bluuebunny/crossref_metadata_2025 huggingface dataset:
New Methods for Resolving Conflicting Requests with Examples from Medical Residency Scheduling
Authors: Lemay Brian , Cohn Amy , Epelman Marina , Gorga Stephen
Published: May 2017

In scheduling medical residents, the objective is often to maximize resident satisfaction across the space of feasible schedules, relative to the many hard constraints that ensure appropriate patient coverage, adequate training opportunities, etc. A common metric of resident satisfaction is the number of time‐off requests that are granted. Simply maximizing this total, however, may lead to undesirable schedules since some requests have higher priority than others. For example, it might be better to grant one resident's request for a family member's wedding in place of two residents’ requests to attend a rugby game. Another approach is to assign a weight to each request and maximize the total weight of granted requests, but determining weights that accurately represent residents’ and schedulers’ preferences can be quite challenging. Instead, we propose to identify the exhaustive collection of maximally feasible and minimally infeasible sets of requests which can then be used by schedulers to select their preferred solution. Specifically, we have developed two algorithms, which we call Sequential Request Selection Via Cuts (Sequential RSVC) and Simultaneous Request Selection Via Cuts (Simultaneous RSVC), to identify these sets by solving two sequences of optimization problems. We present these algorithms along with computational results based on a real‐world problem of scheduling residents at the University of Michigan C.S. Mott Pediatric Emergency Department. Although we focus our exposition on the problem of resident scheduling, our approach is applicable to a broad class of problems with soft constraints.
Small‐sample testing inference in symmetric and log‐symmetric linear regression models
Authors: Medeiros Francisco M. C. , Ferrari Silvia L. P.
Published: May 2017

This paper deals with the issue of testing hypotheses in symmetric and log‐symmetric linear regression models in small and moderate‐sized samples. We focus on four tests, namely, the Wald, likelihood ratio, score, and gradient tests. These tests rely on asymptotic results and are unreliable when the sample size is not large enough to guarantee a good agreement between the exact distribution of the test statistic and the corresponding chi‐squared asymptotic distribution. Bartlett and Bartlett‐type corrections typically attenuate the size distortion of the tests. These corrections are available in the literature for the likelihood ratio and score tests in symmetric linear regression models. Here, we derive a Bartlett‐type correction for the gradient test. We show that the corrections are also valid for the log‐symmetric linear regression models. We numerically compare the various tests and bootstrapped tests, through simulations. Our results suggest that the corrected and bootstrapped tests exhibit type I probability error closer to the chosen nominal level with virtually no power loss. The analytically corrected tests as well as the bootstrapped tests, including the Bartlett‐corrected gradient test derived in this paper, perform with the advantage of not requiring computationally intensive calculations. We present a real data application to illustrate the usefulness of the modified tests.
Level‐specific amputations and resulting regenerative outcomes in the mouse distal phalanx
Authors: Chamberlain Connie S. , Jeffery Justin J. , Leiferman Ellen M. , Yildirim Tugrul , Sun Xin , Baer Geoffrey S. , Murphy William L. , Vanderby Ray
Published: May 2017

Mouse digit tip regeneration involves an intricate coordinated regrowth of the terminal phalanx, nail, dermis and epidermis. During this time, regenerating digits undergo wound healing, blastema formation, and differentiation. However, the regenerative response of the digit is dependent on the level of the amputation. Amputation of <30% of the distal phalanx (P3), with part of the base nail remaining, results in extensive digit regeneration. In contrast, >60% P3 removal results in no regeneration. This level‐dependent regenerative ability of the mouse digit provides a comparative model between regeneration and non‐regeneration that may enable identification of specific factors critical to regeneration. Although the ability to create regenerating and non‐regenerating conditions has been well established, the regenerative response between these regions (“intermediate” zone) has received less scrutiny, and may add insight to the regenerative processes, including the degree of histolysis, and the level of blastema formation. The objective of this study is then to compare the regeneration capacity between amputation levels within the regenerating (<30%), intermediate (40–59%), and non‐regenerating (>60%) regions. Results indicated that regenerative and intermediate amputations led to significant histolysis and blastema formation of the distal phalanx 14 days post‐amputation. Unlike the regenerating digits, intermediate amputations led to incomplete regeneration whereby regrowth of the digits were not to the levels of the intact or regenerating digits. Non‐regenerating amputations did not exhibit significant histolysis or blastema formation. Remarkably, the histolytic process resulted in day 14 P3 lengths that were similar regardless of the initial amputation over 19%. The differences in histolysis, blastema formation and injury outcomes were also marked by changes in the number of proliferating cells and osteoclasts. Altogether, these results indicate that although intermediate amputations result in histolysis and blastema formation similar to regenerating digits, the resulting cellular composition of the blastema differs, contributing to incomplete regeneration.
Effectiveness of topical skin products in the treatment and prevention of incontinence-associated dermatitis: a systematic review
Authors: Pather Priscilla , Hines Sonia , Kynoch Kate , Coyer Fiona
Published: May 2017

EXECUTIVE SUMMARY

Background

Incontinence-associated dermatitis (IAD) is inflammation of the skin resulting from repeated contact with urine and/or feces. It causes pain, redness, swelling and excoriation, and may lead to complications such as fungal skin infections and pressure injuries. It is important to prevent and treat IAD to avoid complications and improve patient outcomes. A number of products are available for protecting skin, but evidence on their effectiveness is limited.

