bluuebunny/crossref_metadata_2025 huggingface dataset:
Concomitant Loss of the Glyoxalase System and Glycolysis Makes the Uncultured Pathogen “Candidatus Liberibacter asiaticus” an Energy Scavenger
Authors: Jain Mukesh , Munoz-Bodnar Alejandra , Gabriel Dean W.
Published: September 2017

Methylglyoxal (MG) is a cytotoxic, nonenzymatic by-product of glycolysis that readily glycates proteins and DNA, resulting in carbonyl stress. Glyoxalase I and II (GloA and GloB) sequentially convert MG into
d
-lactic acid using glutathione (GSH) as a cofactor. The glyoxalase system is essential for the mitigation of MG-induced carbonyl stress, preventing subsequent cell death, and recycling GSH for maintenance of cellular redox poise. All pathogenic liberibacters identified to date are uncultured, including “
Candidatus
Liberibacter asiaticus,” a psyllid endosymbiont and causal agent of the severely damaging citrus disease “huanglongbing.”
In silico
analysis revealed the absence of
gloA
in “
Ca
. Liberibacter asiaticus” and all other pathogenic liberibacters. Both
gloA
and
gloB
are present in
Liberibacter crescens
, the only liberibacter that has been cultured.
L. crescens
GloA was functional in a heterologous host. Marker interruption of
gloA
in
L. crescens
appeared to be lethal. Key glycolytic enzymes were either missing or significantly downregulated in “
Ca
. Liberibacter asiaticus” compared to (cultured)
L. crescens
. Marker interruption of
sut
, a sucrose transporter gene in
L. crescens
, decreased its ability to take up exogenously supplied sucrose in culture. “
Ca
. Liberibacter asiaticus” lacks a homologous sugar transporter but has a functional ATP/ADP translocase, enabling it to thrive both in psyllids and in the sugar-rich citrus phloem by (i) avoiding sucrose uptake, (ii) avoiding MG generation via glycolysis, and (iii) directly importing ATP from the host cell. MG detoxification enzymes appear to be predictive of “
Candidatus
” status for many uncultured pathogenic and environmental bacteria.

IMPORTANCE
Discovered more than 100 years ago, the glyoxalase system is thought to be present across all domains of life and fundamental to cellular growth and viability. The glyoxalase system protects against carbonyl stress caused by methylglyoxal (MG), a highly reactive, mutagenic and cytotoxic compound that is nonenzymatically formed as a by-product of glycolysis. The uncultured alphaproteobacterium “
Ca
. Liberibacter asiaticus” is a well-adapted endosymbiont of the Asian citrus psyllid, which transmits the severely damaging citrus disease “huanglongbing.” “
Ca
. Liberibacter asiaticus” lacks a functional glyoxalase pathway. We report here that the bacterium is able to thrive both in psyllids and in the sugar-rich citrus phloem by (i) avoiding sucrose uptake, (ii) avoiding (significant) MG generation via glycolysis, and (iii) directly importing ATP from the host cell. We hypothesize that failure to culture “
Ca
. Liberibacter asiaticus” is at least partly due to its dependence on host cells for both ATP and MG detoxification.
Identification of an Alternative to Proteus vulgaris as a Laboratory Standard for Hydrogen Sulfide Production
Authors: Randall Nar’Asha , Nance Cara , Huggins Cathy , Huggins James , Bolyard Mark
Published: September 2017

This project involved the evaluation of a biosafety level 1 alternative to Proteus vulgaris as a positive control for the production of hydrogen sulfide. We determined that Citrobacter freundii could serve as an excellent substitute for P. vulgaris, and that lead acetate strips used in conjunction with triple sugar iron media allows for consistent results following evaluation after up to one week.
Participation in a Year-Long CURE Embedded into Major Core Genetics and Cellular and Molecular Biology Laboratory Courses Results in Gains in Foundational Biological Concepts and Experimental Design Skills by Novice Undergraduate Researchers
Authors: Peteroy-Kelly Marcy A. , Marcello Matthew R. , Crispo Erika , Buraei Zafir , Strahs Daniel , Isaacson Marisa , Jaworski Leslie , Lopatto David , Zuzga David
Published: September 2017

This two-year study describes the assessment of student learning gains arising from participation in a year-long curriculum consisting of a classroom undergraduate research experience (CURE) embedded into second-year, major core Genetics and Cellular and Molecular Biology (CMB) laboratory courses. For the first course in our CURE, students used micro-array or RNAseq analyses to identify genes important for environmental stress responses by
Saccharomyces cerevisiae
. The students were tasked with creating overexpressing mutants of their genes and designing their own original experiments to investigate the functions of those genes using the overexpression and null mutants in the second CURE course. In order to evaluate student learning gains, we employed three validated concept inventories in a pretest/posttest format and compared gains on the posttest versus the pretest with student laboratory final grades. Our results demonstrated that there was a significant correlation between students earning lower grades in the Genetics laboratory for both years of this study and gains on the Genetics Concept Assessment (GCA). We also demonstrated a correlation between students earning lower grades in the Genetics laboratory and gains on the Introductory Molecular and Cell Biology Assessment (IMCA) for year 1 of the study. Students furthermore demonstrated significant gains in identifying the variable properties of experimental subjects when assessed using the Rubric for Experimental (RED) design tool. Results from the administration of the CURE survey support these findings. Our results suggest that a year-long CURE enables lower performing students to experience greater gains in their foundational skills for success in the STEM disciplines.
Using a Concept Inventory to Reveal Student Thinking Associated with Common Misconceptions about Antibiotic Resistance
Authors: Stevens Ann M. , Smith Ann C. , Marbach-Ad Gili , Balcom Sarah A. , Buchner John , Daniel Sandra L. , DeStefano Jeffrey J. , El-Sayed Najib M. , Frauwirth Kenneth , Lee Vincent T. , McIver Kevin S. , Melville Stephen B. , Mosser David M. , Popham David L. , Scharf Birgit E. , Schubot Florian D. , Seyler Richard W. , Shields Patricia Ann , Song Wenxia , Stein Daniel C. , Stewart Richard C. , Thompson Katerina V. , Yang Zhaomin , Yarwood Stephanie A.
Published: September 2017

