbidity that prevented angiographic controls, and any death during treatment and follow-up. Data were analyzed as randomized.

Results—

Randomization began on October 15, 2009, and stopped on January 31, 2014, after 513 patients (hydrogel, n=256; bare platinum, n=257); 20 patients were excluded for missing informed consent and 9 for treatment-related criteria. Four hundred eighty-four patients (hydrogel, n=243; bare platinum, n=241) were included in the analysis; 208 (43%) were treated for ruptured aneurysms. Final end point data were available for 456 patients. Forty-five out of 226 (19.9%) patients in the hydrogel group and 66/230 (28.7%) in the control group had an unfavorable composite primary outcome, giving a statistically significant reduction in the proportion of an unfavorable composite primary outcome with hydrogel coils—adjusted for rupture status—of 8.4% (95% confidence interval, 0.5–16.2;
P
=0.036). Adverse and serious adverse events were evenly distributed between groups.

Conclusions—
Our results suggest that endovascular coil embolization with second-generation hydrogel coils may reduce the rate of unfavorable outcome events in patients with small- and medium-sized intracranial aneurysms.

Clinical Trial Registration—

URL:
https://www.drks.de/drks_web/
. Unique identifier: DRKS00003132.
First Carboniferous thylacocephalan from Europe and its significance for the understanding of functional morphology of Concavicarididae Schram, 2014
Authors: Rak Štěpán , Broda Krzysztof , Kumpan Tomáš 
Published: February 2018

Thylacocephala Pinna, Arduini, Pesarini & Teruzzi 1982 are among the most enigmatic arthropods. Their fossil record is very patchy both geographically and stratigraphically. In this paper we describe the first thylacocephalan known from the Carboniferous (Mississippian) of Europe,Concavicaris viktorynisp. nov. Until now Carboniferous representatives of Thylacocephala were know exclusively from the U.S.A. We discuss the stratigraphic and geological context of occurrence of this new species as well as form and function of the unique carapace micro- and macro-ornamentation. A shape and assumed function of the characteristic lirae on theC. viktorynisp. nov. carapace present an important supporting argument for the supposed free-swimming or pelagic mode of life in thylacocephalans. Palaeobiogeographical and evolutionary aspects of surprisingly rich but local occurrence of thylacocephalans in the Lower Carboniferous of the Moravian karst are discussed. Possible sympatric evolution from its predecessorConcavicaris incolais also pointed out.
Enslaved People in an Ancient Syrian City
Authors: Turri Luigi 
Published: February 2018

Abstract
The cuneiform documents found at Tell Atchana, a site on the River Orontes not far from modern city of Antakya, are of pivotal importance for our knowledge of western Syrian society during the Middle and Late Bronze Age. These tablets from ancient Alalakh provide data relating to the city’s daily life and its social structure and administration. Compared to the large amount of information regarding free citizens, the material concerning slave laborers and menial workers—which is the topic of this article—is scanty and not always easy to interpret, for both the public and private sectors.
Connecting the Mediterranean and the Atlantic
Authors: Bonazza Giulia 
Published: February 2018

Abstract
This article aims to demonstrate that slavery persisted in Naples and Rome until the first half of the nineteenth century. My analysis shows that, while from a quantitative point of view slavery may be viewed as a “residual phenomenon,” the life narratives and practices of slavery encountered in these different urban contexts are not unlike those typical of the Italian peninsula in previous centuries: captivity, the role of privateering, the link between slavery and serfdom, and, finally, baptism as a vehicle to freedom were all important aspects of this complex phenomenon. The slavery cases examined for Naples also highlight the complex links between captivity and slavery in the Mediterranean and the Atlantic slave trade. Examples illustrate how the two circuits of slave trades were in reality intertwined.
Hourly Observed Internal Waves by Geostationary Ocean Color Imagery in the East/Japan Sea
Authors: Kim Hyuna , Son Young Baek , Jo Young-Heon 
Published: February 2018

AbstractAs internal waves (IWs) are generated via internal tidal energy near the bottom shelf break of the Korea Strait, continuous evolutions of IWs are extremely difficult to observe using satellite observations. However, the Geostationary Ocean Color Imager (GOCI) has enabled the detection of IWs in the East/Japan Sea (EJS) on an hourly basis to investigate their propagation behavior. For an extended IW analysis, a total of seven packets were identified using GOCI chlorophyll-a concentration (Chl-a) measurements around the Ulleung Basin and Dok Island in the EJS. The results demonstrate that the IW locations had lower Chl-a values than non-IW-affected regions on 10, 11, 13, and 14 August 2013. The lower Chl-a values are due to the significant wave heights of the IWs, which cause surface water masses to be dispersed. In addition, from the continuous trajectories of the waves in the hourly GOCI Chl-a imagery, quantitative physical parameters of the IWs, such as their pathway (northeasterly), phase speed (1.46–1.61 m s−1), amplitude (20.62–26.76 m), and period (12.29 h), could be obtained. Therefore, the advantage of using GOCI is the ability to detect and analyze the physical characteristics of IWs on an hourly time scale.
Changes in Transcranial Ultrasound Velocities in Children with Sickle Cell Disease Undergoing Adenotonsillectomy
Authors: Santarelli Griffin , DeShields Sarah C. , Ishman Stacey L. , Randall Michael , Cunningham Tina D. , Baldassari Cristina M. 
Published: February 2018