Objectives

The current review aimed to establish the effectiveness of topical skin products in reducing the occurrence and/or severity of IAD.

Inclusion criteria Types of participants

Adult patients over the age of 18 years with incontinence and/or diarrhea.

Types of intervention

Topical skin products as individual interventions or part of a skin care regimen.

Types of studies

Both published and unpublished study designs including randomized controlled trials, non-randomized controlled trials, quasi-experimental, before and after, prospective and retrospective cohort, case-control, analytical cross-sectional, descriptive study designs including case series, individual case reports and descriptive cross-sectional studies across all care settings for inclusion.

Outcomes

The primary outcome of interest was the absence or non-development, reduction or resolution, new development or increase in the occurrence of IAD or the increase in severity of IAD. The secondary outcome was any adverse effect caused by the skin care products used.

Search strategy

A three-step search strategy to find both published and unpublished papers was utilized in this review. Studies were limited to those published in English from 1980 to 2016.

Methodological quality

Papers selected were assessed by two independent reviewers using the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI).

Data extraction

Data were extracted using the standardized data extraction tool in JBI-MAStARI. The data extracted included specific details about the interventions, populations, study methods and outcomes.

Data synthesis

Studies were assessed for methodological quality and statistical significance to determine validity and generalizability of study results. It was not possible to pool studies to conduct meta-analysis or test for heterogeneity.

Results

There were a limited number of clinical trials that compared products for efficacy in preventing and treating IAD. Assessment tools and severity scores used to measure skin damage outcomes were dissimilar and prone to subjectivity. It was difficult to ascertain superiority of any individual product.

Conclusion

Information on barrier protective efficacy, side effects and cost can be valuable to both clinicians and care providers. More randomized controlled trials on product effectiveness for prevention and treatment of IAD are highly recommended.
Enhanced Subcooled Flow Boiling Heat Transfer in Microchannel With Piranha Pin Fin
Authors: Yu X. , Woodcock C. , Wang Y. , Plawsky J. , Peles Y.
Published: May 2017

An experimental study on subcooled flow boiling with engineering fluid HFE-7000 in a microchannel fitted with piranha pin fins (PPFs) is presented. Heat fluxes of up to 735 W/cm2 were achieved and mass fluxes ranged from 618 kg/m2s to 2569 kg/m2 s. It was found that the flow boiling heat transfer was significantly enhanced with PPFs. The heat transfer coefficient with flow boiling was double the corresponding single-phase flow. Correlations for two-phase heat transfer coefficient and pressure drop in the nucleate flow boiling regime were developed based on the boiling, Weber, and Jakob numbers. The onset of nucleate boiling (ONB) and the critical heat flux (CHF) conditions were determined through visualization and was typically initiated from the last row of fins where temperatures were highest and flow rates lowest.
Local Changes to the Distal Femoral Growth Plate Following Injury in Mice
Authors: Mangano Drenkard Lauren M. , Kupratis Meghan E. , Li Katie , Gerstenfeld Louis C. , Morgan Elise F.
Published: May 2017

Injury to the growth plate is associated with growth disturbances, most notably premature cessation of growth. The goal of this study was to identify spatial changes in the structure and composition of the growth plate in response to injury to provide a foundation for developing therapies that minimize the consequences for skeletal development. We used contrast-enhanced microcomputed tomography (CECT) and histological analyses of a murine model of growth plate injury to quantify changes in the cartilaginous and osseous tissue of the growth plate. To distinguish between local and global changes, the growth plate was divided into regions of interest near to and far from the injury site. We noted increased thickness and CECT attenuation (a measure correlated with glycosaminoglycan (GAG) content) near the injury, and increased tissue mineral density (TMD) of bone bridges within the injury site, compared to outside the injury site and contralateral growth plates. Furthermore, we noted disruption of the normal zonal organization of the physis. The height of the hypertrophic zone was increased at the injury site, and the relative height of the proliferative zone was decreased across the entire injured growth plate. These results indicate that growth plate injury leads to localized disruption of cellular activity and of endochondral ossification. These local changes in tissue structure and composition may contribute to the observed retardation in femur growth. In particular, the changes in proliferative and hypertrophic zone heights seen following injury may impact growth and could be targeted when developing therapies for growth plate injury.
Exact Closed-Form Fractional Spectral Moments for Linear Fractional
Oscillators Excited by a White Noise
Authors: Artale Valeria , Navarra Giacomo , Ricciardello Angela , Barone Giorgio
Published: May 2017

In the last decades, the research community has shown an increasing interest in the engineering applications of fractional calculus, which allows to accurately characterize the static and dynamic behavior of many complex mechanical systems, e.g., the nonlocal or nonviscous constitutive law. In particular, fractional calculus has gained considerable importance in the random vibration analysis of engineering structures provided with viscoelastic damping. In this case, the evaluation of the dynamic response in the frequency domain presents significant advantages, once a probabilistic characterization of the input is provided. On the other hand, closed-form expressions for the response statistics of dynamical fractional systems are not available even for the simplest cases. Taking advantage of the residue theorem, in this paper the exact expressions of the spectral moments of integer and complex orders (i.e., fractional spectral moments of linear fractional oscillators driven by acceleration time histories obtained as samples of stationary Gaussian white noise processes are determined.
Performance of lung ultrasonography for the diagnosis of communityacquired pneumonia in hospitalized children
Authors: Man Sorin Claudiu , Fufezan Otilia , Sas Valentina , Schnell Cristina
Published: May 2017