Misconceptions, also known as alternate conceptions, about key concepts often hinder the ability of students to learn new knowledge. Concept inventories (CIs) are designed to assess students’ understanding of key concepts, especially those prone to misconceptions. Two-tiered CIs include prompts that ask students to explain the logic behind their answer choice. Such two-tiered CIs afford an opportunity for faculty to explore the student thinking behind the common misconceptions represented by their choice of a distractor. In this study, we specifically sought to probe the misconceptions that students hold prior to beginning an introductory microbiology course (i.e., preconceptions). Faculty-learning communities at two research-intensive universities used the validated Host-Pathogen Interaction Concept Inventory (HPI-CI) to reveal student preconceptions. Our method of deep analysis involved communal review and discussion of students’ explanations for their CI answer choice. This approach provided insight valuable for curriculum development. Here the process is illustrated using one question from the HPI-CI related to the important topic of antibiotic resistance. The frequencies with which students chose particular multiple-choice responses for this question were highly correlated between institutions, implying common underlying misconceptions. Examination of student explanations using our analysis approach, coupled with group discussions within and between institutions, revealed patterns in student thinking to the participating faculty. Similar application of a two-tiered concept inventory by general microbiology instructors, either individually or in groups, at other institutions will allow them to better understand student thinking related to key concepts in their curriculum.
The entrapped twin: a case of fetus-in-fetu
Authors: Yaacob Rashide , Zainal Mokhtar Annisa , Abang Jamari Dyg Zahratul Hamrak , Jaafar Norliana
Published: September 2017

Fetus-in-fetu (FIF) is a rare entity in which malformed parasitic twin grows inside the body of its twin. It is most commonly presented with mass in the abdomen. We present a case of a 15-year-old boy who presented with abdominal mass since infancy. Radiological investigations are suggestive of FIF. Intraoperatively, malformed fetus in a sac was found and excised. Postoperatively the patient recovers well and was put on follow-up.
Case of methaemoglobinaemia caused by tree oils and kerosene
Authors: Gupta Kartik , Jha Milind , Jadon Ranveer S , Sood Rita
Published: September 2017

We report a case of a young man who allegedly consumed 100 mL of an indigenous pesticide which is used for the killing of rats in households in India. The constituents were azadirachtin oil (40%), tea oil (15%), pine oil (25%) and kerosene oil (20%). He presented to us with shortness of breath and altered sensorium and was found to have fMetHb (fraction of methaemoglobin) level of 80%, which has been postulated to have a fatal outcome. He responded to a low dose of methylene blue along with intravenous vitamin C and the level of fMetHb came down to 20% within 1 hour. His sensorium improved markedly with a decrease in fMetHb to non-toxic levels and he was discharged 5 days after admission. A literature review pertaining to these constituents individually or in combination causing methaemoglobinaemia is discussed in the context of this case.
Disentangling age–gender interactions associated with risks of fatal and non-fatal road traffic injuries in the Sultanate of Oman
Authors: Al-Aamri Amira K , Padmadas Sabu S , Zhang Li-Chun , Al-Maniri Abdullah A
Published: September 2017

Objective

Road traffic injuries (RTIs) are the leading cause of disability-adjusted life years lost in Oman, Saudi Arabia and United Arab Emirates. Injury prevention strategies often overlook the interaction of individual and behavioural risk factors in assessing the severity of RTI outcomes. We conducted a systematic investigation of the underlying interactive effects of age and gender on the severity of fatal and non-fatal RTI outcomes in the Sultanate of Oman.

Methods

We used the Royal Oman Police national database of road traffic crashes for the period 2010–2014. Our study was based on 35 785 registered incidents: of these, 10.2% fatal injuries, 6.2% serious, 27.3% moderate, 37.3% mild injuries and 19% only vehicle damage but no human injuries. We applied a generalised ordered logit regression to estimate the effect of age and gender on RTI severity, controlling for risk behaviours, personal characteristics, vehicle, road, traffic, environment conditions and geographical location.

Results

The most dominant group at risk of all types of RTIs was young male drivers. The probability of severe incapacitating injuries was the highest for drivers aged 25–29 (26.6%) years, whereas the probability of fatal injuries was the highest for those aged 20–24 (26.9%) years. Analysis of three-way interactions of age, gender and causes of crash show that overspeeding was the primary cause of different types of RTIs. In particular, the probability of fatal injuries among male drivers attributed to overspeeding ranged from 3%–6% for those aged 35 years and above to 13.4% and 17.7% for those aged 25–29 years and 20–24 years, respectively.

