bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impacts of Interleukin-18 Polymorphisms on the Incidence of Delayed-Onset Cytomegalovirus Infection in a Cohort of Kidney Transplant Recipients
Authors: Pérez-Flores Isabel , Santiago Jose Luis , Fernández-Pérez Cristina , Urcelay Elena , Moreno de la Higuera María Ángeles , Romero Natividad Calvo , Cubillo Beatriz Rodríguez , Sánchez-Fructuoso Ana Isabel 
Published: August 2019

Abstract

Background
The incidence of cytomegalovirus (CMV) infection in solid organ transplant recipients may be reduced by antiviral prophylaxis, but this strategy may lead to delayed-onset CMV infection. The proinflammatory cytokine interleukin (IL)-18 plays a major role in viral host defense responses. This study examines the impacts of 2 single-nucleotide polymorphisms (SNPs) in the promoter region of the IL-18 gene, -607C/A (rs1946518) and -137G/C (rs187238), on the incidence of delayed-onset CMV infection in patients undergoing kidney transplant.

Methods
This retrospective study analyzed 2 IL-18 SNPs in consecutive adult kidney transplant recipients using real-time polymerase chain reaction with TaqMan probes. Participants were enrolled over the period 2005–2013 and stratified according to their IL-18 SNP genotype. The concordance index (Harrell’s c-index) was used as a measure of the discriminatory power of the predictive models constructed with bootstrapping to correct for optimistic bias.

Results
Seven hundred nine patients received transplants in the study period, and 498 met selection criteria. Cytomegalovirus infection and disease incidence were 38% and 7.5%, respectively. In multivariate competing risk regression models, carriers of the -607C/-137G haplotype who received prophylaxis showed a higher incidence of CMV replication after antiviral agent discontinuation (hazard ratio = 2.42 [95% confidence interval, 1.11–5.26]; P = .026), whereas CMV disease was not observed in those given prophylaxis who were noncarriers of this polymorphism (P = .009).

Conclusions
Our findings suggest that the -607C/-137G IL-18 haplotype is associated with a higher incidence of postprophylaxis CMV replication. The prior identification of this polymorphism could help select alternative measures to prevent delayed-onset CMV infection in these patients.
Candidate Predisposition Variants in Kaposi Sarcoma as Detected by Whole-Genome Sequencing
Authors: Rinne Sanni J , Sipilä Lauri J , Sulo Päivi , Jouanguy Emmanuelle , Béziat Vivien , Abel Laurent , Casanova Jean-Laurent , Parvaneh Nima , Balighi Kamran , Guttman-Yassky Emma , Sarid Ronit , Aaltonen Lauri A , Aavikko Mervi 
Published: August 2019

Abstract
Familial clustering of classic Kaposi sarcoma (CKS) is rare with, approximately 100 families reported to date. We studied 2 consanguineous families, 1 Iranian and 1 Israeli, with multiple cases of adult CKS and without overt underlying immunodeficiency. We performed genome-wide linkage analysis and whole-genome sequencing to discover the putative genetic cause for predisposition. A 9-kb homozygous intronic deletion in RP11-259O2.1 in the Iranian family and 2 homozygous variants, 1 in SCUBE2 and the other in CDHR5, in the Israeli family were identified as possible candidates. The presented variants provide a robust starting point for validation in independent samples.
Successful Treatment of Mycobacterium chelonae Keratitis Within a Corneal Transplant Using Intrastromal Amikacin Injections—A Case Report Demonstrating the Fundamental Principles and Challenges of Infective Keratitis Management and Novel Therapeutic Approaches
Authors: Merridew Nancy Louisa , Phagura Ravinder Singh , Anderson Edward , Cooley Louise Anne , Pollock Graeme Alfred , McEwan Belinda , McCartney Paul James , Trad Mohamad-Ali 
Published: August 2019

AbstractMycobacterium chelonae keratitis is rare and difficult to treat. This is the first known case worldwide of effective treatment using intrastromal amikacin injections in a corneal transplant recipient who had metastatic breast cancer. The challenges and principles of management, applicable to other causes of infective keratitis, are reviewed.
What Types Should Not Be†
Authors: Bentzen Bruno 
Published: August 2019

ABSTRACTIn a series of papers Ladyman and Presnell raise an interesting challenge of providing a pre-mathematical justification for homotopy type theory. In response, they propose what they claim to be an informal semantics for homotopy type theory where types and terms are regarded as mathematical concepts. The aim of this paper is to raise some issues which need to be resolved for the successful development of their types-as-concepts interpretation.
Self-reported painful joint count and assessor-reported tender joint count as instruments to assess pain in hand osteoarthritis
Authors: Kroon Féline P B , Damman Wendy , van der Plas Johan L , van Beest Sjoerd , Rosendaal Frits R , van der Heijde Désirée , Kloppenburg Margreet 
Published: August 2019

Abstract

Objectives
To evaluate self-reported and assessor-reported joint counts for pain and their value in measuring pain and joint activity in hand OA patients.