Aims: The objective of the study was to assess the performance of lung ultrasonography (LUS) as compared to chest radiography and the clinical criteria for the diagnosis of pneumonia in children.Materials and methods: This was a retrospective study in which data were collected from medical files of 81 children admitted with a clinical suspicion of pneumonia in which both an LUS and a chest radiograph during the hospitalization were performed. Reference standard used for the diagnosis of pneumonia were chest radiographs (consolidation, parenchymal infiltrates, and interstitial infiltrate) and clinical criteria. LUSfindings were reported as normal, parenchymal consolidations and pleural effusions. Results: Radiological pneumonia was reported in 72 of the 81 patients (88.9%). LUS identified parenchymal consolidations in 62 cases. LUS correctly identified radiological pneumonia with a sensitivity of 79.2% and a specificity of 44.4%. The positive predictive value (PPV) was 91.9% and the negative predictive value (NPV) was 21.0%. When clinical criteria were used as reference standard, the sensitivity, specificity, PPV and NPV of correctly identifying clinical pneumonia cases by LUS (only consolidations) were 80.0%, 66.7%, 96.8% and 21.0%. When indicative for the presence of pneumonia either the ultrasound consolidation or the ultrasound detected pleural effusion were considered when the sensitivity, PPV and NPV increased to 96.0% (95%CI: 88.8-99.2), 97.3% (95%CI: 92.0-99.1), and 57.1% (95%CI: 27.7-82.2), respectively.Conclusions: In our opinion, our findings together withprevious ones available in the literature recommend LUS as a valuable investigation for the diagnosis of community-acquiredpneumonia in children.
A novel ultrasound-based technique to establish a correlation between disease activity and local carotid stiffness parameters in rheumatoid arthritis
Authors: Şirin Özcan Ayşe Nur , Aslan Abdullah Nabi , Ünal Özlem , Ercan Karabekir , Küçükşahin Orhan
Published: May 2017

Aim: Cardiovascular (CV) disease is the reason for most mortality cases in RA and cannot be explained only by the presence of traditional CV risk factors. In this study, we aimed to investigate the relationship between local carotid stiffness (CS) parameters measured by a novel ultrasound method and inflammatory disease activity in rheumatoid arthritis (RA) patients. Material and methods: The study was conducted with 70 RA patients and 35 control subjects. According to their disease activity score (DAS-28), the RA patients were classified into active RA (n = 36; DAS-28 > 3.2) and inactive RA (n = 34; DAS-28 ≤ 3.2) groups. A novel non-invasive echo-tracking system was used to measure carotid intima-media thickness (C-IMT), diameter, pulsatile strain, distensibility, and carotid pulse wave velocity (PWV) on 128 sites of the common carotid artery. Erythrocytesedimentation rate (ESR) and C-reactive protein (CRP) levels were also determined.Results: Carotid PWV and IMT were significantly higher in the active RA patients (8.20±1.47 m/s and 6.88±1.50 mm, respectively) compared to the inactive group (6.06±1.21 mm and 7.32±1.19 m/s, respectively) and the control subjects (0.68±0.12 mm and 6.41±0.98, respectively). In all RA patients, a statistically significant correlation was found between carotid PWV and age (r=0.435, p<0.001), ESR (r=0.257, p=0.033), and DAS-28 (r=0.314, p=0.009). According to the multivariate logistic regression analysis, age, DAS-28, and ESR were independent predictors of CS.Conclusion: A strong correlation was found between disease activity and local CS parameters in patients with RA. We also demonstrated that both active and inactive RA patients showed increased PWV values compared with the control subjects. This easily applicable and previously confirmed method can be used in future to assess cardiovascular risk in broad study populations from different risk groups.
Laser irradiation of Mg-Al-Zn alloy: Reduced electrochemical kinetics and enhanced performance in simulated body fluid
Authors: Florian David C. , Melia Michael A. , Steuer Fritz W. , Briglia Bruce F. , Purzycki Michael K. , Scully John R. , Fitz-Gerald James M.
Published: May 2017

As a lightweight metal with mechanical properties similar to natural bone, Mg and its alloys are great prospects for biodegradable, load bearing implants. However, rapid degradation and H2 gas production in physiological media has prevented widespread use of Mg alloys. Surface heterogeneities in the form of intermetallic particles dominate the corrosion response. This research shows that surface homogenization significantly improved the biological corrosion response observed during immersion in simulated body fluid (SBF). The laser processed Mg alloy exhibited a 50% reduction in mass loss and H2 evolution after 24 h of immersion in SBF when compared to the wrought, cast alloy. The laser processed samples exhibited increased wettability as evident from wetting angle studies, further suggesting improved biocompatibility. Electrochemical analysis by potentiodynamic polarization measurements showed that the anodic and cathodic kinetics were reduced following laser processing and are attributed to the surface chemical homogeneity.
A strain stiffening theory for transient polymer networks under asymptotically nonlinear oscillatory shear
Authors: Bharadwaj N. Ashwin , Schweizer Kenneth S. , Ewoldt Randy H.
Published: May 2017