Conclusions

The high burden of severe and fatal RTIs in Oman was primarily attributed to overspeed driving behaviour of young male drivers in the 20–29 years age range. Our findings highlight the critical need for designing early gender-sensitive road safety interventions targeting young male and female drivers.
Publication of interventional phase 3 and 4 clinical trials in radiation oncology: an observational study
Authors: Pérez-Alija Jaime , Gallego Pedro , Linares Isabel , Ambroa Eva , Pedro Agustí
Published: September 2017

Objectives

Clinical trials produce the best data available for decision-making in modern evidence-based medicine. We aimed to determine the rate of non-publication of interventional phase 3 and 4 clinical trials involving patients with cancer undergoing radiotherapy.

Setting

The ClinicalTrials.gov database was searched for interventional phase 3 and 4 trials in radiotherapy with a primary completion date before 1 January 2013. We determined how many of these registry entries have not published the compulsory deposition of their results in the database and performed a systematic search for published studies in peer-reviewed journals.

Results

Of 576 trials, 484 (84.0%) did not deposit a summary result in the registry. In addition, 44.9% of them did not publish their results in a peer-reviewed journal. Similar percentages were found for most cancer subtypes: brain (41%), breast (38%), cervical (66%), colorectal (38%), lung (48%), prostate (45%), bladder (56%), head and neck (56%) and lymphoma (33%).

Conclusion

Our results show that most trials in radiation oncology did not report the results in the registry. Almost half of these trials have not been published in the biomedical literature. This means that a large number of study participants were exposed to the risks of trial participation without the supposed benefits that sharing and publishing of results would offer to future generations of patients.
Urine cytology screening of French workers exposed to occupational urinary tract carcinogens: a prospective cohort study over a 20-year period
Authors: Dutheil Frederic , Rouanet Lucile , Mulliez Aurélien , Naughton Geraldine , Fontana Luc , Druet-Cabanac Michel , Moustafa Farès , Chamoux Alain
Published: September 2017

Objectives

To demonstrate that urine cytology screening can provide relevant epidemiological data for earlier detection of urothelial cancer caused by occupational exposure.

Design

Prospective cohort study.

Setting

Industries using urothelial carcinogens in France. Urine samples were collected on site, after a work week and were analysed at the University Hospital of Clermont-Ferrand, France.

Participants

Participants were workers exposed to urothelial carcinogens. Women and current smokers at time of study recruitment were exclusion criteria.

Outcomes

Urine cells atypia were ranged into three classes: negative/normal, atypical/suspicious/dysplasia or positive/malignant.

Results

We included 2020 workers over a period of 20 years from 1993 to 2013: 606 worked in rubber manufacturing, 692 from metal processing, 245 in chemical industry and 477 in roadwork and building industry. Workers had a mean exposure of 15.2±10.4 years before their first urine cytology screening. There was a mean of 3.4±4.3 urine cytology screenings per worker between 1993 and 2013. 6478 cytology were normal, 462 suspicious and 13 malignant. Suspicious and malignant cytology occurred in 4.8% of workers exposed for 1–10 years, 6.2% for 11–20 years of exposure, 7.6% for 21–30 years and 8.6% for >30 years (p<0.001). Using exposure for 1–10 years as reference, the adjusted OR of receiving a suspicious or malignant diagnosis increased with duration of exposure: OR=1.50 (95% CI 1.10 to 2.05, p=0.01) for 21–30 years and OR=1.78 (95% CI 1.23 to 2.56, p=0.002) for >30 years of exposure. Using metal processing as reference, the risk of pathological urine cytology results increased for rubber manufacturing (OR=1.32, 95% CI 1.05 to 1.65, p=0.02), with a trend for roadwork and building industry (OR=1.39, 95% CI 0.98 to 1.97, p=0.07) and for chemical industry (OR=1.34, 95% CI 0.94 to 1.93, p=0.11).

Conclusions

Urine cytology is a useful tool in occupational medicine. We promote new guidelines with an early screening of urothelial cancer by cytology, starting with beginning of exposure.
A randomised controlled trial of an intervention delivered by app instant messaging to increase the acceptability of effective contraception among young people in Tajikistan: study protocol
Authors: McCarthy Ona , Leurent Baptiste , Edwards Phil , Tokhirov Ravshan , Free Caroline
Published: September 2017

Introduction

Women in lower income countries experience unintended pregnancies at a higher rate compared with women in higher income countries. Unintended pregnancy is associated with numerous poorer health outcomes for both women and their children. In Tajikistan, an estimated 26% of married individuals aged 15–24 years have an unmet need for contraception. The strong cultural value placed on childbearing and oppositional attitudes towards contraception are major barriers to contraceptive uptake in the country.

Mobile phone ownership is widespread in Tajikistan. The option of receiving reproductive health support on your personal phone may be an appealing alternative to attending a clinic, particularly for young people. The London School of Hygiene & Tropical Medicine and the Tajik Family Planning Association have partnered to develop and evaluate a contraceptive behavioural intervention delivered by mobile phone. The intervention was developed in 2015–2016 guided by behavioural science. It consists of short instant messages sent through an app over 4 months, contains information about contraception and behaviour change methods.

Methods and analysis

This randomised controlled trial is designed to evaluate the effect of the intervention on self-reported acceptability of effective contraception at 4 months. 570 men and women aged 16–24 years will be allocated with a ratio of 1:1 to receive the intervention messages or the control messages about trial participation. The messages will be sent through the Tajik Family Planning Association’s ‘healthy lifestyles’ app, which contains basic information about contraception.