Methods
A total of 524 patients marked painful joints on hand diagrams. Nurses assessed tenderness upon palpation. Pain was measured with a visual analogue scale pain and the Australian/Canadian hand OA index subscale pain. Synovitis and bone marrow lesions in right hand distal/proximal interphalangeal joints on MRI served as measure of joint activity. Agreement was assessed on the patient (intraclass correlation coefficient, Bland–Altman plot) and joint level (percentage absolute agreement). Correlations with measures of pain and joint activity were analysed, and joint level associations with synovitis/bone marrow lesions were calculated.

Results
Self-reported painful joint count (median 8, interquartile range 4–13) was consistently higher than assessor-reported tender joint count (3, 1–7). Agreement between patients and nurses on overall scores was low. Percentage absolute agreement on the joint level was 61–89%. Joint counts correlated similarly but weakly with measures of pain and joint activity (r = 0.14–0.38). On the joint level, assessor-reported tenderness was more strongly associated with synovitis/bone marrow lesions than self-reported pain.

Conclusion
In hand OA, self- and assessor-reported joint counts cannot be used interchangeably, and measure other pain aspects than questionnaires. Assessor-reported tenderness was most closely related to MRI-defined joint activity.
How Statelessness, Citizenship, and Out-migration Contribute to Stratification Among Rural Elderly in the Highlands of Thailand
Authors: Flaim Amanda , Williams Lindy B , Ahlquist Daniel B 
Published: August 2019

Abstract
In rural communities across the Global South, families are relying on temporary and permanent out-migration for work to navigate destabilizing agrarian transformations. While research indicates that success of this household livelihood strategy may depend on the legal status of international migrants, precarious legal status is not solely a problem relegated to people who cross national borders. Indeed, millions worldwide are stateless in the countries of their birth. In this mixed-method study, we assess the importance of legal status for elderly well-being among highlanders in Northern Thailand—rural communities that are experiencing both extensive out-migration and protracted statelessness. We find that elderly wealth and work outcomes are shaped by the legal status of both out-migrants and of the rural elderly themselves. Specifically, we show that when rural elderly or their migrant relatives are stateless, the elderly are more likely to engage in wage work and less likely to gain financial benefits of out-migration to the extent that citizens do. Through ethnographic engagement, we locate the contributions of legal status to rural stratification in its complex entanglements with land access and ethno-nationalism in the region, and in the ways that state and market infrastructures deploy citizenship to surveil highlanders and other minorities in Thailand. Amidst growing calls to resolve statelessness in the Global South, our research suggests that the combination of out-migration and uneven extension of citizenship in rural communities is likely to exacerbate stratification, both for migrants and for those who rarely leave home.
Acute Encephalitis Syndrome with an Unusual Diagnosis
Authors: Thomas Mili , Swarnam Kamala , Remadevi Gopika Sekhar , Pillai A Marthanda 
Published: August 2019

Abstract
Four-year old boy was admitted with acute onset of fever with seizures and altered sensorium. His mother had history of contact with influenza A H1N1 virus (H1N1) infection. Blood counts, electrolytes, blood sugar and ammonia were normal. Liver enzymes were mildly elevated. CSF study showed elevated protein, normal sugar and no pleocytosis. Cerebrospinal fluid (CSF) viral panel was negative. Magnetic resonance imaging brain was suggestive of acute necrotizing encephalopathy. His throat swab and sputum polymerase chain reaction was positive for H1N1. He was managed with ventilation, intravenous steroids and other supportive measures. At discharge his sensorium improved but had neurological sequelae. We are presenting this case as this is a very rare complication of H1N1 infection with high rate of mortality. Early supportive measures and steroids/intravenous immunoglobulin may save the patient.
Childhood Scurvy: A Nearly Extinct Disease Posing a New Diagnostic Challenge, a Case Report
Authors: Gupta Neeraj , Toteja Nisha , Sasidharan Rohit , Singh Kuldeep 
Published: August 2019