We construct a microstructure-based constitutive model that successfully predicts experimental rheology signatures that no other model has previously described. The experimental observations are the low-dimensional descriptions of asymptotically nonlinear oscillatory shear [Ewoldt and Bharadwaj, Rheol. Acta 52, 201–209 (2013)], also known as medium-amplitude oscillatory shear, characterized by four frequency-dependent material measures: [e1](ω), [e3](ω), [v1](ω) and [v3](ω). These slightly nonlinear rheological measurements are the systematic step beyond linear viscoelastic characterization. The material is a transiently crosslinked polymeric hydrogel of aqueous polyvinyl alcohol cross-linked by sodium tetraborate (borax) [Bharadwaj and Ewoldt, J. Rheol. 59, 557–592 (2015)], which shows nonlinear elastic stiffening inferred from [e1](ω) > 0. Here, we hypothesize that the appropriate physical model is a transient network of strain-stiffening elastic elements. We rationalize that all nonlinearities are driven by the instantaneous stretch magnitude Q between junctions, either through strain-stiffening of network elements or through deformation-assisted network structuring. These two physical aspects are embedded into a single nonlinear parameter that successfully captures both elastic energy storage ([e1](ω) and [e3](ω)]) and viscous energy dissipation ([v1](ω) and [v3](ω)), including frequency-dependent sign changes. Analytical results are derived for all four asymptotic nonlinearities. The quantitative agreement provides fit parameters that are related to molecular features and network architecture. While the work here is focused on a specific polymeric system, it represents the broad potential contribution of asymptotic, leading-order nonlinearities to enable structure-rheology insight, constitutive model development, and model selection for soft materials in general.
Reticulon 3–dependent ER-PM contact sites control EGFR nonclathrin endocytosis
Authors: Caldieri Giusi , Barbieri Elisa , Nappo Gilda , Raimondi Andrea , Bonora Massimo , Conte Alexia , Verhoef Lisette G. G. C. , Confalonieri Stefano , Malabarba Maria Grazia , Bianchi Fabrizio , Cuomo Alessandro , Bonaldi Tiziana , Martini Emanuele , Mazza Davide , Pinton Paolo , Tacchetti Carlo , Polo Simona , Di Fiore Pier Paolo , Sigismund Sara
Published: May 2017

ER-PM contacts in nonclathrin endocytosis

The epidermal growth factor receptor (EGFR) is internalized through both clathrin-mediated endocytosis and nonclathrin endocytosis (NCE). The two pathways act in concert to sustain EGFR signaling or its long-term attenuation. The mechanistic underpinnings of EGFR-NCE are unclear. Caldieri
et al.
used a variety of cell and molecular biology approaches to identify nine regulators of EGFR-NCE (see the Perspective by Tan and Anderson). They also identified an additional cargo of the pathway (CD147). One of the regulators of the pathway was the endoplasmic reticulum (ER)-resident protein reticulon 3 (RTN3). Unexpectedly, EGFR-NCE required the formation of specific contacts between the plasma membrane (PM) and the cortical ER, mediated by RTN3. ER-PM contact sites were required in the very early steps of the internalization process for the maturation of NCE tubular intermediates.

Science
, this issue p.
617
; see also p.
584
Myriad take two: Can genomic databases remain secret?
Authors: Guerrini Christi J. , McGuire Amy L. , Majumder Mary A.
Published: May 2017

Trade-secrecy laws clash with a right to one's health data
Male sex in houseflies is determined by
Mdmd
, a paralog of the generic splice factor gene
CWC22
Authors: Sharma Akash , Heinze Svenia D. , Wu Yanli , Kohlbrenner Tea , Morilla Ian , Brunner Claudia , Wimmer Ernst A. , van de Zande Louis , Robinson Mark D. , Beukeboom Leo W. , Bopp Daniel
Published: May 2017

Disrupting housefly gene reverses sex

Sex comes in many forms, even when considered at the molecular level. In different animals, the chromosomes and specific genes that function in sex determination vary widely. As a case in point, the familiar housefly displays a highly variable sex determination system. In this animal, the male determiner (M-factor) instructs male development when it is active, but female development results when it is inactive. Sharma
et al.
now identify the housefly M-factor, which arose via the co-option of existing genes, gene duplication, and neofunctionalization. The findings elucidate the remarkable diversity in sex-determining pathways and the forces that drive this diversity.

Science
, this issue p.
642
Three-dimensional holey-graphene/niobia composite architectures for ultrahigh-rate energy storage
Authors: Sun Hongtao , Mei Lin , Liang Junfei , Zhao Zipeng , Lee Chain , Fei Huilong , Ding Mengning , Lau Jonathan , Li Mufan , Wang Chen , Xu Xu , Hao Guolin , Papandrea Benjamin , Shakir Imran , Dunn Bruce , Huang Yu , Duan Xiangfeng
Published: May 2017

As with donuts, the holes matter

Improving the density of stored charge and increasing the speed at which it can move through a material are usually opposing objectives. Sun
et al.
developed a Nb
2
O
5
/holey graphene framework composite with tailored porosity. The three-dimensional, hierarchically porous holey graphene acted as a conductive scaffold to support Nb
2
O
5
. A high mass loading and improved power capability were reached by tailoring the porosity in the holey graphene backbone with higher charge transport in the composite architecture. The interconnected graphene network provided excellent electron transport, and the hierarchical porous structure in the graphene sheets facilitated rapid ion transport and mitigated diffusion limitations.