Ethics and dissemination

The trial was granted ethical approval by the London School of Hygiene & Tropical Medicine Interventions Research Ethics Committee on 16 May 2016 and by the Tajik National Scientific and Research Centre on Paediatrics and Child Surgery on 15 April 2016. The results of the trial will be submitted for publication in peer-reviewed academic journals and disseminated to study stakeholders.

Trial registration number

Clinicaltrial.govNCT02905513.

Date of registration

14 September 2016.

WHO trial registration dataset

http://apps.who.int/trialsearch/Trial2.aspx?TrialID=NCT02905513
Verbal augmented feedback in the rehabilitation of lower extremity musculoskeletal dysfunctions: a systematic review
Authors: Storberget Marianne , Grødahl Linn Helen J , Snodgrass Suzanne , Vliet Paulette van , Heneghan Nicola
Published: September 2017

Background

Verbal augmented feedback (VAF) is commonly used in physiotherapy rehabilitation of individuals with lower extremity musculoskeletal dysfunction or to induce motor learning for injury prevention. Its effectiveness for acquisition, retention and transfer of learning of new skills in this population is unknown.

Objectives

First, to investigate the effect of VAF for rehabilitation and prevention of lower extremity musculoskeletal dysfunction. Second, to determine its effect on motor learning and the stages of acquisition, retention and transfer in this population.

Design

Systematic review designed in accordance with the Centre for Reviews and Dissemination and reported in line with Preferred Reporting Items for Systematic Review and Meta-analysis.

Method

MEDLINE, Embase, PubMed and five additional databases were searched to identify primary studies with a focus on VAF for prevention and rehabilitation of lower extremity musculoskeletal dysfunction. One reviewer screened the titles and abstracts. Two reviewers retrieved full text articles for final inclusion. The first reviewer extracted data, whereas the second reviewer audited. Two reviewers independently assessed risk of bias and quality of evidence using Cochrane Collaboration’s tool and Grading of Recommendations Assessment, Development and Evaluation, respectively.

Results

Six studies were included, with a total sample of 304 participants. Participants included patients with lateral ankle sprain (n=76), postoperative ACL reconstruction (n=16) and healthy individuals in injury prevention (n=212). All six studies included acquisition, whereas retention was found in five studies. Only one study examined transfer of the achieved motor learning (n=36). VAF was found to be effective for improving lower extremity biomechanics and postural control with moderate evidence from five studies.

Conclusion

VAF should be considered in the rehabilitation of lower extremity musculoskeletal dysfunctions. However, it cannot be unequivocally confirmed that VAF is effective in this population, owing to study heterogeneity and a lack of high-quality evidence. Nevertheless, positive effects on lower extremity biomechanics and postural control have been identified. This suggests that further research into this topic is warranted where an investigation of long-term effects of interventions is required. All stages (acquisition, retention and transfer) should be evaluated.
Gene expression signatures of mating system evolution
Authors: Renn Suzy C.P. , Machado Heather E. , Duftner Nina , Sessa Anna K. , Harris Rayna M. , Hofmann Hans A.
Published: September 2017

The diversity of mating systems among animals is astounding. Importantly, similar mating systems have evolved even across distantly related taxa. However, our understanding of the mechanisms underlying these convergently evolved phenotypes is limited. Here, we examine on a genomic scale the neuromolecular basis of social organization in cichlids of the tribe Ectodini from Lake Tanganyika. Using field-collected males and females of four closely related species representing two independent evolutionary transitions from polygyny to monogamy, we take a comparative transcriptomic approach to test the hypothesis that these independent transitions have recruited similar gene sets. Our results demonstrate that while lineage and species exert a strong influence on neural gene expression profiles, social phenotype can also drive gene expression evolution. Specifically, 331 genes (∼6% of those assayed) were associated with monogamous mating systems independent of species or sex. Among these genes, we find a strong bias (4:1 ratio) toward genes with increased expression in monogamous individuals. A highly conserved nonapeptide system known to be involved in the regulation of social behavior across animals was not associated with mating system in our analysis. Overall, our findings suggest deep molecular homologies underlying the convergent or parallel evolution of monogamy in different cichlid lineages of Ectodini.
Cache-Aware SPM Allocation to Reduce Worst-Case Execution Time for Hybrid SPM-Caches
Authors: Wu Lan , Zhang Wei
Published: September 2017

Scratch-Pad Memories (SPMs) have been increasingly used in real-time and embedded systems. However, it is still unknown and challenging to reduce the worst-case execution time (WCET) for hybrid SPM-cache architecture, where an SPM and a cache memory are placed on-chip in parallel to cooperatively improve performance and/or energy efficiency. In this paper, we study four SPM allocation strategies to reduce the WCET for hybrid SPM-caches with different complexities. These algorithms differ by whether or not they can cooperate with the cache or be aware of the WCET. Our evaluation shows that the cache-aware and WCET-oriented SPM allocation can minimize the WCET for real-time benchmarks with little or even positive impact on the average-case execution time (ACET).
Middle Devonian coccosteid (Arthrodira, Placodermi) biostratigraphy of Scotland and Estonia
Authors: Newman Michael J. , Den Blaauwen Jan L. , Tuuling Tormi
Published: September 2017