Abstract
Scurvy is seldom encountered in modern day clinical practice. Children can present with nonspecific features which can mimic several other common conditions. We describe here a four-year-old child who presented with severe pain and weakness of bilateral lower limbs and found to be severely malnourished. The diagnosis of scurvy was suspected in the context of underlying malnutrition after excluding other ominous pathologies. Pathognomic radiological changes clinched the diagnosis, and the best supportive evidence was the dramatic response to vitamin C supplementation.
Evaluation of the Active Melioidosis Detect™ test as a point-of-care tool for the early diagnosis of melioidosis: a comparison with culture in Laos
Authors: Rizzi Maria Chiara , Rattanavong Sayaphet , Bouthasavong Latsaniphone , Seubsanith Amphayvanh , Vongsouvath Manivanh , Davong Viengmon , De Silvestri Annalisa , Manciulli Tommaso , Newton Paul N , Dance David A B 
Published: August 2019

Abstract

Background
Melioidosis is difficult to diagnose clinically and culture of Burkholderia pseudomallei is the current, imperfect gold standard. However, a reliable point-of-care test (POCT) could enable earlier treatment and improve outcomes.

Methods
We evaluated the sensitivity and specificity of the Active Melioidosis Detect™ (AMD) rapid test as a POCT and determined how much it reduced the time to diagnosis compared with culture.

Results
We tested 106 whole blood, plasma and buffy coat samples, 96 urine, 28 sputum and 20 pus samples from 112 patients, of whom 26 (23.2%) were culture-positive for B. pseudomallei. AMD sensitivity and specificity were 65.4 and 87.2%, respectively, the latter related to 10 weak positive reactions on urine samples, considered likely false positives. The positive predictive value was 60.7%, negative predictive value was 89.3% and concordance rate between operators reading the test was 95.7%; time to diagnosis decreased by a median of 23 h.

Conclusions
Our findings confirm that a strongly positive AMD result can reduce the time to diagnosis of melioidosis. However, the AMD currently has a disappointing overall sensitivity, especially with blood fractions, and specificity problems when testing urine samples.
Melanoblast transcriptome analysis reveals novel pathways promoting melanoma metastasis
Authors: Marie Kerrie L. , Sassano Antonella , Yang Howard H. , Michalowski Aleksandra M. , Michael Helen T. , Guo Theresa , Tsai Yien Che , Weissman Allan M. , Lee Maxwell P. , Jenkins Lisa M. , Zaidi M. Raza , Pérez-Guijarro Eva , Day Chi-Ping , Arnheiter Heinz , Davis Sean , Meltzer Paul S. , Merlino Glenn , Mishra Pravin J. 
Published: August 2019

AbstractCutaneous malignant melanoma is an aggressive cancer of melanocytes with a strong propensity to metastasize. We posited that melanoma cells acquire metastatic capability by adopting an embryonic-like phenotype, and that a lineage approach would uncover novel metastatic melanoma biology. We used a genetically engineered mouse model to generate a rich melanoblast transcriptome dataset, identified melanoblast-specific genes whose expression contributed to metastatic competence, and derived a 43-gene signature that predicted patient survival. We identified a melanoblast gene,KDELR3, whose loss impaired experimental metastasis. In contrast,KDELR1deficiency enhanced metastasis, providing the first example of different disease etiologies within the KDELR-family of retrograde transporters. We show that KDELR3 regulates the metastasis suppressor, KAI1, and report an interaction with the E3 ubiquitin-protein ligase gp78, a regulator of KAI1 degradation. Our work demonstrates that the melanoblast transcriptome can be mined to uncover novel targetable pathways for melanoma therapy.
Lipid droplet accumulating microglia represent a dysfunctional and pro-inflammatory state in the aging brain
Authors: Marschallinger Julia , Iram Tal , Zardeneta Macy , Lee Song E. , Lehallier Benoit , Haney Michael S. , Pluvinage John V. , Mathur Vidhu , Hahn Oliver , Morgens David W. , Kim Justin , Tevini Julia , Felder Thomas K. , Wolinski Heimo , Bertozzi Carolyn R. , Bassik Michael C. , Aigner Ludwig , Wyss-Coray Tony 
Published: August 2019