Science
, this issue p.
599
Charge delivery goes the distance
Authors: Cheng Hui-Ming , Li Feng
Published: May 2017

A holey graphene scaffold speeds electrons and ions into thicker nanomaterial electrodes
Investigating Clinical Issues by Genotyping of Medically Important Fungi: Why and How?
Authors: Alanio Alexandre , Desnos-Ollivier Marie , Garcia-Hermoso Dea , Bretagne Stéphane
Published: May 2017

Genotyping studies of medically important fungi have addressed elucidation of outbreaks, nosocomial transmissions, infection routes, and genotype-phenotype correlations, of which secondary resistance has been most intensively investigated. Two methods have emerged because of their high discriminatory power and reproducibility: multilocus sequence typing (MLST) and microsatellite length polymorphism (MLP) using short tandem repeat (STR) markers. MLST relies on single-nucleotide polymorphisms within the coding regions of housekeeping genes. STR polymorphisms are based on the number of repeats of short DNA fragments, mostly outside coding regions, and thus are expected to be more polymorphic and more rapidly evolving than MLST markers. There is no consensus on a universal typing system. Either one or both of these approaches are now available for
Candida
spp.,
Aspergillus
spp.,
Fusarium
spp.,
Scedosporium
spp.,
Cryptococcus neoformans
,
Pneumocystis jirovecii
, and endemic mycoses. The choice of the method and the number of loci to be tested depend on the clinical question being addressed. Next-generation sequencing is becoming the most appropriate method for fungi with no MLP or MLST typing available. Whatever the molecular tool used, collection of clinical data (e.g., time of hospitalization and sharing of similar rooms) is mandatory for investigating outbreaks and nosocomial transmission.
Heparanase Upregulation Contributes to Porcine Reproductive and Respiratory Syndrome Virus Release
Authors: Guo Chunhe , Zhu Zhenbang , Guo Yang , Wang Xiaoying , Yu Piao , Xiao Shuqi , Chen Yaosheng , Cao Yongchang , Liu Xiaohong
Published: May 2017

Porcine reproductive and respiratory syndrome virus (PRRSV) continues to cause substantial economic losses to the pig industry worldwide. Heparan sulfate (HS) is used by PRRSV for initial attachment to target cells. However, the role of HS in the late phase of PRRSV infection and the mechanism of virus release from host cells remain largely unknown. In this study, we showed that PRRSV infection caused a decrease in HS expression and upregulated heparanase, the only known enzyme capable of degrading HS. We subsequently demonstrated that the NF-κB signaling pathway and cathepsin L protease were involved in regulation of PRRSV infection-induced heparanase. In addition, we found that ablation of heparanase expression using small interfering RNA duplexes increased cell surface expression of HS and suppressed PRRSV replication and release, whereas overexpression of heparanase reduced HS surface expression and enhanced PRRSV replication and release. These data suggest that PRRSV activates NF-κB and cathepsin L to upregulate and process heparanase, and then the active heparanase cleaves HS, resulting in viral release. Our findings provide new insight into the molecular mechanism of PRRSV egress from host cells, which might help us to further understand PRRSV pathogenesis.

IMPORTANCE
Porcine reproductive and respiratory syndrome virus (PRRSV) causes great economic losses each year to the pig industry worldwide. The molecular mechanism of PRRSV release from host cells largely remains a mystery. In this study, we demonstrate that PRRSV activates NF-κB and cathepsin L to upregulate and process heparanase, and then the active heparanase is released to the extracellular space and exerts enzymatic activity to cleave heparan sulfate, resulting in viral release. Our findings provide new insight into the molecular mechanism of PRRSV egress from host cells, which might help us to further understand PRRSV pathogenesis.
Epstein-Barr Virus Rta-Mediated Accumulation of DNA Methylation Interferes with CTCF Binding in both Host and Viral Genomes
Authors: Chen Yen-Ju , Chen Yu-Lian , Chang Yao , Wu Chung-Chun , Ko Ying-Chieh , Tsao Sai Wah , Chen Jen-Yang , Lin Su-Fang
Published: May 2017