A coccosteid nuchal bone from the Middle Devonian Tamme Cliffs locality in Estonia is described as
Dickosteus
cf.
threiplandi
,
D
.
threiplandi
being a common species in the Middle Devonian of the Orcadian Basin, Scotland. A number of other bones from Tamme Cliffs are also placed in this genus. It is already known that the coccosteids
Coccosteus cuspidatus
and probably
Millerosteus minor
are present in both areas. A final coccosteid genus
Watsonosteus
has been shown previously to also be present in both areas. We can confirm that the sequence of coccosteid genera is the same in both the Orcadian Basin and Estonia and is, from the lowest horizon,
Coccosteus
–
Dickosteus
–
Millerosteus
–
Watsonosteus
. The coccosteids in Estonia are also associated with other Scottish faunal elements (including co-specific species), such as other placoderms, acanthodians and sarcopterygians. This implies a very close connection between the two areas in the Middle Devonian. Some of the acanthodian species of the Orcadian Basin are also present in Belarus and Severnaya Zemlya, suggesting that other Orcadian Basin forms, including coccosteids may be present at these localities and perhaps elsewhere on the Old Red Sandstone continent. Further investigation may allow a continent-wide correlation at species level across the whole continent.
Demarcation of the boundary between Middle Devonian Upper Stromness Flagstone and Rousay Flagstone formations in Westray, Orkney
Authors: Leather David
Published: September 2017

The only official maps to show a boundary between the Middle Devonian Stromness and Rousay Flagstones on Orkney are those published by the Geological Survey in 1932 and 1935. Since then, the difficulties of defining and locating this boundary have challenged many workers in the Orcadian Lake Basin. In 2015, the introduction of biozones by Uisdean Michie, based on fossil fish, and the recent discovery in Westray of the zone fossils
Osteolepis panderi
and
Thursius pholidotus
in a prominent fish bed across the island, has permitted the boundary for the base of the Rousay Formation to be determined in that part of Orkney. It is suggested that other characteristics of the fish bed of this rhythmic cycle of sediments, together with those in adjacent cycles, may be used as a marker for further correlation and mapping across the basin.
Algorithmic Compression of Finite Tree Languages by Rigid Acyclic Grammars
Authors: Eberhard Sebastian , Ebner Gabriel , Hetzl Stefan
Published: September 2017

We present an algorithm to optimally compress a finite set of terms using a vectorial totally rigid acyclic tree grammar. This class of grammars has a tight connection to proof theory, and the grammar compression problem considered in this article has applications in automated deduction. The algorithm is based on a polynomial-time reduction to the MaxSAT optimization problem. The crucial step necessary to justify this reduction consists of applying a term rewriting relation to vectorial totally rigid acyclic tree grammars. Our implementation of this algorithm performs well on a large real-world dataset.
The Problems With Prosecutors
Authors: Sklansky David Alan
Published: September 2017

Most scholarship on prosecutors in the United States is diagnostic, prescriptive, or both; the motivating questions are, What is the problem with prosecutors, and how do we fix it? Answering those questions has been difficult, in part because there are at least seven different problems with American prosecutors. Six of those problems are relatively familiar: the power of prosecutors, the discretion they exercise, the illegality in which they too often are found to have engaged, the punitive ideology that shapes many of their practices, their often-frustrating unaccountability, and organizational inertia within prosecutors’ offices. These problems intersect, so they are difficult to address separately. The seventh problem is discussed less often but may be the most basic: the ambiguity of the prosecutor's role. That problem needs to be understood as well if progress is to be made addressing the other six.
Social Mobilization
Authors: Rogers Todd , Goldstein Noah J. , Fox Craig R.
Published: September 2017

This article reviews research from several behavioral disciplines to derive strategies for prompting people to perform behaviors that are individually costly and provide negligible individual or social benefits but are meaningful when performed by a large number of individuals. Whereas the term social influence encompasses all the ways in which people influence other people, social mobilization refers specifically to principles that can be used to influence a large number of individuals to participate in such activities. The motivational force of social mobilization is amplified by the fact that others benefit from the encouraged behaviors, and its overall impact is enhanced by the fact that people are embedded within social networks. This article may be useful to those interested in the provision of public goods, collective action, and prosocial behavior, and we give special attention to field experiments on election participation, environmentally sustainable behaviors, and charitable giving.
Oxidative Stress Delays Prometaphase/Metaphase of the First Cleavage in Mouse Zygotes via the MAD2L1‐Mediated Spindle Assembly Checkpoint
Authors: Wu Que , Li Zhiling , Huang Yue , Qian Diting , Chen Man , Xiao Wanfen , Wang Bin
Published: September 2017

In zygotes, DNA damage delays the first cleavage to enable repair. Our previous study found that 0.03 mM hydrogen peroxide (H2O2) was the minimum concentration required for induction of oxidative DNA damage in mouse zygotes and that this represented the most similar situation to the clinical phenomenon. In this study, we quantified the cleavage rates of cells in blastocysts at different developmental stages, followed by immunofluorescence to detect activation of γ‐H2A histone family member X (a marker of DNA damage) in zygotes to confirm that oxidative DNA damage was induced in H2O2‐treated zygotes. Monitoring H3S10P (phosphorylation of Ser10 on histone H3; a prometaphase/metaphase marker) levels at different hour postinsemination revealed that treatment of zygotes with 0.03 mM H2O2 resulted in a prometaphase/metaphase delay. Furthermore, immunofluorescence staining for mitotic arrest deficient 2‐like 1 and the protein kinase TTK, components of the spindle assembly checkpoint (SAC), suggested that this delay possibly involved SAC activation. These studies of the relationships between oxidative stress and SAC can promote the success rate of in vitro fertilization.
Diagnostic Challenge: A Report of Two Adult-Onset Still’s Disease Cases
Authors: Niranvichaiya Sakunee , Triwongwaranat Daranporn
Published: September 2017