AbstractMicroglia become progressively activated and seemingly dysfunctional with age, and genetic studies have linked these cells to the pathogenesis of a growing number of neurodegenerative diseases. Here we report a striking buildup of lipid droplets in microglia with aging in mouse and human brains. These cells, which we call lipid droplet-accumulating microglia (LAM), are defective in phagocytosis, produce high levels of reactive oxygen species, and secrete pro-inflammatory cytokines. RNA sequencing analysis of LAM revealed a transcriptional profile driven by innate inflammation distinct from previously reported microglial states. An unbiased CRISPR-Cas9 screen identified genetic modifiers of lipid droplet formation; surprisingly, variants of several of these genes, including progranulin, are causes of autosomal dominant forms of human neurodegenerative diseases. We thus propose that LAM contribute to age-related and genetic forms of neurodegeneration.
SIZ1 is a nuclear host target of the nematode effector GpRbp1 from Globodera pallida that acts as a negative regulator of basal plant defense to cyst nematodes
Authors: Diaz-Granados Amalia , Sterken Mark G. , Persoon Jarno , Overmars Hein , Pokhare Somnath S. , Mazur Magdalena J , Martin-Ramirez Sergio , Holterman Martijn , Martin Eliza C. , Pomp Rikus , Finkers-Tomczak Anna , Roosien Jan , Elashry Abdenaser , Grundler Florian , Petrescu Andrei J , Smant Geert , Goverse Aska 
Published: August 2019

AbstractSoil-borne cyst nematodes are obligatory sedentary parasites that cause severe losses to cultivation of major crops such as potato and soybean. Cyst nematodes establish specialised permanent feeding sites within the roots of their host by manipulating plant morphology and physiology through secreted effectors. Here we identified host targets of effector GpRbp-1 and studied their roles in plant-nematode interactions. GpRbp-1 was found to interact in yeast and in planta with the potato and Arabidopsis homologues of Siz/PIAS-type E3 SUMO ligase SIZ1. Our results show that a pathogen effector targets the master regulator SIZ1 in plant cells, which has not been demonstrated earlier to our knowledge. The interaction of GpRbp-1 and SIZ1 localizes to the plant nucleus, suggesting that the nuclear functions of SIZ1 as regulator of plant immunity and physiology may be modulated by GpRbp-1. Furthermore, nematode infection assays and transcriptomic profiling indicate that SIZ1 is required for susceptibility to cyst nematodes. So, these data indicate that E3 SUMO ligases may play an important role in plant-nematode interactions. Based on the prediction of SUMO acceptor and interaction sites in GpRbp-1, a model is proposed in which the effector may recruit SIZ1 to be SUMOylated for full functionality in host cells.Significance statementHere we show that a pathogen effector can target SIZ1, a key protein involved in regulating several aspects of plant biology, most likely to manipulate the SUMOylation of host proteins for successful infection of plants.
Maternal malnutrition impacts placental morphology and transport. An origin for poor offspring growth and vulnerability to disease
Authors: Connor Kristin L , Kibschull Mark , Matysiak-Zablocki Elzbieta , Nguyen Tina Tu-Thu Ngoc , Matthews Stephen G , Lye Stephen J , Bloise Enrrico 
Published: August 2019

AbstractThe placenta promotes fetal growth through nutrient transfer and selective barrier systems. An optimally developed placenta can adapt to changes in the pregnancy environment, buffering the fetus from adverse exposures. We hypothesised that the placenta adapts differently to suboptimal maternal diets, evidenced by changes in placental morphology, developmental markers, and key transport systems. Mice were fed a control diet (CON) during pregnancy, or undernourished (UN) by 30% of control intake from gestational day (GD)5.5-18.5, or fed 60% high fat diet (HF) eight weeks before and during pregnancy. At GD18.5, placental morphometry, development, and transport were assessed. Junctional and labyrinthine areas of UN and HF placentae were smaller than CON by >10%. Fetal blood space area and fetal blood space:fetal weight ratios were reduced in HF vs. CON and UN. Trophoblast giant cell marker Ctsq mRNA expression was lower in UN vs. HF, and expression of glycogen cell markers Cx31.1 and Pcdh12 was lower in HF vs. UN. Efflux transporter Abcb1a mRNA expression was lower in HF vs. UN, and Abcg2 expression was lower in UN vs. HF. mRNA expression of fatty acid binding protein Fabppm was higher in UN vs. CON and HF. mRNA and protein levels of the lipid transporter FAT/CD36 were lower in UN, and FATP4 protein levels were lower in HF vs. UN. UN placentae appear less mature with aberrant transport. HF placentae adapt to excessive nutrient supply. Understanding placental adaptations to common nutritional adversities may reveal mechanisms underlying the developmental origins of later disease.
Inferring neuronal ionic conductances from membrane potentials using CNNs
Authors: Ben-Shalom Roy , Balewski Jan , Siththaranjan Anand , Baratham Vyassa , Kyoung Henry , Kim Kyung Geun , Bender Kevin J. , Bouchard Kristofer E. 
Published: August 2019