Rta, an Epstein-Barr virus (EBV) immediate-early protein, reactivates viral lytic replication that is closely associated with tumorigenesis. In previous studies, we demonstrated that in epithelial cells Rta efficiently induced cellular senescence, which is an irreversible G
1
arrest likely to provide a favorable environment for productive replications of EBV and Kaposi's sarcoma-associated herpesvirus (KSHV). To restrict progression of the cell cycle, Rta simultaneously upregulates CDK inhibitors and downregulates MYC, CCND1, and JUN, among others. Rta has long been known as a potent transcriptional activator, thus its role in gene repression is unexpected.
In silico
analysis revealed that the promoter regions of
MYC
,
CCND1
, and
JUN
are common in (i) the presence of CpG islands, (ii) strong chromatin immunoprecipitation (ChIP) signals of CCCTC-binding factor (CTCF), and (iii) having at least one Rta binding site. By combining ChIP assays and DNA methylation analysis, here we provide evidence showing that Rta binding accumulated CpG methylation and decreased CTCF occupancy in the regulatory regions of
MYC
,
CCND1
, and
JUN
, which were associated with downregulated gene expression. Stable residence of CTCF in the viral latency and reactivation control regions is a hallmark of viral latency. Here, we observed that Rta-mediated decreased binding of CTCF in the viral genome is concurrent with virus reactivation. Via interfering with CTCF binding, in the host genome Rta can function as a transcriptional repressor for gene silencing, while in the viral genome Rta acts as an activator for lytic gene loci by removing a topological constraint established by CTCF.

IMPORTANCE
CTCF is a multifunctional protein that variously participates in gene expression and higher-order chromatin structure of the cellular and viral genomes. In certain loci of the genome, CTCF occupancy and DNA methylation are mutually exclusive. Here, we demonstrate that the Epstein-Barr virus (EBV) immediate-early protein, Rta, known to be a transcriptional activator, can also function as a transcriptional repressor. Via enriching CpG methylation and decreasing CTCF reloading, Rta binding efficiently shut down the expression of
MYC
,
CCND1
, and
JUN
, thus impeding cell cycle progression. Rta-mediated disruption of CTCF binding was also detected in the latency/reactivation control regions of the EBV genome, and this in turn led to viral lytic cycle progression. As emerging evidence indicates that a methylated EBV genome is a preferable substrate for EBV Zta, the other immediate-early protein, our results suggest a mechanistic link in understanding the molecular processes of viral latent-lytic switch.
Implementation of Isavuconazole in a Fluorescence-Based High-Performance Liquid Chromatography Kit Allowing Simultaneous Detection of All Four Currently Licensed Mold-Active Triazoles
Authors: Jørgensen René , Andersen Siri Rytcher , Astvad Karen Marie Thyssen , Arendrup Maiken Cavling
Published: May 2017

Isavuconazole is a new broad-spectrum triazole agent recently approved for the treatment of both invasive aspergillosis and mucormycosis. Currently, there is no consensus regarding the potential need for TDM of isavuconazole, and no therapeutic window has been defined. However, at the ECIL-6 meeting in 2015, it was advised that TDM is indicated in a number of different settings. In this study, we describe a rapid and validated isocratic HPLC method for fluorescence-based detection and quantification of isavuconazole in human plasma/serum samples. The method is simple and efficient with good accuracy and precision and importantly only requires a small volume of patient plasma/serum. Furthermore, this method is highly sensitive and selective and can be detected simultaneously with the three other triazoles, itraconazole, voriconazole, and posaconazole, without the need for expensive mass spectrometry equipment.
Subcategories of tendinopathy using ultrasound tissue characterization (utc): dorsal mid-portion achilles tendinopathy is more severe than ventral achilles tendinopathy
Authors: Wynter Bee W , Ubhi J , Kumar B
Published: May 2017

Aim

To evaluate the association between tendon structure and clinical severity. Looking specifically at location of pathology, comparing ventral versus dorsal tendinopathy.

Methods

Patients were recruited from a tertiary tendinopathy center between Jan 2015 – June 2016. Inclusion criteria included patients with midportion Achilles tendinopathy, aged between 1870. Patients with insertional Achilles tendinopathy or other suspected etiology were excluded. Patients were assessed using ultrasound tissue characterization (UTC) scanning. UTC software was used to analyse a 2 cm block 24 cm from the calcaneum for percentage of echo type I, II, III and IV. With percentage echo type I+II used as the primary outcome. A doctor also categorised patients into predominately dorsal or ventral pathology based on UTC imaging. VISAA and VAS scores were used for clinical outcome measures. Statistics were undertaken using SPSS, data was not normally distributed

Results

Overall 33 tendons with mid portion Achilles tendinopathy were analysed, the overall percentage echo type I+II showed no correlation to either VISAA (p=0.745, r=0.0600) or VAS (p=0.157, r=0.248). When divided into dorsal and ventral Achilles tendinopathy there was a significant difference between baseline VISAA scores with a lower VISAA score 35 (SD±19) in dorsal group compared with the ventral group 60 (SD±17.1) (p=0.009). There was also a higher VAS score in the dorsal group (mean = 6, SD±2.28) at baseline compared with ventral (mean = 5, SD±3.07), although this was not significant (p=0.416).