This study reports two adult-onset Still’s disease (AOSD) cases that met both Yamaguchi’s and Fautrel’s criteria and that presented with notable clinical manifestations. One case presented with atypical dermographism-like rash with an extremely high ferritin level. The other case presented with typical salmon-pink maculopapular rash but had atypical positive rheumatoid factor. This suggests that although negative rheumatoid factor is one of the criteria used for the diagnosis of AOSD, a positive rheumatoid factor result does not exclude AOSD. Beside a classic rash, characterized by transient salmon-pink maculopapular rash, we also find atypical dermographism-like rash. These findings remind us that there exist various types of rash from AOSD.
A Design of Functional Layer with Robust Constitutive Parameters for Multilayer Metamaterials
Authors: Gong Zhijie , Wu Chao , Li Quan , Wei Zeyong , Li Hongqiang
Published: September 2017

We propose a functional layer design with robust effective parameters for multilayer metamaterial. The functional layer is consisting of two identical dielectric material layers and one layer of metallic structures sandwiched in between. The symmetric design ensures that, following standard retrieval technique, effective parameters retrieved for a single functional layer in vacuum can be used to characterize its electromagnetic contribution when stacked in a multilayer system. When applied to the fishnet structures, effective parameters of the symmetric functional layer system show great robustness against the varying of the number of layers. The symmetric functional layer design is also investigated on multilayer metamaterials consisting of several layers of different kinds of metallic structures. Transmission and reflection spectra are obtained for real structures and their effective models by finite-differential-time-domain simulation and transfer matrix method calculation, respectively. It turns out that the effective model shows great equivalency to the real structures, and the effective parameters of symmetric functional layer design are robust at both normal and oblique incident cases. Our work provides a practical approach to design and characterize multilayer metamaterials with the well-known effective parameters retrieval technique.
Threshold Dynamics of a Stochastic Chemostat Model with Two Nutrients and One Microorganism
Authors: Zhang Jian , Miao Anqi , Zhang Tongqian
Published: September 2017

A new stochastic chemostat model with two substitutable nutrients and one microorganism is proposed and investigated. Firstly, for the corresponding deterministic model, the threshold for extinction and permanence of the microorganism is obtained by analyzing the stability of the equilibria. Then, for the stochastic model, the threshold of the stochastic chemostat for extinction and permanence of the microorganism is explored. Difference of the threshold of the deterministic model and the stochastic model shows that a large stochastic disturbance can affect the persistence of the microorganism and is harmful to the cultivation of the microorganism. To illustrate this phenomenon, we give some computer simulations with different intensity of stochastic noise disturbance.
Upper Limb Deep Vein Thrombosis in Patient with Hemophilia A and Heterozygosity for Prothrombin G20210A: A Case Report and Review of the Literature
Authors: Darawshy Fares , Kalish Yosef , Hendi Issam , Abu Rmelieh Ayman , Khoury Tawfik
Published: September 2017

Deep vein thrombosis (DVT) is a rare disease in patients with hemophilia A. We report a case of 22-year-old male with severe hemophilia A who presented to the emergency room with 5-day history of right arm pain that was attributed initially to bleeding event. In the absence of external signs of bleeding or hematoma and normal hemoglobin level, we suspected an underlying DVT. Doppler ultrasonography of the right upper limb revealed thrombosis of the subclavian vein and this was confirmed by CT venography. The d-dimer level was normal and investigations for prothrombotic state revealed heterozygosity for prothrombin G20210A mutation. Treatment with factor VIII and low molecular weight heparin led to successful resolution and marked improvement of his clinical condition.
R-Spondin1/LGR5 Activates TGFβ Signaling and Suppresses Colon Cancer Metastasis
Authors: Zhou Xiaolin , Geng Liying , Wang Degeng , Yi Haowei , Talmon Geoffrey , Wang Jing
Published: September 2017

Leucine-rich repeat containing G-protein–coupled receptor 5 (LGR5), an intestinal stem cell marker, is known to exhibit tumor suppressor activity in colon cancer, the mechanism of which is not understood. Here we show that R-spondin 1 (RSPO1)/LGR5 directly activates TGFβ signaling cooperatively with TGFβ type II receptor in colon cancer cells, enhancing TGFβ-mediated growth inhibition and stress-induced apoptosis. Knockdown of LGR5 attenuated downstream TGFβ signaling and increased cell proliferation, survival, and metastasis in an orthotopic model of colon cancer in vivo. Upon RSPO1 stimulation, LGR5 formed complexes with TGFβ receptors. Studies of patient specimens indicate that LGR5 expression was reduced in advanced stages and positively correlated with markers of TGFβ activation in colon cancer. Our study uncovers a novel cross-talk between LGR5 and TGFβ signaling in colon cancer and identifies LGR5 as a new modulator of TGFβ signaling able to suppress colon cancer metastasis. Cancer Res; 77(23); 6589–602. ©2017 AACR.
Expression and Genetic Variation in Neuroendocrine Signaling Pathways in Lethal and Nonlethal Prostate Cancer among Men Diagnosed with Localized Disease
Authors: Lu Donghao , Carlsson Jessica , Penney Kathryn L. , Davidsson Sabina , Andersson Swen-Olof , Mucci Lorelei A. , Valdimarsdóttir Unnur , Andrén Ove , Fang Fang , Fall Katja
Published: September 2017

Background: Recent data suggest that neuroendocrine signaling pathways may play a role in the progression of prostate cancer, particularly for early-stage disease. We aimed to explore whether expression of selected genes in the adrenergic, serotoninergic, glucocorticoid, and dopaminergic pathways differs in prostate tumor tissue from men with lethal disease compared with men with nonlethal disease.