AbstractThe neuron is the fundamental unit of computation in the nervous system, and different neuron types produce different temporal patterns of voltage fluctuations in response to input currents. Understanding the mechanism of single neuron firing patterns requires accurate knowledge of the spatial densities of diverse ion channels along the membrane. However, direct measurements of these microscopic variables are difficult to obtain experimentally. Alternatively, one can attempt to infer those microscopic variables from the membrane potential (a mesoscopic variable), or features thereof, which are more experimentally tractable. One approach in this direction is to infer the ionic densities as parameters of a neuronal model. Traditionally this is done using a Multi-Objective Optimization (MOO) method to minimize the differences between features extracted from a simulated neuron’s membrane potential and the same features extracted from target data. Here, we use Convolutional Neural Networks (CNNs) to directly regress generative parameters (e.g., ionic conductances, membrane resistance, etc.,) from simulated time-varying membrane potentials in response to an input stimulus. We simulated diverse neuron models of increasing complexity (Izikivich: 4 parameters; Hodgkin-Huxley: 7 parameters; Mainen-Sejnowski: 10 parameters) with a large range of variation in the underlying parameter values. We show that hyperparameter optimized CNNs can accurately infer the values of generative variables for these neuron models, and that these results far surpass the previous state-of-the-art method (MOO). We discuss the benefits of optimizing the CNN architecture, improvements in accuracy with additional training data, and some observed limitations. Based on these results, we propose that CNNs may be able to infer the spatial distribution of diverse ionic densities from spatially resolved measurements of neuronal membrane potentials (e.g. voltage imaging).
Kaposi’s sarcoma-associated herpesvirus ORF66 is essential for late gene expression and virus production via interaction with ORF34
Authors: Watanabe Tadashi , Nishimura Mayu , Izumi Taisuke , Kuriyama Kazushi , Iwaisako Yuki , Hosokawa Kouhei , Takaori-Kondo Akifumi , Fujimuro Masahiro 
Published: August 2019

ABSTRACTKaposi’s sarcoma-associated herpesvirus (KSHV) is closely associated with B-cell and endothelial cell malignancies. After the initial infection, KSHV retains its viral genome in the nucleus of the host cell and establishes a lifelong latency. During lytic infection, KSHV encoded lytic-related proteins are expressed in a sequential manner and are classified as immediate early, early, and late gene transcripts. The transcriptional initiation of KSHV late genes is thought to require the complex formation of the virus specific pre-initiation complex (vPIC), which may consist of at least 6 transcription factors (ORF18, 24, 30, 31, 34, and 66). However, the functional role of ORF66 in vPIC during KSHV replication remains largely unclear. Here, we generated ORF66-deficient KSHV using a BAC system to evaluate its role during viral replication. While ORF66-deficient KSHV demonstrated mainly attenuated late gene expression and decreased viral production, viral DNA replication was unaffected. CHIP analysis showed that ORF66 bound to the promoters of late gene (K8.1), but did not to those of latent gene (ORF72), immediate early gene (ORF16) and early gene (ORF46/47). Furthermore, we found that three highly conserved C-X-X-C sequences and a conserved leucine-repeat in the C-terminal region of ORF66 were essential for interaction with ORF34 and viral production. The interaction between ORF66 and ORF34 occurred in a zinc-dependent manner. Our data support a model, in which ORF66 serves as a critical vPIC component to promote late viral gene expression and viral production.IMPORTANCEKSHV ORF66, a late gene product, and vPIC are thought to contribute significantly to late gene expression during the lytic replication. However, the physiological importance of ORF66 in terms of viral replication and vPIC formation remains poorly understood. Therfore, we generated a ORF66-deficient BAC clone and evaluated its viral replication. Results showed that ORF66 played a critical role in virus production and the transcription of L genes. To our knowledge, this is the first report showing ORF66 function in virus replication using ORF66-deficient KSHV. We also clarified that ORF66 interacted with the transcription start site ofK8.1gene, a late gene. Furthermore, we identified the ORF34-binding motifs in the ORF66 C-terminus: three C-X-X-C sequences and a leucine-repeat sequence, which are highly conserved among β- and γ-herpesviruses. Our study provides insights into the regulatory mechanisms of not only the late gene expression of KSHV but also those of other herpesviruses.