Conclusions

This highlights the possibility of using UTC to subcategories patients into ventral and dorsal which seems to correlate to increased clinical severity in the dorsal group. This is perhaps due to increased tension and stretching acting through this part of the tendon on loading and thus more nociceptive stimulation and greater dysfunction of the tendon. This could be used to help determine differing rehabilitation interventions in future with differing intensities for the two groups. It further highlights as previous studies1,2have that there is no direct correlation between overall structure and clinical severity.
Multimorbidity as an important issue among women: results of a gender difference investigation in a large population-based cross-sectional study in West Asia
Authors: Alimohammadian Masoomeh , Majidi Azam , Yaseri Mehdi , Ahmadi Batoul , Islami Farhad , Derakhshan Mohammad , Delavari Alireza , Amani Mohammad , Feyz-Sani Akbar , Poustchi Hossein , Pourshams Akram , Sadjadi Amir Mahdi , Khoshnia Masoud , Qaravi Samad , Abnet Christian C , Dawsey Sanford , Brennan Paul , Kamangar Farin , Boffetta Paolo , Sadjadi Alireza , Malekzadeh Reza
Published: May 2017

Objectives

To investigate the impact of gender on multimorbidity in northern Iran.

Design

A cross-sectional analysis of the Golestan cohort data.

Setting

Golestan Province, Iran.

Study population

49 946 residents (age 40–75 years) of Golestan Province, Iran.

Main outcome measures

Researchers collected data related to multimorbidity, defined as co-existence of two or more chronic diseases in an individual, at the beginning of a representative cohort study which recruited its participants from 2004 to 2008. The researchers utilised simple and multiple Poisson regression models with robust variances to examine the simultaneous effects of multiple factors.

Results

Women had a 25.0% prevalence of multimorbidity, whereas men had a 13.4% prevalence (p<0.001). Women of all age-groups had a higher prevalence of multimorbidity. Of note, multimorbidity began at a lower age (40–49 years) in women (17.3%) compared with men (8.6%) of the same age (p<0.001). This study identified significant interactions between gender as well as socioeconomic status, ethnicity, physical activity, marital status, education level and smoking (p<0.01).

Conclusion

Prevention and control of multimorbidity requires health promotion programmes to increase public awareness about the modifiable risk factors, particularly among women.
Health status and needs of cancer survivors attending the Sydney Survivorship Centre clinics and programmes: a protocol for longitudinal evaluation of the centre’s services
Authors: Vardy Janette L , Tan Cindy , Turner Jane D , Dhillon Haryana
Published: May 2017

Introduction

The care of cancer survivors after primary adjuvant treatment is recognised as a distinct phase of the cancer journey. Recent research highlights the importance of lifestyle factors in treating symptoms, potentially decreasing risk of a cancer recurrence and modifying the risk of developing other chronic illnesses that are increased in the cancer population. Survivorship services aim to deliver care that addresses these issues. The overall aims are to determine the health status of cancer survivors and to evaluate the services offered by the Sydney Survivorship Centre (SSC).

Methods and analysis

This is an observational single-centre study evaluating the longitudinal physical and psychological health, symptoms, quality of life and lifestyle (physical activity and nutrition) of early stage cancer survivors attending the multidisciplinary Sydney Survivorship Clinic and survivors (at any stage of the cancer journey) and caregivers participating in SSC courses. Evaluation of patient satisfaction is included. Patient-reported outcomes and patient characteristics will be summarised using descriptive statistics with Spearman rank sum correlation coefficients to determine associations between patient-reported outcomes. Regression modelling may be used to further evaluate associations and to investigate risk factors and predictors of health outcomes. Qualitative data will be analysed using thematic analysis to identify themes. Sample size will be determined by attendance of consenting patients at clinics and courses.

Ethics and dissemination

The study has received ethics approval from the Concord Repatriation General Hospital Human Research Ethics Committee (HREC/14/CRGH/23). The results will be published and presented at appropriate conferences.

This study will provide important information regarding the health status and needs of Australian cancer survivors and the ability of the survivorship centre to address these needs. These data will shape the future direction of survivorship care in Australia and facilitate the design of interventions or measures to provide better quality of care to this patient population.
The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium
Authors: Moghadasi Setareh , Meeks Huong D , Vreeswijk Maaike PG , Janssen Linda AM , Borg Åke , Ehrencrona Hans , Paulsson-Karlsson Ylva , Wappenschmidt Barbara , Engel Christoph , Gehrig Andrea , Arnold Norbert , Hansen Thomas Van Overeem , Thomassen Mads , Jensen Uffe Birk , Kruse Torben A , Ejlertsen Bent , Gerdes Anne-Marie , Pedersen Inge Søkilde , Caputo Sandrine M , Couch Fergus , Hallberg Emily J , van den Ouweland Ans MW , Collée Margriet J , Teugels Erik , Adank Muriel A , van der Luijt Rob B , Mensenkamp Arjen R , Oosterwijk Jan C , Blok Marinus J , Janin Nicolas , Claes Kathleen BM , Tucker Kathy , Viassolo Valeria , Toland Amanda Ewart , Eccles Diana E , Devilee Peter , Van Asperen Christie J , Spurdle Amanda B , Goldgar David E , García Encarna Gómez
Published: May 2017

Background

We previously showed that the BRCA1 variant c.5096G>A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1*R1699Q carriers.

Methods

Data were collected from 129 BRCA1*R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions.

Results

In this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83).