Methods: On the basis of the Swedish Watchful Waiting Cohort, we included 511 men diagnosed with incidental prostate cancer through transurethral resection of the prostate during 1977–1998 with follow-up up to 30 years. For those with tumor tissue (N = 262), we measured mRNA expression of 223 selected genes included in neuroendocrine pathways. Using DNA from normal prostate tissue (N = 396), we genotyped 36 SNPs from 14 receptor genes. Lethal prostate cancer was the primary outcome in analyses with pathway gene expression and genetic variants.

Results: Differential expression of genes in the serotoninergic pathway was associated with risk of lethal prostate cancer (P = 0.007); similar but weaker associations were noted for the adrenergic (P = 0.014) and glucocorticoid (P = 0.020) pathways. Variants of the HTR2A (rs2296972; P = 0.002) and NR3CI (rs33388; P = 0.035) genes (within the serotoninergic and glucocorticoid pathways) were associated with lethal cancer in overdominant models. These genetic variants were correlated with expression of several genes in corresponding pathways (P < 0.05).

Conclusions: Our findings lend support to hypothesis that the neuroendocrine pathways, particularly serotoninergic pathway, are associated with lethal outcome in the natural course of localized prostate cancer.

Impact: This study provides evidence of the role of neuroendocrine pathways in prostate cancer progression that may have clinical utility. Cancer Epidemiol Biomarkers Prev; 26(12); 1781–7. ©2017 AACR.
A Pilot Trial of Humanized Anti-GD2 Monoclonal Antibody (hu14.18K322A) with Chemotherapy and Natural Killer Cells in Children with Recurrent/Refractory Neuroblastoma
Authors: Federico Sara M. , McCarville M. Beth , Shulkin Barry L. , Sondel Paul M. , Hank Jacquelyn A. , Hutson Paul , Meagher Michael , Shafer Aaron , Ng Catherine Y. , Leung Wing , Janssen William E. , Wu Jianrong , Mao Shenghua , Brennan Rachel C. , Santana Victor M. , Pappo Alberto S. , Furman Wayne L.
Published: September 2017

Purpose: Anti-GD2 mAbs, acting via antibody-dependent cell-mediated cytotoxicity, may enhance the effects of chemotherapy. This pilot trial investigated a fixed dose of a unique anti-GD2 mAb, hu14.18K322A, combined with chemotherapy, cytokines, and haploidentical natural killer (NK) cells.

Experimental Design: Children with recurrent/refractory neuroblastoma received up to six courses of hu14.18K322A (40 mg/m2/dose, days 2–5), GM-CSF, and IL2 with chemotherapy: cyclophosphamide/topotecan (courses 1,2), irinotecan/temozolomide (courses 3,4), and ifosfamide/carboplatin/etoposide (courses 5,6). Parentally derived NK cells were administered with courses 2, 4, and 6. Serum for pharmacokinetic studies of hu14.18K322A, soluble IL2 receptor alpha (sIL2Rα) levels, and human antihuman antibodies (HAHA) were obtained.

Results: Thirteen heavily pretreated patients (9 with prior anti-GD2 therapy) completed 65 courses. One patient developed an unacceptable toxicity (grade 4 thrombocytopenia >35 days). Four patients discontinued treatment for adverse events (hu14.18K322A allergic reaction, viral infection, surgical death, second malignancy). Common toxicities included grade 3/4 myelosuppression (13/13 patients) and grade 1/2 pain (13/13 patients). Eleven patients received 29 NK-cell infusions. The response rate was 61.5% (4 complete responses, 1 very good partial response, 3 partial responses) and five had stable disease. The median time to progression was 274 days (range, 239–568 days); 10 of 13 patients (77%) survived 1 year. Hu14.18K322A pharmacokinetics was not affected by chemotherapy or HAHA. All patients had increased sIL2Rα levels, indicating immune activation.

Conclusions: Chemotherapy plus hu14.18K322A, cytokines, and NK cells is feasible and resulted in clinically meaningful responses in patients with refractory/recurrent neuroblastoma. Further studies of this approach are warranted in patients with relapsed and newly diagnosed neuroblastoma. Clin Cancer Res; 23(21); 6441–9. ©2017 AACR.
Radiomics Analysis for Evaluation of Pathological Complete Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer
Authors: Liu Zhenyu , Zhang Xiao-Yan , Shi Yan-Jie , Wang Lin , Zhu Hai-Tao , Tang Zhenchao , Wang Shuo , Li Xiao-Ting , Tian Jie , Sun Ying-Shi
Published: September 2017

Purpose: To develop and validate a radiomics model for evaluating pathologic complete response (pCR) to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer (LARC).