Objectives(1) To assess for changes in cerebral blood flow velocity in children with sickle cell disease and obstructive sleep apnea (OSA) following adenotonsillectomy. (2) To determine if clinical factors such as OSA severity affect cerebral blood flow velocity values.Study DesignCase series with chart review over 10 years.SettingsTwo tertiary children's hospitals.Subjects and MethodsChildren aged 2 to 18 years with a history of sickle cell disease and OSA, as defined by an apnea hypopnea index (AHI) >1 on polysomnography, were eligible for inclusion. Transcranial Doppler ultrasonography was used to assess cerebral blood flow velocity before and after adenotonsillectomy.ResultsFifteen patients met inclusion criteria; 73% (n = 11) were female. The mean preoperative AHI was 8.9 (range, 1.2‐22.2). Six (40%) patients had severe OSA (AHI >10). Following adenotonsillectomy, there was a significant reduction in mean (95% CI) cerebral blood flow velocities of the left terminal internal cerebral artery, 91.2 (79.4‐103.1) to 75.7 (61.7‐89.8; P =. 018), and the right middle cerebral artery, 134.3 (119.2‐149.3) to 116.5 (106.5‐126.5; P =. 003). There was not a significant correlation between baseline AHI and change in cerebral blood flow velocities.ConclusionAdenotonsillectomy may result in a reduction in some cerebral blood flow velocities. Further research is needed to determine if changes in cerebral velocities as assessed by transcranial Doppler ultrasonography translate into a reduced risk of stroke for children with sickle cell disease and OSA.
Unilateral Vocal Fold Paralysis and Risk of Pneumonia: A Nationwide Population‐Based Cohort Study
Authors: Tsai Ming‐Shao , Yang Yao‐Hsu , Liu Chia‐Yen , Lin Meng‐Hung , Chang Geng‐He , Tsai Yao‐Te , Li Hsueh‐Yu , Tsai Ying‐Huang , Hsu Cheng‐Ming 
Published: February 2018

ObjectiveTo investigate pneumonia risk among patients with unilateral vocal fold paralysis (UVFP).Study DesignRetrospective population‐based cohort study.SettingThis study used data from the National Health Insurance Research Database of Taiwan, a nationwide population‐based database.Subjects and MethodsA total of 419 patients newly diagnosed with UVFP between January 1, 1997, and December 31, 2013, were identified from the Longitudinal Health Insurance Database 2000, a nationally representative database of 1 million randomly selected patients. Moreover, 1676 patients without UVFP were matched to patients with UVFP at a 1:4 ratio based on age, sex, socioeconomic status, urbanization level, and site‐specific cancers. Patients were followed up until death or the end of the study period (December 31, 2013). The primary outcome was the occurrence of pneumonia.ResultsThe cumulative incidence of pneumonia was significantly higher for patients with UVFP than those without UFVP (P <. 001). The adjusted Cox proportional hazard model showed that UVFP was significantly associated with a higher incidence of pneumonia (hazard ratio, 1.97; 95% CI, 1.35‐2.86; P <. 001). Subgroup analyses demonstrated that UVFP was an independent risk factor of pneumonia for 4 subgroups: young (18‐50 years), older (≥51 years), male, and cancer.ConclusionThis is the first nationwide population‐based cohort study to investigate the association between UVFP and pneumonia. The findings indicate that UVFP is an independent risk factor of pneumonia. Given the study results, physicians should be aware of the potential for pneumonia occurrence following UVFP.
Asymmetric Hearing Loss Prompting MRI Referral in a Military Population: Redefining Audiometric Criteria
Authors: Tolisano Anthony M. , Burgos Ricardo M. , Lustik Michael B. , Mitchell Lex A. , Littlefield Philip D. 
Published: February 2018

ObjectiveTo reevaluate asymmetric sensorineural hearing loss (ASNHL) criteria used to justify magnetic resonance imaging (MRI) in the evaluation of retrocochlear tumors in a military population.Study DesignRetrospective case‐control study.SettingTertiary care military medical center.Subjects and MethodsPatients with military service and a history of ASNHL prompting referral for MRI, with or without retrocochlear tumors, were compared between 2005 and 2016. Predictor variables included pure tone ASNHL, speech audiometry, and a history of noise exposure. Logistic regression models for hearing asymmetries were performed, and receiver operator curves were used to calculate sensitivity and specificity.ResultsThirty‐eight retrocochlear tumors were identified. The MRI diagnosis rate for patients with ASHNL was 0.85%. Patients with tumors were slightly older (42 vs 37 years, P =. 021) and had less noise exposure (47% vs 85%, P <. 001). A sensitivity of 0.83 and a specificity of 0.58 were calculated for asymmetries ≥10 dB at 2000 Hz without adjusting for noise exposure. Instituting this imaging threshold would have reduced the number of MRI scans by half while missing 16% of tumors.ConclusionThe tumor diagnosis rate among those undergoing MRI for ASNHL is low in the military population, likely because service‐related noise exposure commonly causes ASNHL. Optimal MRI referral criteria should conserve resources while balancing the risks of over‐ and underdiagnosis. For those with a history of military service, an asymmetry ≥10 dB at 2000 Hz among patients meeting current ANSHL referral criteria is most predictive of a retrocochlear tumor.