Conclusion

Our results confirm that BRCA1*R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history.
Seed bank dynamics of blowout penstemon in relation to local patterns of sand movement on the Ferris Dunes, south-central Wyoming
Authors: Tilini Kassie L. , Meyer Susan E. , Allen Phil S.
Published: May 2017

Plants restricted to active sand dunes possess traits that enable both survival in a harsh environment and local migration in response to a shifting habitat mosaic. We examined seed bank dynamics of Penstemon haydenii S. Watson (blowout penstemon) in relation to local sand movement. We measured within-year sand movement along a 400 m transect and examined plant density, seed production, and seed density in relation to this movement. Plant densities were highest in areas of moderate sand movement. Annual seed rain averaged 13 seeds·m−2, whereas persistent seed bank density (0–10 cm depth) averaged only 0.1 seeds·m−2. A laboratory burial experiment with nondormant (chilled) seeds showed that most deeply buried seeds (>6 cm) were held in enforced dormancy under spring conditions, while seeds at intermediate depths (4–6 cm) were induced into secondary dormancy that was broken by subsequent drying and re-chilling, thus promoting seed carryover until the following spring. Most near-surface seeds produced seedlings. Enforced and secondary dormancy provide mechanisms for maintaining a persistent seed bank of more deeply buried seeds that could become part of the active seed bank as sand movement re-exposes them near the surface. This could facilitate both population persistence and migration as previously occupied habitat becomes unsuitable.
Negotiating a career in physics: Early stages in India
Authors: Dasgupta Arundhati
Published: May 2017

In this work we discuss anecdotal evidence of social biases and prejudices that may form barriers in building a successful career for women in physics. We discuss the opportunities that exist, and how to use them for career advancement. This work is written for the Special Issue entitled Proceedings of The First Regional Conference for Women in Physics (RCWP-2016), 25–27 April, 2016, Islamabad, Pakistan. To connect with the theme, this paper is based on India, a nation geopolitically close, and where the author’s early career in physics was shaped.
Vascular function and arginine and dimethylarginines in gentamicin-induced renal failure: a possible effect of heme oxygenase 1 inducer hemin
Authors: Aycan-Ustyol Esra , Kabasakal Merve , Bekpinar Seldag , Alp-Yıldırım F. Ilkay , Tepe Ozge , Giris Murat , Ozluk Yasemin , Unlucerci Yesim , Uydes-Dogan B. Sonmez , Uysal Mujdat
Published: May 2017

Increased oxidative stress and disturbance in nitric oxide bioavailability lead to endothelial dysfunction and cardiovascular complication in renal disease. Gentamicin (GM), a commonly used antibiotic, exhibits a toxic effect on renal proximal tubules. Prevention of its nephrotoxicity is important. Therefore, we investigated whether heme oxygenase 1 HO-1) induction influenced kidney and vascular function in GM-administered rats. GM (100 mg·kg–1·day–1; i.p.) was given to rats alone or together with hemin (20 mg·kg–1 on alternate days; i.p.) for 14 days. Plasma and kidney l-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) as well as kidney 4-hydroxynonenal (HNE) levels and myeloperoxidase (MPO) activity were measured. Histopathological examinations of kidney and relaxation and contraction responses of aorta were also examined. GM increased serum SDMA, urea nitrogen (BUN), and creatinine levels and caused histopathological alterations in the kidney. GM elevated HO-1 protein and mRNA expressions, 4-HNE level, and MPO activity and decreased antioxidant enzyme activities and l-arginine levels in the kidney. Decreased relaxation and contraction were detected in the aorta. Hemin restored renal oxidative stress and inflammatory changes together with vascular dysfunction, but did not affect SDMA, BUN, or creatinine levels. We conclude that HO-1 induction may be effective in improving renal oxidative stress, inflammation, and vascular dysfunction mediated by GM.
Fermilab proton accelerator complex status and improvement plans
Authors: Shiltsev Vladimir
Published: May 2017

Fermilab carries out an extensive program of accelerator-based high energy particle physics research at the Intensity Frontier that relies on the operation of 8 GeV and 120 GeV proton beamlines for a number of fixed target experiments. Routine operation with a world-record 700 kW of average 120 GeV beam power on the neutrino target was achieved in 2017 as a result of the Proton Improvement Plan (PIP) upgrade. There are plans to further increase the power from 900–1000 kW. The next major upgrade of the FNAL accelerator complex, called PIP-II, is under development. It aims at 1.2 MW beam power on target at the start of the LBNF/DUNE experiment in the middle of the next decade and assumes replacement of the existing 40 years old 400 MeV normal-conducting Linac with a modern 800 MeV superconducting RF linear accelerator. There are several concepts to further double the beam power to [Formula: see text] 2.4 MW after replacement of the existing 8 GeV Booster synchrotron. In this review, we discuss current performance of the Fermilab proton accelerator complex, the upgrade plans for the next two decades and the accelerator R&D program to address cost and performance risks for these upgrades.
Remarks on Heisenberg–Euler-type electrodynamics
Authors: Kruglov S. I.
Published: May 2017

We consider Heisenberg–Euler-type model of nonlinear electrodynamics with two parameters. Heisenberg–Euler electrodynamics is a particular case of this model. Corrections to Coulomb’s law at [Formula: see text] are obtained and energy conditions are studied. The total electrostatic energy of charged particles is finite. The charged black hole solution in the framework of nonlinear electrodynamics is investigated. We find the asymptotic of the metric and mass functions at [Formula: see text]. Corrections to the Reissner–Nordström solution are obtained.