Experimental Design: We enrolled 222 patients (152 in the primary cohort and 70 in the validation cohort) with clinicopathologically confirmed LARC who received chemoradiotherapy before surgery. All patients underwent T2-weighted and diffusion-weighted imaging before and after chemoradiotherapy; 2,252 radiomic features were extracted from each patient before and after treatment imaging. The two-sample t test and the least absolute shrinkage and selection operator regression were used for feature selection, whereupon a radiomics signature was built with support vector machines. Multivariable logistic regression analysis was then used to develop a radiomics model incorporating the radiomics signature and independent clinicopathologic risk factors. The performance of the radiomics model was assessed by its calibration, discrimination, and clinical usefulness with independent validation.

Results: The radiomics signature comprised 30 selected features and showed good discrimination performance in both the primary and validation cohorts. The individualized radiomics model, which incorporated the radiomics signature and tumor length, also showed good discrimination, with an area under the receiver operating characteristic curve of 0.9756 (95% confidence interval, 0.9185–0.9711) in the validation cohort, and good calibration. Decision curve analysis confirmed the clinical utility of the radiomics model.

Conclusions: Using pre- and posttreatment MRI data, we developed a radiomics model with excellent performance for individualized, noninvasive prediction of pCR. This model may be used to identify LARC patients who can omit surgery after chemoradiotherapy. Clin Cancer Res; 23(23); 7253–62. ©2017 AACR.
In-depth Genetic Analysis of Sclerosing Epithelioid Fibrosarcoma Reveals Recurrent Genomic Alterations and Potential Treatment Targets
Authors: Arbajian Elsa , Puls Florian , Antonescu Cristina R. , Amary Fernanda , Sciot Raf , Debiec-Rychter Maria , Sumathi Vaiyapuri P. , Järås Marcus , Magnusson Linda , Nilsson Jenny , Hofvander Jakob , Mertens Fredrik
Published: September 2017

Purpose: Sclerosing epithelioid fibrosarcoma (SEF) is a highly aggressive soft tissue sarcoma closely related to low-grade fibromyxoid sarcoma (LGFMS). Some tumors display morphologic characteristics of both SEF and LGFMS, hence they are known as hybrid SEF/LGFMS. Despite the overlap of gene fusion variants between these two tumor types, SEF is much more aggressive. The current study aimed to further characterize SEF and hybrid SEF/LGFMS genetically to better understand the role of the characteristic fusion genes and possible additional genetic alterations in tumorigenesis.

Experimental Design: We performed whole-exome sequencing, SNP array analysis, RNA sequencing (RNA-seq), global gene expression analyses, and/or IHC on a series of 13 SEFs and 6 hybrid SEF/LGFMS. We also expressed the FUS-CREB3L2 and EWSR1-CREB3L1 fusion genes conditionally in a fibroblast cell line; these cells were subsequently analyzed by RNA-seq, and expression of the CD24 protein was assessed by FACS analysis.

Results: The SNP array analysis detected a large number of structural aberrations in SEF and SEF/LGFMS, many of which were recurrent, notably DMD microdeletions. RNA-seq identified FUS-CREM and PAX5-CREB3L1 as alternative fusion genes in one SEF each. CD24 was strongly upregulated, presumably a direct target of the fusion proteins. This was further confirmed by the gene expression analysis and FACS analysis on Tet-On 3G cells expressing EWSR1-CREB3L1.

Conclusions: Although gene fusions are the primary tumorigenic events in both SEF and LGFMS, additional genomic changes explain the differences in aggressiveness and clinical outcome between the two types. CD24 and DMD constitute potential therapeutic targets. Clin Cancer Res; 23(23); 7426–34. ©2017 AACR.
ABC294640, A Novel Sphingosine Kinase 2 Inhibitor, Induces Oncogenic Virus–Infected Cell Autophagic Death and Represses Tumor Growth
Authors: Dai Lu , Bai Aiping , Smith Charles D. , Rodriguez Paulo C. , Yu Fangyou , Qin Zhiqiang
Published: September 2017

Kaposi sarcoma–associated herpes virus (KSHV) is the etiologic agent of several malignancies, including Kaposi sarcoma and primary effusion lymphoma (PEL), which preferentially arise in HIV+ patients and lack effective treatment. Sphingosine kinase 2 (SphK2) is a key factor within sphingolipid metabolism, responsible for the conversion of proapoptotic ceramides to antiapoptotic sphingosine-1-phosphate (S1P). We have previously demonstrated that targeting SphK2 using a novel selective inhibitor, ABC294640, leads to the accumulation of intracellular ceramides and induces apoptosis in KSHV-infected primary endothelial cells and PEL tumor cells but not in uninfected cells. In this study, we found that ABC294640 induces autophagic death instead of apoptosis in a KSHV long-term–infected immortalized endothelial cell-line, TIVE-LTC, but not in uninfected TIVE cells, through the upregulation of LC3B protein. Transcriptomic analysis indicates that many genes related to cellular stress responses, cell cycle/proliferation, and cellular metabolic process are altered in TIVE-LTC exposed to ABC294640. One of the candidates, Egr-1, was found to directly regulate LC3B expression and was required for the ABC294640-induced autophagic death. By using a Kaposi sarcoma–like nude mice model with TIVE-LTC, we found that ABC294640 treatment significantly suppressed KSHV-induced tumor growth in vivo, which indicates that targeting sphingolipid metabolism, especially SphK2, may represent a promising therapeutic strategy against KSHV-related malignancies. Mol Cancer Ther; 16(12); 2724–34. ©2017 AACR.